Volume 6 No. 3 – September 2009 The PACT Group continues to … · A poster presentation highlighting the last six years of the PACT project will be on display. The poster will

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NNNEEEWWWSSSLLLEEETTTTTTEEERRR Volume 6 No. 3 – September 2009

The PACT Group continues to provide educational opportunities and materials, regulatory information, and production assistance to the cell therapy community

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Education Updates ________________________

The PACT Cell Therapy Book to Be Released in September

A comprehensive, multi-authored book has been drafted under the leadership of Dr. Adrian Gee from the Baylor College of Medicine. This publication features PACT representatives and experts external to the PACT project as co-authors. Cell Therapy: cGMP Facilities and Manufacturing is the source for a comprehensive discussion of facility design and operation with practical approaches to a variety of day-to-day activities, such as staff training and competency, cleaning procedures, and environmental monitoring. This in-depth book also includes detailed reviews of quality processes, the framework of regulations, and professional standards. It meets a previously unmet need for a thorough facility-focused resource, Cell Therapy: cGMP Facilities and Manufacturing will be an important addition to the cell therapy professional’s library.

Please visit the PACT website www.pactgroup.net, or the dedicated URL on the publisher’s website http://www.springer.com/life+sci/cell+biology/book/978-0-387-89583-3 for information on how to order an advanced copy of the book. It will be released on September 25, 2009 in North America and in October 2009 in Europe.

Web Seminar Quarterly Update

A Web Seminar on “Interpretations of the Final Rule: cGMP and Investigational New Drugs Intended for Use in Phase I Clinical Trials” is scheduled for October 15, 2009 at 1:00 PM ET This Web Seminar will be the 15th since PACT’s inception and will include presentations from Dr. Scott Burger from Advanced Cell & Gene Therapy, LLC, and a speaker from FDA/CBER. Please visit our website for details in September.

July 16, 2009 Web Seminar

A web seminar on “Deviation Management of 351 and 361 products” was held on July 16, 2009 with Ms. Ellen Areman, a Senior Consultant from Biologics Consulting Group, Inc., as the speaker. In preparation for this seminar, we compiled a list of sample deviation scenarios for Ms. Areman to consider for discussion. Over 250 individuals attended this web seminar. The live recording (wmv file), slide presentations, transcription of the Q & A session including FDA comments, and polling slides from the seminar have been posted to the PACT website under Education-PACT Web Seminars.

http://www.pactgroup.net/

http://www.springer.com/life+sci/cell+biology/book/978-0-387-89583-3

NEWSLETTER Volume 6 No. 3 – 2009

Additional Educational Resources Standard Operating Procedures (SOPs) The PACT Group is pleased to announce that we have expanded our library of SOPs available for request. PACT is now offering SOPs on Validation, Regulatory Compliance, and Deviation Management. Additionally, we have expanded our SOP catalog in the Quality Management and Environmental Monitoring categories. These SOPs have been a successful resource to the cell therapy community with over 100 individual requests received for these documents, to date. These requests have come from within the United States and from a variety of countries throughout the world including India, the United Kingdom, Argentina, Australia, Iran, and Switzerland. Visit our website for a comprehensive list of all SOPs available within the listed categories and for information on how to request these SOPs.

Cleaning Procedures Deviation Management Environmental Monitoring Organization, Oversight, and Regulatory Compliance Personnel Training Quality Management Standard Operating Procedure (SOP): Development and Management Validation

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PACT Publications ________________________ Dr. Adrian Gee, from the Baylor College of Medicine, authored an article on behalf of the PACT Group that

was published in the summer 2009 issue of the ISCT Telegraft. “Drowning between the Bench and the Bedside – or Reflections from an Aging Translational Scientist” provides an insightful perspective on the regulatory and documentation issues individuals within the cell therapy field face on a regular basis.

An abstract titled “Educational Program for Cell Therapy: A Review of Efforts Sponsored by the Production Assistance for

Cellular Therapies (PACT) Group” has been accepted as a poster for presentation at the 2009 AABB Annual Meeting in October that will be in New Orleans, LA. This poster will outline the successful educational initiatives the PACT Group has completed during the past five years and outline some potential future educational programs for the cell therapy community.

An abstract titled “Production Assistance for Cellular Therapies (PACT): Six-year Experience from the United States

National Heart Lung and Blood Institute (NHLBI) Contract Research Program in Cell and Tissue Therapies” has been accepted for a poster presentation at the 2009 World Stem Cell Summit Meeting in September that will be held in Baltimore, MD. The manuscript provides details about the PACT Group’s six-year experience as a federally funded contract manufacturing and educational resource to the cell therapy community. It will also feature selected translational results from approved PACT applications and include information about the future of the PACT program.

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PACT Internal Projects ______________________ The PACT facilities have recently completed a study using the Isolex® 300i Magnetic Cell Selection System®

device to perform testing on small volume bone marrow specimens. Publication of these data was recently completed under the direction of Dr. David H. McKenna, Jr. from the University of Minnesota. The paper titled “CD34+ Cell Selection Using Small Volume Marrow Aspirate: A Platform for Novel Cell Therapies and Regenerative Medicine” was submitted for publication consideration to the journal Cytotherapy.

Dr. Albert Donnenberg from the University of Pittsburgh submitted a manuscript to Cytotherapy titled

“Preparation of Autologous Bone Marrow Derived CD34+ Enriched Cellular Products for Cardiac therapy.” The paper is related to the BM Isolex® internal project but tested testing larger volume bone marrow specimens with a different specimen preparative regimen.

PACT conducted a shipping validation study to establish acceptable conditions for a variety of cell types, to

facilitate cell product preservation and integrity during transit and to ensure that the cellular production remains stable and sterile during shipment. Cell product generation, sample testing and data collection have been completed. A manuscript is currently being drafted with an anticipated publication submission this year.

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PACT- Attended Meetings ________________________________

PACT representatives attended the following meetings this past quarter: MSC 2009 Meeting on Regenerative Medicine and Adult Stem Cell Therapy Meeting - August 17-19, 2009 in

Cleveland, OH.

ISCT Somatic: Innovation in CB and MSC Therapies Meeting - September 14-15, 2009 in Bethesda, MD. PACT’s NHLBI Project Officer, Elizabeth Wagner, presented an update on PACT Group activities at this meeting.

PACT representatives will be attending and presenting at the following September and October 2009 meetings:

2009 World Stem Cell Summit - September 21-23, 2009 in Baltimore, MD. A poster presentation highlighting the last six years of the PACT project will be on display. The poster will include selected results from representative translational studies.

2009 NHLBI SCCT Symposium – September 30, 2009 at the NIH campus in Bethesda, MD

2009 AABB Annual Meeting and TXPO - October 24-27, 2009 in New Orleans, LA. A poster will be presented outlining the educational initiatives of the PACT program.


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PACT Program Update

The current PACT program will end November 30, 2009. The program is being competitively renewed and it is anticipated that the new PACT program will begin December 1, 2009. PACT will continue to accept and evaluate new applications for production assistance. The timeline and scope of each application will be considered on an individual basis. There are two potential outcomes for approved PACT projects when the work proposed cannot be completed before November 30, 2009.

In the first scenario, PACT representatives will work with applicants to revise the timeline and milestones if possible, so that some aspects of the work can be completed under the current contract period. The remainder of the proposed work will become a new application to be submitted to the new PACT program.

For the second scenario, if the milestones and timeline of the proposed work cannot be altered, the application will be held by the current PACT program and will be considered for production assistance at the beginning of the renewed PACT program.

Go to www.pactgroup.net and select “Applications” for more information on the current PACT application process. The preliminary application is provided on-line along with informational documents to assist you in completing the application. ___________________

Contact PACT _________________ _

PACT Administrative Center Contact Person(s): Jamie Winestone or Debbie Wood Address: The EMMES Corporation Telephone: 301.251.1161

401 North Washington Street Fax: 240.306.2527 Suite 700 Email: [email protected] Rockville, MD 20850

Website: www.pactgroup.net

This project has been funded in whole or in part with Federal funds from the NHLBI NIH.

-PACT Facilities- Baylor College of Medicine Contract Number: N01-HB-37163

University of Minnesota Contract Number: N01-HB-37164 University of Pittsburgh Contract Number: N01-HB-37165

-PACT Administrative Center- EMMES Corporation Contract Number: N01-HB-37166


mailto:[email protected]


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NNNEEEWWWSSSLLLEEETTTTTTEEERRR Volume 6 No. 2 – June 2009

The PACT Group continues to provide educational opportunities and materials, regulatory information, and production assistance to the cell therapy community

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2009 NHLBI PACT Workshop

From April 23-24, 2009 NIH/NHLBI and PACT hosted a workshop titled “Converging Concepts in Cell Therapy” at the Natcher Conference Center on the NIH campus in Bethesda, MD. The workshop was organized by NIH/NHLBI and PACT in collaboration with AABB, ISCT, ISBTc and FDA/CBER. Seven scientific sessions focused on unique biotechnology-based approaches to product characterization, cell processing, cell trafficking and imaging techniques and treatments involving a select group of cell-based products.

Selected slide presentations from the workshop are available on the PACT website under Education, and a manuscript summarizing the meeting is being drafted for publication.


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We would like to thank the following speakers for taking the time to be here and making this event possible.

T-Regulatory Cells David H. McKenna, Jr., M.D. University of Minnesota Bruce L. Levine, Ph.D. University of Pennsylvania Claudio G. Brunstein, M.D. University of Minnesota

Mesenchymal Stem Cells Adrian P. Gee, MI Biol., Ph.D. Baylor College of Medicine Ian K. McNiece, Ph.D. University of Miami Katarina Le Blanc, MD, Ph.D. Karolinska Institutet, Sweden

Antigen-Specific T-Cells Shelly Heimfeld, Ph.D. Fred Hutchinson Cancer Research Center Philip D. Greenberg, M.D. University of Washington Cliona M. Rooney, Ph.D. Baylor College of Medicine

Engineered T-Cells Bernard A. Fox, Ph.D. Earle A. Chiles Research Institute Carl H. June, M.D. University of Pennsylvania Steven A. Rosenberg, M.D., Ph.D. National Cancer Institute

Natural Killer Cells David Stroncek, M.D. National Institutes of Health Jeffrey S. Miller, M.D. University of Minnesota Richard W. Childs, M.D. National Heart, Lung, and Blood Institute

Dendritic Cells Theresa L. Whiteside, Ph.D. University of Pittsburgh Cancer Institute Pawel Kkalinski., M.D., Ph.D. University of Pittsburgh Sharon A. Riddler, M.D., M.P.H. University of Pittsburgh

Cell Trafficking and Imaging Techniques Marianna Sabatino, M.D. National Institutes of Health Erin F. Simonds, B.S., Ph.D. Candidate Stanford University School of Medicine Zhenghong Lee, Ph.D. University Hospitals Case Medical Center Eric T. Ahrens, Ph.D. Carnegie Mellon University

Web seminar quarterly update

A Web Seminar on “Deviation Management of 351 and 361 products” is scheduled for July 16, 2009 at 1:00 ET.

This web seminar will be the 14th since PACT’s inception. Ellen Areman, a Senior Consultant from Biologics Consulting, Inc., will be the speaker at this seminar. In preparation for this seminar we are compiling a list of sample deviation scenarios for Ms. Areman to consider for discussion. Please submit any scenarios you would like discussed during the web seminar via email to [email protected]. Registration will open June 16th on the PACT website.

Additional Educational Resources Standard Operating Procedures (SOPs) The PACT group is pleased to announce we have expanded our library of SOPs available for request. PACT is now offering SOPs on Validation, Regulatory Compliance, and Deviation Management. Additionally we have expanded our SOP catalog in the Quality Management and Environmental Monitoring categories. Visit our website for a comprehensive list of all SOPs available within the listed categories and for information on how to request these SOPs.

Cleaning Procedures Deviation Management Environmental Monitoring Organization, Oversight and Regulatory Compliance Personnel Training Quality Management Standard Operating Procedure (SOP): Development and Management Validation



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________________________

PACT Publications ________________________ Reed W, et al. 2009. Production Assistance for Cellular Therapies (PACT): Five-year Experience from the United

States National Heart Lung and Blood Institute (NHLBI) Contract Research Program in Cell and Tissue Therapies. Transfusion 49 (4): 786-796. The manuscript provides details about the PACT Group’s five-year experience as a federally funded contract manufacturing and educational resource to the cell therapy community.

A comprehensive multi-authored book titled Cell Therapy: GMP Facilities and Manufacturing under the leadership

of Dr. Adrian Gee from Baylor College of Medicine, features PACT representatives and experts external to PACT as co-authors. The book is currently in its final reviews by the publisher and printing company, and has an anticipated publication date of August 2009.

_________________ _____

PACT Internal Projects _______________________ _ The PACT facilities have recently completed a study using the Isolex® device to perform testing on small

volumes of bone marrow. Publication of this data is currently in process under the direction of Dr. David McKenna from the University of Minnesota. The paper is nearing completion, and should be submitted for journal publication by PACT in the coming months.

A second PACT internal project on validation of shipped cellular products is also nearing completion. The

three PACT facilities have compiled on a variety of cell types before and after shipping to study the effects of this variable on cell therapy products. Dr. Theresa Whiteside from the University of Pittsburgh Cancer Institute has begun drafting the manuscript for this project, and the centers are currently collecting data on the final phase of the study which involves product generation and functional assay testing. It is anticipated that the project will be completed and a manuscript for publication will be submitted by the PACT group later this year.

________________________________


PACT representatives attended the following meetings this past quarter:

NHLBI PACT Sponsored Workshop “Converging Concepts in Cell Therapy” The PACT group hosted the Meeting April 23-24, 2009 in Bethesda, MD. PACT representatives served as speakers and moderators at the workshop.

15th Annual International Society for Cellular Therapy (ISCT) PACT representatives attended and presented at the 2009 ISCT annual meeting May 2-6, 2009 in San Diego, CA.

94th Annual Meeting of the American Association of Immunologists (AAI) PACT representatives attended and presented at the meeting May 8-12, 2009 in Seattle, WA.

PACT representatives will be attending and presenting at the following August and September 2009 meetings:

MSC 2009 Meeting on Regenerative Medicine and Adult Stem Cell Therapy Meeting - August 17-19, 2009 in Cleveland, OH

9th Annual Somatic Cell Therapy (SCT) Meeting - September 14-15, 2009 in Bethesda, MD


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___________ ________

PACT Program Update ______________ _____

The current PACT program is anticipated to end November 30, 2009. The program is being competitively renewed, and it is anticipated that the new PACT program will begin December 1, 2009. PACT will continue to accept and evaluate new applications. The timeline and scope of each application will be considered on an individual basis. There are two potential outcomes for approved PACT projects when the work proposed cannot be completed before November 30, 2009.

In the first, PACT representatives will work with applicants to revise the timeline and milestones if possible, so that some work can be completed. The remainder of the proposed work will become anew application to be submitted to the new PACT program.

For the second outcome, if the milestones and timeline of the proposed work cannot be altered, the application will be held by the current PACT program and will be considered at the beginning of the renewed PACT program.

Go to www.pactgroup.net and select “Applications” for more information on the current PACT application process. The preliminary application is provided on-line along with informational documents to assist you in completing the application. _________________________________________

Register to Receive PACT Updates _________________________________________

Register at www.pactgroup.net under the “Resources” tab to receive early notification of PACT-sponsored web seminars and workshops! ___________________

Contact PACT _________________ _












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Volume 6 No. 1 – March 2009

The PACT Group continues to provide educational opportunities and materials, regulatory information, and production assistance to the cell therapy community.

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April 2009 NHLBI PACT Workshop

From April 23-24, 2009 NHLBI and PACT will be conducting a workshop titled “Converging Concepts in Cell Therapy” at the Natcher Conference Center on the NIH campus in Bethesda, MD. There is no charge for attendance, and registration is currently open and can be accessed from the PACT website at www.pactgroup.net. The program will feature discussions of cell processing issues and treatment indications involving a variety of cell types, along with cell trafficking and imaging techniques. The workshop is being planned by a committee with representatives from NIH, NHLBI, PACT, AABB, ISCT, ISBTc and FDA/CBER. Please see the flyer below, and visit our website for more details.


NEWSLETTER Volume 6 No. 1 – March 2009

Web seminar quarterly update

A Web Seminar on “Deviation Management of 351 and 361 products” is scheduled for July 16, 2009. This web seminar will be the 14th since PACT’s inception. Please visit our website for details in June.

January 26, 2009 Web Seminar A web seminar on “Qualification: Vendor, Equipment, and Supplies” was held on January 26, 2009 with Ms. Fran Rabe from the University of Minnesota, Dr. Adrian Gee from the Baylor College of Medicine, and Mr. Christopher Chun from the American Red Cross in Salt Lake City presenting on these three topics respectively. Over 200 individuals attended this web seminar. The live recording (wmv file), slide presentations, and transcription of the Q & A session have been posted to the PACT website under Education-PACT Web Seminars.

Additional Educational Resources Standard Operating Procedures (SOPs) The following SOPs have been made available to requesting individuals. Visit our website for information regarding this educational resource and how to request these SOPs.

Generation and Management of SOPs Facility Cleaning Personnel Training Retrospective Documentation of Training Environmental Monitoring Facility Quality Management Transportation of Cryopreserved Cells Procedure For Use And Response to Equipment Monitoring Systems

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________________________

PACT Publications ________________________

A manuscript titled “Production Assistance For Cellular Therapies (PACT): Five-Year Experience From The United States National Heart Lung And Blood Institute (NHLBI) Contract Research Program in Cell and Tissue Therapies” has been accepted for publication by the journal Transfusion and is currently available on-line through electronic publication. The manuscript provides details about the PACT Group’s five-year experience as a federally funded contract manufacturing and educational resource to the cell therapy community, and will be published in the journal in the coming months.

The International Society for Cellular Therapy (ISCT) publishes a quarterly Telegraft as a forum for current ideas,

events and projects occurring in the Cell Therapy community. Since its inception five years ago, the PACT group has been actively involved in the Telegraft with submissions to seven issues. Listed below are the citations of all of PACT supported articles in the Telegraft, including the most recent by Dr. Allison Hubel. The article titled “Improving Your Preservation Practice” by Dr. Hubel will serve as a follow up to her PACT web seminar on cryopreservation, which occurred in February 2008.

o Allison Hubel, PhD. Improving Your Preservation Practice. Volume 16, No. 1: Spring 2009 (will be

published in this future edition of the Telegraft) o Nathan Kassalow. In the U.S., A National Heart, Lung and Blood Institute (NHLBI) Program Drives

Interest and Assistance in Developing Novel Cellular Therapeutics. Volume 15, No. 4: Winter 2008 o Deborah L. Griffin MS, Ludovic Zimmerlin MS, J. Peter Rubin MD, and Albert D. Donnenberg PhD.

Translational Scale-Up: Bridging the Gap between Research and Clinical Processing of Pre-Adipocytes. Volume 15, No. 3: Fall 2008

o Cliona Rooney PhD and Adrian Gee M.I.Biol., Ph.D. Treatment and Prevention of Viral Infections after

Hematopoietic Stem Cell Transplantation. Volume 15, No. 2: Spring 2008

o David H. McKenna, Jr., M.D. and Jeffrey S. Miller, M.D. Activation of Natural Killer Cells: A Shipping Study. Volume 15, No. 1: Winter 2007/2008

o William Reed, MD. In the US, National Institutes of Health Drive Interest and Assistance in Developing

Novel Cellular Therapeutics. Volume 14, No. 3: Summer 2007

o Traci Heath Mondoro, Ph.D. NHLBI Somatic Cell Processing Facilities and Administrative Center. Volume 10, No. 4: Winter 2003/2004

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PACT representatives attended the following meetings this past quarter:

5th International Conference – Cell Therapy Cardiovascular Research Foundation PACT representatives attended the 2009 Conference January 11-14, 2009 in New York, NY.

2009 Bone Marrow Transplant Tandem Meetings PACT representatives attended the 2009 BMT Tandem Meetings February 11-15, 2009 in Tampa, FL.

12th US-Japan Cellular and Gene Therapy Conference on Immune Regulation PACT representatives attended the 2009 US-Japan Conference February 26, 2009 in Bethesda, MD.


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PACT - Attended Meeting Con’t PACT representatives will be attending and presenting at the following April and May 2009 meetings:

• 15th Annual International Society for Cellular Therapy (ISCT) Meeting May 2-6, 2009 San Diego, CA • 94th Annual Meeting of the American Association of Immunologists (AAI) May 8-12, 2009 Seattle, WA

___________________

Apply On-Line ___________________

Go to www.pactgroup.net and select “Applications” for more information. The preliminary application is provided on-line along with informational documents to assist you in completing the application. Once a preliminary application has been approved following Steering Committee review, a full application is invited. The full application is also submitted on-line and is accessed using the same link to the Application Process page for the preliminary application. _________________________________________


Register at www.pactgroup.net to receive early notification of PACT-sponsored web seminars and workshops! ___________________

Contact PACT ___________________





PACT accepts applications on an ongoing basis for contract manufacturing of cell therapy products

Apply Now!

-PACT Facilities-

Baylor College of Medicine Contract Number: N01-HB-37163 University of Minnesota Contract Number: N01-HB-37164 University of Pittsburgh Contract Number: N01-HB-37165






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NNNEEEWWWSSSLLLEEETTTTTTEEERRR Volume 5 No. 4 – December 2008 Volume 5 No. 4 – December 2008

PACT offers scale-up capability and expertise in the translational development needed to produce cell therapy products for use in clinical trials under

cGMP and cGTP regulations

A Year in Review A Year in Review 2008 has been another successful year for the PACT project. To date, we have received over 65 application requests for the manufacturing of cell therapy products. Over 180 cell products have been administered to patients from fourteen separate, approved applications. On the educational front, we have conducted four web seminars and a workshop on GMP facilities that was held at the University of Pittsburgh in May. A comprehensive online textbook on Cellular Therapy: cGMP Facilities and Manufacturing is completed and is in the submission process. PACT has participated in various technical projects including a study on shipping validation of human cellular products, and a study on isolation of HPCs from small volume bone marrow. Publications are anticipated on these recently completed projects in the next year.

2008 has been another successful year for the PACT project. To date, we have received over 65 application requests for the manufacturing of cell therapy products. Over 180 cell products have been administered to patients from fourteen separate, approved applications. On the educational front, we have conducted four web seminars and a workshop on GMP facilities that was held at the University of Pittsburgh in May. A comprehensive online textbook on Cellular Therapy: cGMP Facilities and Manufacturing is completed and is in the submission process. PACT has participated in various technical projects including a study on shipping validation of human cellular products, and a study on isolation of HPCs from small volume bone marrow. Publications are anticipated on these recently completed projects in the next year. __________________________________________________ Educational Updates _________________________ Four Web Seminars were held in 2008. The PACT Group has conducted a total of twelve web seminars since its inception. Materials including slides, recordings and Q & A transcripts for these are available on the PACT website under Educational Material – PACT Web Seminars.

Web Seminars

February 21, 2008 - “Cryopreservation of Cell Therapy Products” with Dr. Allison Hubel (University of Minnesota) as the speaker. This topic was well received with over 250 attendees participating in the February web seminar. The web and audio recordings and the Q & A session transcription are available on the PACT website.

June 25, 2008 - “NHLBI Training and Funding Opportunities” with Dr. Traci Mondoro (National Heart, Lung, and Blood Institute) and “Overview of Cell Therapy in Lung Biology and Disease” with Dr. Carol Blaisdell (National Heart, Lung, and Blood Institute) as speakers. The slide presentation materials and the transcribed Q & A session are available on the PACT website.

NEWSLETTER Volume 5 No. 4 – December 2008

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Web Seminars Con’t July 31, 2008 - “Validation Processes” with Dr. Carolyn A. Keever-Taylor (Medical College of Wisconsin) as the

speaker. Over 175 attendees participated in the July web seminar. The web and audio recording and Q & A transcription are available on the PACT website.

November 6, 2008 - “Effective and Result-based Training” with Dr. Larry Midgett (National Seminars Group) and Ms. Diane Kadidlo (University of Minnesota) as speakers. Over 125 attendees participated in the November web seminar. The web and audio recording and Q & A transcription are available on the PACT website.

Workshop May 5-6, 2008 Workshop. A GMP training workshop titled “Innovative Cellular Therapies and Methods at GMP Cell Therapy Facilities” was held at the University of Pittsburgh in Pittsburgh, PA. Presentation topics included facility design, consideration for optimization of culture conditions of various cell types, cryopreservation and laboratory procedures regarding product release criteria. CME/CE credits, through our collaboration with AABB, were provided to requesting attendees and speaker presentations have been posted to the PACT website.

Additional Educational Resources

Standard Operating Procedures

The following SOPS listed below, have been made available by PACT to requesting individuals. Visit our website for information regarding this educational resource.

Generation & Management of SOPs Cleaning Procedures for the GMP Cell Processing Facility Suite Personnel Training Retrospective Documentation of Training Environmental Monitoring Transportation of Cryopreserved Cells Procedure for Use and Response to Equipment Monitoring Systems Facilities Quality Management

Cytokine and Antibody List

PACT has provided an abridged list of commercially available cytokines and antibodies on the PACT website under the Resources link.


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(Disclaimer: The lists of antibody and cytokine products and their corresponding vendors are for collaborative research and informational use only. This list was generated after polling cell-processing facilities regarding cytokine/antibody use. This is not and should not be considered a comprehensive listing of all commercially available cellular therapy products. The NHLBI and entities of PACT neither support nor endorse the vendors and products listed.)

_____________________________________ PACT - attended Meetings in 2008 _____________________________________

FDA Cell Therapy Liaison Meeting, February 5, 2008/Bethesda, MD. PACT representatives attended the FDA Cell Therapy Liaison meeting held at AABB headquarters.

2008 Bone Marrow Transplant Tandem Meetings, February 13-17, 2008/San Diego, CA. PACT facility representatives attended.

AABB Spring Conference on Cellular Therapy, March 28-29, 2008/Orlando, FL. PACT representatives attended the conference.

NIH Symposium “Challenges & Promise of Cell-Based Therapies”, May 6, 2008/Bethesda, MD. PACT representatives attended the NIH symposium.

14th Annual Meeting of the International Society for Cellular Therapy (ISCT), May 17-20, 2008/Miami, FL (Abstract poster presentations)

11th Annual Meeting of the American Society of Gene Therapy (ASGT,) May 28-June 1, 2008/Boston, MA. PACT facility representatives attended the conference.

6th Annual Meeting of the International Society for Stem Cell Research (ISSCR), June 11-14, 2008/Philadelphia, PA. (Abstract poster presentations)

8th Annual Somatic Cell Therapy (SCT) Symposium 2008 (Sponsored in part by PACT), September 22-24, 2008/Bethesda, MD. PACT members attended the Somatic Cell Therapy (SCT) Annual Meeting. Posters were displayed at the SCT symposium that further described PACT’s involvement in cell therapy research. In addition, PACT members served as speakers and moderators for portions of the Symposium.

FDA/CBER Public Workshop: Rapid methods for Detecting Mycoplasma Contamination in the Manufacture of Vaccines, Including Pandemic Influenza Vaccines, and Other Biological Product, September 22-23, 2008/Gaithersburg, MD. PACT representative attended the workshop.

AABB Annual Meeting & TXPO 2008, October 4-7, 2008/Montreal, Canada. An abstract of the PACT Experience manuscript accepted for publication in Transfusion was presented at the poster session of the meeting. Additional PACT members attended and presented at the meeting.

AABB Audioconferences, PACT AC and facility representatives attended AABB audioconferences related to cell therapy at the AABB office in Bethesda, MD.

National Academies Human Embryonic Stem Cell Research Advisory Committee Symposium on Translation of Stem Cells into Clinical Stem Cell Therapeutics, November 20, 2008/Washington, DC. PACT representatives attended the Symposium at the National Academy of Sciences, as well as serving as speakers and moderators for one of the sessions.

American Society of Hematology - 50th Annual Meeting, December 6-9, 2008/San Francisco, CA. PACT literature was distributed at the NIH booth.


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________________________________ PACT Technical Projects ________________________________

The PACT Group conducted a two-phase bone marrow cell processing protocol for use on the Isolex®

system. Validation runs were performed at a single facility for use across all PACT centers during the second phase of the study. Data are currently being analyzed for an anticipated publication.

A shipping validation study was conducted at the three PACT facilities. The objective of this project was to establish acceptable conditions for a variety of cell types to facilitate cell product preservation and integrity during transit, and to ensure that the cellular product remains stable and sterile during shipment. Six different types of cell product have been shipped, received, processed and re-characterized at the receiving facilities. Data are currently being analyzed and a publication is being considered.

_________________________________________ 2008 PACT Publications _________________________________________

Manuscripts

Lee J-J, Foon KA, et al. 2008. Type 1-polarized Dendritic Cells Loaded with Autologous Tumor are a Potent Immunogenic Against Chronic Lymphocytic Leukemia. Journal of Leukocyte Biology. 84: 319–325.

Gee AP, et al. 2008. A Multicenter Comparison Study Between the Endosafe® PTS™ Rapid-release Testing System and Traditional Test Methods for Detecting Endotoxin in Cell-therapy Products. Cytotherapy. 10 (4): 427-435.

Reed W, et al. 2008. Production Assistance for Cellular Therapies (PACT): Four-year Experience from the United States National Heart Lung and Blood Institute (NHLBI) Contract Research Program in Cell and Tissue Therapies. Transfusion (in press).

Whiteside TL, Piazza P, Reiter A, Stanson J, Connolly NC, Rinaldo CR, Jr., Riddler SA. 2008. Preparation of DC-based Vaccine Containing Inactivated Autologous Virus for Therapy of Patients with Chronic HIV-1 Infection. Clinical Vaccine Immunology (in press).

Abstracts

Griffin DL, Pfiefer ME, Zimmerlin L, Rubin JP, and Donnenberg AD. 2008. Translational Scale-up: Bridging the Gap Between Research and Clinical Processing of Pre-adipocytes [abstract]. 6th ISSCR Annual Meeting, Philadelphia, PA, June 11-14, 2008.

Reed W, et al. 2008. Production Assistance for Cellular Therapies (PACT): Four-year Experience from the United States National Heart Lung and Blood Institute (NHLBI) Contract Research Program in Cell and Tissue Therapies [poster abstract]. 2008 AABB Annual Meeting, Montreal, Canada, October 2008.

ISCT Telegraft columns

McKenna DH, Miller JS. 2008. PACT Perspectives: Activation of Natural Killer Cells: A Shipping Study. Winter 2007/2008 ISCT Telegraft Volume 15, Number 1, page 9.

Rooney C, Gee AP. 2008. Report from PACT - Treatment and Prevention of Viral Infections after Hematopoietic Stem Cell Transplantation. Summer 2008 ISCT Telegraft Volume 15, Number 2, page 1.

Griffin D, et al. 2008. Report from PACT - Translational Scale-up of Adipose Stem Cells. Fall 2008 ISCT Telegraft Volume 15, Number 3, page 8.


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Kassalow, N. 2008 “In the U.S., A National Heart, Lung and Blood Institute (NHLBI) Program Drives Interest and Assistance in Developing Novel Cellular Therapeutics” (Submitted to Telegraft for Winter 2008/2009 edition.)

Cell Therapy Book PACT and several individuals, external to PACT and from the EU have authored a book covering practical aspects of cellular therapy connected with the implementation of GMP/GTP regulations. The book has been submitted to the publisher and is in the editing phase. The book is expected to be available both electronically and in hard copy with publication anticipated in the spring of 2009. _______________________________________ Clinical Trial Funding Now Available! _______________________________________ PACT is currently accepting applications from investigators who are seeking financial support for their clinical trial. Matching funds are available to investigators who have an approved PACT application to manufacture a cell therapy product for their clinical trial and at least 50% funding from another source for the proposed clinical trial. Investigators approved for PACT manufacturing support are encouraged to discuss this opportunity with their assigned technical liaison. The ultimate goal of this funding initiative is to provide the scientific community with both cell therapy products and clinical trial funding to support cell therapy products reaching the clinical trial stage of development. Several interested investigators have inquired about the application process and currently two investigators have submitted Clinical Trial Funding applications and are undergoing programmatic review for approval. Clinical trial funding requests will be reviewed by the designated PACT facility representative and the NHLBI to determine if the proposal is compatible with the program objectives and requirements. Funding to conduct the clinical trial is contingent upon demonstrating adequate efforts in acquiring funds from other resources. If approved, PACT will provide matching funds up to $150,000 for the clinical trial. Interested applicants may contact [email protected] with questions.

Upcoming in 2009

April 2009 NHLBI PACT Workshop On April 23-24, 2009 NHLBI and PACT will be conducting a workshop titled “Converging Concepts in

Cell Therapy” at the Natcher Auditorium on the NIH campus in Bethesda, MD. There is no cost to the attendees, and registration will begin in early 2009. The workshop is being planned by a committee with representatives from NIH, NHLBI, PACT, AABB, ISCT and ISBTc. The workshop will feature presentations on the Cell Processing and Treatment indications of T-Regulatory Cells, Mesenchymal Stem Cells, Antigen Specific T-Cells, Engineered T Cells, Natural Killer Cells, Dendritic Cells, and Cell Trafficking and Imaging Techniques. For more information, please visit www.pactgroup.net.

PACT Web Seminars January 29, 2009 - “Qualification: Vendor, Equipment, and Supplies” April 9, 2009 - “Deviation Management of 351 and 361 Products” September 10, 2009 - “Interpretation of the Final Rule: cGMP and Investigational New Drugs Intended for Use in Phase 1 Clinical Trials”




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Apply Now!

_________________________ Apply On-Line! _________________________ Go to www.pactgroup.net and select “Applications” for more information. The preliminary application is provided on-line along with informational documents to assist you in completing the application. Once a preliminary application has been approved following PACT Steering Committee review, a full application is invited. The full application is also submitted on-line and is accessed using the same link to the Application Process page for the preliminary application. ___________________________________ Register to Receive PACT Updates ___________________________________ Receive early notification of PACT-sponsored Web Seminars and Workshops! Go to www.pactgroup.net and register. _________________________ Contact PACT _________________________ PACT Administrative Center

Contact Person(s): Jamie Winestone or Debbie Wood Address: The EMMES Corporation Telephone: 301.251.1161

401 North Washington Street Fax: 240.306.2527 Suite 700 Email: [email protected] Rockville, Maryland 20850

Website: http://www.pactgroup.net/


-PACT Manufacturing Facilities- Baylor College of Medicine Contract Number: N01-HB-37163 The University of Minnesota Contract Number: N01-HB-37164 The University of Pittsburgh Contract Number: N01-HB-37165






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NNNEEEWWWSSSLLLEEETTTTTTEEERRR Volume 5 No. 3 – September 2008

The PACT Group continues to provide education, regulatory, and production assistance to the cell therapy community

________________________

Education Updates ________________________ Two web seminars were held during this quarter

June 25, 2008 Web Seminar A web seminar on “NHLBI Funding and Training Opportunities” and an “Overview of Cell Therapy in Lung Biology and Disease” was held on June 25, 2008 with Drs. Traci Heath Mondoro and Carol J. Blaisdell from the National Heart Lung and Blood Institute presenting on these topics respectively. The slide presentations have been posted on our website at www.pactgroup.net under Education-PACT Web Seminars.

July 31, 2008 Web Seminar Dr. Carolyn A. Keever-Taylor from the Medical College of Wisconsin was invited to present on “Validation Processes” on July 31, 2008. Over 200 individuals attended this web seminar. The live recording (wmv file), slide presentation, and transcription of the Q & A have been posted to the PACT website under Education-PACT Web Seminars.

A Web Seminar on “How to be an Effective Trainer:” is scheduled for November 6, 2008. This web seminar will mark our 12th web seminar since PACT’s inception. Please visit our website for details in October.


NEWSLETTER Volume 5 No. 3 – September 2008

Additional Educational Resources Standard Operating Procedures (SOPs) The following SOPs have been made available to requesting individuals. Visit our website for information regarding this educational resource and how to request these SOPs.

Generation and Management of SOPs Facility Cleaning Personnel Training Retrospective Documentation of Training Environmental Monitoring Facility Quality Management (new) Transportation of Cryopreserved Cells (new) Procedure For Use And Response to Equipment Monitoring Systems (new)

___________________

PACT Projects ___________________

PACT is nearing completion of a Cell Therapy book. All draft chapters have been submitted and are in the process of being formatted for submission to the publisher. The purpose of this book is to provide the cell therapy community with practical aspects of cellular therapy connected with the implementation of GMP/GTP regulations. We anticipate making the book available electronically and to provide supplements and updates to the book on a regular basis.

A shipping validation study is being conducted at the three PACT facilities. The objective of this project is to

establish acceptable conditions for a variety of cell types to facilitate cell product preservation and integrity during transit and to ensure that the cellular product remains stable and sterile during shipment. Six different types of cell product have been shipped, received, processed, and re-characterized at the receiving facilities. Data are currently being collected from the study and will be prepared for publication when it is complete.

________________________


The manuscript titled “A Multi-Center Comparison Study between the Endosafe® PTS™ Rapid Release Testing System and Traditional Test Methods for Detecting Endotoxin in Cell Therapy Products” has been published in Cytotherapy (Cytotherapy 10 (4): 427-435). This study was conducted among the three PACT cell manufacturing facilities and the National Institutes of Health’s Department of Transfusion Medicine.

A manuscript titled “Production Assistance For Cellular Therapies (PACT): Four-Year Experience From

The United States National Heart Lung And Blood Institute (NHLBI) Contract Research Program in Cell and Tissue Therapies” has been accepted for publication by the journal Transfusion in September. The manuscript provides details about the PACT Groups four-year experience as a federally funded contract manufacturing and educational resource to the cell therapy community.

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_________________________

Cell Therapy Forum _________________________

The following article was published in the Summer 2008 ISCT Telegraft (Volume 15 Number2 )

Treatment and Prevention of Viral Infections after Hematopoietic Stem Cell Transplantation

Cliona Rooney and Adrian Gee, for Baylor College of Medicine and PACT Group. Center for Cell and Gene Therapy, Baylor College of Medicine, The Methodist Hospital and Texas Children's Hospital, Houston, TX 77030. Patients receiving hematopoietic stem cell transplants from allogeneic donors are at risk from graft versus host disease (GVHD) and graft rejection. These complications are reduced by inhibition or elimination of both donor and host T cells, using therapeutic regimens whose intensity increases with the degree of genetic mismatch between donor and host. As a result, many patients are unable to control infections with common pathogens, which are mild or subclinical in healthy persons. Viral infections were the cause of 19% of deaths of all stem cell transplant recipients reported by the Center for International Blood and Marrow Transplant Research (CIBMTR) between 1998 and 2002. In some populations the risk is higher – for example viral infections were responsible for 39% of deaths among recipients of HLA-mismatched or unrelated donor stem cells in Texas Children’s Hospital between 1998 and 2007. Antiviral drugs are available for only some viruses and most are associated with significant toxicities. The majority of severe infections result from the uncontrolled reactivation of persistent herpes viruses like Cytomegalovirus (CMV) and Epstein-Barr virus (EBV) with adenovirus infections running close behind. Although the incidence of severe infections with other viruses is low, together they represent a major cause of mortality and morbidity in allogeneic stem cell recipients. Uncontrolled viral infections are clearly related to the lack of virus-specific T cells in these patients and an obvious solution to the problem is to return virus-specific T cells to the patients. The peripheral blood (PB) of most donors contains memory T cells specific for most common viruses, with frequencies ranging from <0.1 to 10% of T cells. However about 10% of PB T-cells are alloreactive, so that infusion of sufficient T cells to reconstitute anti-viral immunity carries a high risk of GVHD. Virus-specific T cells can be selectively grown from donor blood, by co-culture of bulk T cells with viral antigens presented on antigen-presenting cells, a procedure that results in selective expansion of virus specific T cells and concomitant loss of unstimulated alloreactive T cells. The final product can be characterized to ensure virus specificity and lack of reactivity with recipient alloantigens and can then be infused into the stem cell recipient. Several studies have shown that virus-specific T cells expand massively after infusion, rapidly reconstitute virus-specific immunity, provide protection against clinical infection and resolve disease without causing GVHD.1;2 What are the problems with this safe and effective strategy?

• T cells specific for many different viruses are required • Time taken to expand sufficient T cells for infusion • Requirement for a specialized cell culture facility • Lack of memory T cells in naïve donors

PACT has produced T cells specific for three viruses, CMV, EBV and adenovirus (trivirus-specific CTLs), in a single culture.3 To activate and expand virus-specific T cells, adherent peripheral blood monocytes and EBV-transformed B cell lines (EBV-LCLs) were used as antigen presenting cells (APCs). The CMV antigen, pp65, was provided as a transgene in an adenovirus vector, which was able to transduce APCs and provide adenoviral antigens.4 EBV antigens were provided by the EBV-LCL. After infusion, trivirus-specific T cells restored immunity to EBV and CMV but adenovirus-specific T cells could be detected only in patients with concurrent adenovirus infection. Reactivations with all three viruses were controlled without additional therapy. Transgenes encoding protective antigen from other viruses or pathogens could be included in adenovirus vectors to provide T cell immunity to a broader range of viruses. The production of virus-specific T cells is a complex process, requiring the production of both T cells and APCs and taking up to 3 months. Therefore high risk patients must be identified prior to transplant so that CTLs can be initiated prophylactically.


4

Efforts to streamline virus-specific T cell production have been boosted by the observation that small numbers of T cells (~104 per Kg) can expand sufficiently to reconstitute immunity in the lymphopenic stem cell recipient, particularly in the presence of virus infection. Thus if alloreactive T cells can be depleted from PBMC, there may be no need for in vitro expansion of T cells prior to infusion. Alloreactive T cells may be depleted in vivo using genetic transfer of suicide genes or by depletion of alloreactive T cells in vitro.5;6 Alternatively, virus-specific T cells can be isolated using selectable conjugates of viral peptide epitopes embedded in HLA molecules (tetramers or pentamers) that are recognized by virus-specific T cells, or by selection of T cells that secrete IFN-γ after stimulation with viral antigens.7;8 These manipulations require little or no culture, could be available to and performed by stem cell production laboratories, so that T cells may be selected from bone marrow donor blood when infection is detected. An alternative strategy, previously used with considerable success in solid organ transplant recipients, is the use of allogeneic, banked virus-specific T cells.9 This strategy will be evaluated in HSCT recipients in an upcoming study in which trivirus-specific T cells will be produced by PACT for infusion into stem cell recipients with uncontrolled virus infections. The study will evaluate the persistence of the allogeneic T cells and their ability to control infection until endogenous immunity recovers. Reference List 1. Rooney CM, Smith CA, Ng CYC et al. Infusion of cytotoxic T cells for the prevention and treatment of Epstein-Barr virus-induced lymphoma in allogeneic transplant recipients. Blood 1998;92:1549-1555. 2. Walter EA, Greenberg PD, Gilbert MJ et al. Reconstitution of cellular immunity against cytomegalovirus in recipients of allogeneic bone marrow by transfer of T-cell clones from the donor. N Engl J Med 1995;333:1038-1044. 3. Leen AM, Myers GD, Sili U et al. Monoculture-derived T lymphocytes specific for multiple viruses expand and produce clinically relevant effects in immunocompromised individuals. Nat.Med. 2006;12:1160-1166. 4. Leen AM, Sili U, Vanin EF et al. Conserved CTL epitopes on the adenovirus hexon protein expand subgroup cross-reactive and subgroup-specific CD8+ T cells. Blood 2004;104:2432-2440. 5. Amrolia PJ, Muccioli-Casadei G, Huls H et al. Adoptive immunotherapy with allodepleted donor T-cells improves immune reconstitution after haploidentical stem cell transplantation. Blood 2006;108:1797-1808. 6. Ciceri F, Bonini C, Marktel S et al. Antitumor effects of HSV-TK-engineered donor lymphocytes after allogeneic stem-cell transplantation. Blood 2007;109:4698-4707. 7. Cobbold M, Khan N, Pourgheysari B et al. Adoptive transfer of cytomegalovirus-specific CTL to stem cell transplant patients after selection by HLA-peptide tetramers. J Exp.Med. 2005;202:379-386. 8. Feuchtinger T, Matthes-Martin S, Richard C et al. Safe adoptive transfer of virus-specific T-cell immunity for the treatment of systemic adenovirus infection after allogeneic stem cell transplantation. Br.J Haematol. 2006;134:64-76. 9. Haque T, Wilkie GM, Jones MM et al. Allogeneic cytotoxic T-cell therapy for EBV-positive posttransplantation lymphoproliferative disease: results of a phase 2 multicenter clinical trial. Blood 2007;110:1123-1131. ________________________________


PACT representatives attended the following meeting:

6th Int’l Society for Stem Cell Research (ISSCR) Meeting June 11-14, 2008, Pennsylvania Convention Center Philadelphia, PA.

PACT representatives will be attending and presenting at the following September and October 2008 meetings: 8th Annual Somatic Cell Therapy (SCT) Meeting American Association of Blood Banks (AABB) Annual Meeting September 22-24, 2008 October 4-7, 2008 Bethesda Hyatt Regency Montreal Convention Center Bethesda, MD Montreal, Canada (PACT is serving as a co-sponsor)


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Apply Now!

___________________

Apply On-Line ___________________

Go to www.pactgroup.net and select “Applications” for more information. The preliminary application is provided on-line along with informational documents to assist you in completing the application. Once a preliminary application has been approved following Steering Committee review, a full application is invited. The full application is also submitted on-line and is accessed using the same link to the Application Process page for the preliminary application. _________________________________________



Contact PACT ___________________












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NNNEEEWWWSSSLLLEEETTTTTTEEERRR Volume 5 No. 2 – June 2008

The PACT Group provides education, regulatory and production assistance to the cell therapy community through contract manufacturing of therapeutic cell products

________________________

Education Updates ________________________ June 25, 2008 Web Seminar A web seminar on “NHLBI Funding and Training Opportunities” and an “Overview of Cell Therapy in Lung Biology and Disease” will be held on June 25, 2008, at 1:00pm ET (Eastern Time) with Dr. Traci Heath Mondoro and Dr. Carol J. Blaisdell from National Heart Lung and Blood Institute presenting on these topics respectively. Please visit our website at www.pactgroup.net to register for this informative web seminar. July 2008 Web Seminar A web seminar on “Validation Processes” will be held in July 2008 with Dr. Carolyn A. Taylor, Director of the BMT Processing Laboratories at the Medical College of Wisconsin presenting on this topic. Visit our website for details on this upcoming web seminar. October 11, 2007 Web Seminar Q & A Session The Q & A transcription of the web seminar on “Cryopreservation” has been posted to the PACT website under Education-PACT Web Seminars.

May 5-6, 2008 Workshop A PACT-sponsored workshop entitled “Innovative Cellular Therapies and Methods at Cell Therapy Facilitates” was hosted by the University of Pittsburgh in Pittsburgh, PA May 5-6, 2008, and included tours of the University of Pittsburgh Cancer Institute’s Immune Monitoring and Cell Processing Laboratory (IMCPL) and Hematopoietic Stem Cell Laboratory (HSCLab). The following objectives and their supporting topics were addressed:

To develop a fundamental understanding of how Good Manufacturing Practice operates in a cell therapy facility: GMP facility design Cryopreservation Monitoring assays Considerations for optimization of culture conditions for various cell types Flow cytometry


NEWSLETTER Volume 5 No. 2 – June 2008

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May 5-6 Workshop objectives continued…

To provide a Clinical and Lab Perspectives of various innovative cell therapies: : Production of human umbilical cord blood-derived T-regulatory cells HIV dendritic cells Natural killer cells Cytotoxic T-lymphocytes Adipose stem cells

To learn valuable laboratory skills and techniques through observation: Lab practicals on flow cytometry, endotoxin and mycoplasma detection, and brief tours were conducted at both

facilities. Workshop speakers were from the Baylor College of Medicine, the University of Minnesota, and the University of Pittsburgh Cancer Institute. Additional Educational Resources Standard Operating Procedures (SOPs) PACT has made available the following SOPs listed below to requesting individuals. Visit our website for information regarding this educational resource.

Generation and Management of SOPs Facility Cleaning Staff Training (general facility orientation and prospective/retrospective training checklists) Environmental Monitoring

___________________

PACT Projects ___________________

PACT is nearing completion of a Cell Therapy book. All draft chapters have been submitted and are currently under review. The purpose of this book is to provide the cell therapy community with practical aspects of cellular therapy connected with the implementation of GMP/GTP regulations. We anticipate making the book available electronically and to provide supplements and updates to the book on a regular basis.

________________________


A manuscript titled “A Multi-Center Comparison Study between the Endosafe® PTS™ Rapid Release Testing System and Traditional Test Methods for Detecting Endotoxin in Cell Therapy Products” has been approved for publication to Cytotherapy. This study was conducted among the 3 PACT cell manufacturing facilities and the National Institutes of Health’s Department of Transfusion Medicine.

A manuscript titled “Production Assistance For Cellular Therapies (PACT): Four-Year Experience From The

United States National Heart Lung And Blood Institute (NHLBI) Contract Research Program in Cell and Tissue Therapies” will be submitted for publication in late June. The manuscript provides details about the PACT Groups four-year experience as a federally funded contract manufacturing and educational resource to the cell therapy community.


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_________________________


Abstract submitted in April 2008 to the ISCT Telegraft (Volume 15 Number 1)

Activation of Natural Killer Cells: A Shipping Study David H. McKenna, Jr., M.D. and Jeffrey S. Miller, M.D. for the University of Minnesota and PACT

If a cell therapy must be administered as a fresh (i.e., non-cryopreserved) product, difficulties may arise when distant clinical sites are involved. In preparation for a clinical trial at Tufts-New England Medical Center (Hans Klingemann, et al) we performed shipping studies to validate in-transit activation of natural killer (NK) cells.1

NK cells were manufactured as per our standard methods2 and prepared for shipment: • Collection of non-mobilized peripheral blood mononuclear cell (MNC) apheresis product from normal research

donor • CD3+ cell-depletion using the Miltenyi CliniMACS® Cell Selection System (Miltenyi Biotec) • Initiation of culture of CD3+ cell-depleted fraction in X-VIVO 15, without gentamicin and phenol red (Cambrex

BioScience), supplemented with 10% human AB serum (Valley Biomedical) and 1000 IU/mL IL-2 (Chiron) in VueLife™ Teflon bags (American Fluoroseal Corporation)

• Packaging of cells in an insulated shipping container (with temperature monitoring device) using temperature stabilizing packs (brought to ~33°C) to maintain body temperature range conditions during shipment

• Shipment of cells overnight from Minneapolis, MN to Columbus, OH and back to Minneapolis via commercial courier (AirNet)

• Upon receipt of cells in lab, wash and re-suspension in 5% human serum albumin (Baxter Healthcare) • Completion of quality control/lot release testing including: TNC, % NK (CD3/56+) cells, T (CD3+) cell dose,

viability, sterility, endotoxin and Gram stain (Table 1 shows the testing specifications)

A total of six runs were completed, and all lot release testing specifications were met with exception of one NK cell phenotype which was 18%. In this case the NK cell content in the starting MNC product was unusually low (6%). Length of shipment ranged from 14-16 hours; the lowest temperature during shipment ranged from 26.9° -32.5°C for all runs. CD3+ cell-depleted NK cell products displayed a greater degree of cytotoxicity as compared to the CD3+ cell-depleted control products for all runs tested (n=5). These studies demonstrated that NK cell products can be successfully transported for use at a distant clinical site. This study was supported in part by the National Heart, Lung, and Blood Institute Contract N01-HB-47095 (Production Assistance for Cellular Therapies, or PACT). In addition to providing cell therapy products for clinical trials and sponsoring educational activities, PACT is actively involved in projects related to quality control and standardization in cell therapy. As part of this effort, additional shipping studies involving various types of products are underway.

References 1) Kadidlo D, Bostrom N, Adams S, Fautsch S, McCullough J, Wagner J, Miller J, McKenna D. Validation of Natural Killer Cell Activation During Long-Distance Shipping [abstract]. Transfusion 2006; 46(9S): 59A-60A. 2) McKenna D, Sumstad D, Bostrom N, Kadidlo D, Fautsch S, McNearney S, DeWaard R, McGlave P, Weisdorf D, Wagner J, McCullough J, and Miller J. GMP-production of natural killer cells for immunotherapy: a six year single institution experience. Transfusion 2007; 47(3): 520-528.

Table 1. NK cell product testing specifications Test/Assay Specification

NK Cell Phenotype (% CD3-/CD56+) >20% T (CD3+) Cell Dose (E+05/kg)* <5.00E+05/kg

Viability >70% Gram Stain No organisms

Endotoxin (LAL Method)* <5EU/kg Bacterial/Fungal Culture No Growth

*Based upon 70 kg recipient


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________________________________


PACT representatives attended the following meetings:

AABB Cell Therapy Spring Conference March 28-29, 2008, Buena Vista Palace, Orlando, FL

NIH Symposium entitled “Challenges & Promise of Cell-Based Therapies” May 6, 2008, Natcher Conference Center NIH, Bethesda, MD

2008 Annual ISCT Meeting May 17-20, 2008, Hyatt Regency Miami, Miami, FL

American Society of Gene Therapy (ASGT) 11th Annual Meeting May 28-June 1, 2008, John B. Hynes Convention Center, Boston, MA

PACT representatives will be attending the following June and September 2008 meetings: 6th Int’l Society for Stem Cell Research (ISSCR) meeting 8th Annual Somatic Cell Therapy meeting June 11-14, 2008 September 22-24, 2008 Pennsylvania Convention Center Bethesda Hyatt Regency Philadelphia, PA Bethesda, MD


Apply Now!

___________________

Apply On-Line ___________________

Go to www.pactgroup.net and select “Applications” for more information. The preliminary application is provided on-line along with informational documents to assist you in completing the application.



5

Once a preliminary application has been approved following Steering Committee review, a full application is invited. The full application is also submitted on-line and is accessed using the same link to the Application Process page for the preliminary application.

_________________________________________



Contact PACT ___________________










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NNNEEEWWWSSSLLLEEETTTTTTEEERRR Volume 5 No. 1 – March 2008 _________________________

Educational Updates _________________________

October 11, 2007 Web Seminar Q & A Session The Q & A transcription of the web seminar on “Preparing for an FDA Inspection” has been posted to the PACT website under Education-PACT Web Seminars. February 21, 2008 Web Seminar A web seminar on “Cryopreservation” with Dr. Allison Hubel (University of Minnesota) as speaker was held on February 21, 2008. Over 175 individuals registered for this web seminar and the Q & A transcription will be posted to the PACT website soon. More information about our web seminar speaker Dr. Hubel

Dr. Hubel will be participating as a speaker at the University of Minnesota Biomedical Engineering Institute Short Course Series on “Preservation of Cells, Tissues, and Gametes” from May 21-23, 2008. A brochure of the course description can be found on our website at http://64.23.27.234/education/WebSeminars/hubelbrochure08.pdf. For more information and to register visit http://www.me.umn.edu/education/shortcourses/preservation/

May 2008 Workshop A PACT-sponsored workshop will be hosted by the University of Pittsburgh in Pittsburgh, PA May 5-6, 2008 and will include tours of the University of Pittsburgh Cancer Institute’s Immune Monitoring and Cell Processing Laboratory (IMCPL) and Hematopoietic Stem Cell (HSC) Laboratory. A lab practical on flow cytometry, endotoxin and mycoplasma detection, and brief tours will be conducted at both facilities. Workshop speakers will be from the Baylor College of Medicine, the University of Minnesota, and the University of Pittsburgh Cancer Institute. Visit our newly re-designed website and sign up for notification regarding additional details on workshop objectives and registration. Attendee space is limited to 30. June 2008 Web Seminar A web seminar on “NHLBI Funding and Training Opportunities” will be held in June 2008 with speakers from National Heart Lung and Blood Institute presenting on this topic. Visit our website for details over the next few months. Additional Educational Resources Standard Operating Procedures PACT has made available the following SOPs listed below to requesting individuals. Visit our website for information regarding this educational resource.

Environmental Monitoring Facility Cleaning SOP on Writing SOPs Staff Training (general facility orientation and prospective/retrospective training checklists)

The PACT Group provides education, regulatory and production assistance to the cell therapy community through contract manufacturing of

therapeutic cell products


2

________________________________

PACT Projects ________________________________

PACT is nearing completion of a Cell Therapy book. All draft chapters have been submitted and are currently under review. The purpose of this book is to provide the cell therapy community with practical aspects of cellular therapy connected with the implementation of GMP/GTP regulations. We anticipate making the book available electronically and to provide supplements and updates to the book on a regular basis.

________________________________

PACT - Publications ________________________________

The PACT Group has completed its comparison study of the Endosafe® system. The study was a comparison of the Endosafe® system to traditional LAL methods in the detection of endotoxin in cell therapy products. We are in the process of submitting a manuscript titled “A Multi-Center Comparison Study between the Endosafe® PTS™ Rapid Release Testing System and Traditional Test Methods for Detecting Endotoxin in Cell Therapy Products”.

A manuscript titled “Production Assistance For Cellular Therapies (PACT): Four-Year Experience From The

United States National Heart Lung And Blood Institute (NHLBI) Contract Research Program in Cell and Tissue Therapies” is currently being drafted and is anticipated to be submitted for publication by second quarter 2008. The manuscript provides details about the PACT Groups four-year experience as a federally funded contract manufacturing and educational resource to the cell therapy community.

________________________________

PACT- attended Meetings ________________________________

FDA Cell Therapy Liaison Meeting PACT representatives attended the FDA Cell Therapy liaison meeting on February 5, 2008 at AABB headquarters in Bethesda, MD

2008 Bone Marrow Transplant Tandem Meetings PACT representatives attended the 2008 BMT Tandem Meetings February 13-17, 2008 at the Manchester Grand Hyatt San Diego, CA

PACT representatives will be attending the following March and May 2008 meetings:

¤ AABB Cell Therapy Spring Conference ¤ 2008 Annual ISCT Meeting March 28-29, 2008 May 17-20, 2008 Buena Vista Palace, Orlando, FL Hyatt Regency Miami, Miami, FL

________________________


Abstract submitted in February 2008 for the 6th ISSCR Annual Meeting June 2008

TRANSLATIONAL SCALE-UP: BRIDGING THE GAP BETWEEN RESEARCH AND CLINICAL PROCESSING OF PRE-ADIPOCYTES

Griffin DL, Pfeifer ME, Zimmerlin L, Rubin JP, Donnenberg AD

Adipose tissue is a rich source of multipotential tissue stem cells and, as such, represents a promising source for regenerative therapy. Preclinical experiments isolating tissue stem and progenitor cells from whole fat and liposuction slurry have been performed in a research laboratory environment at the University of Pittsburgh Cancer Institute. As part of a PACT (Production Assistance for Cellular Therapy) project funded by the National Heart, Lung and Blood Institute, the HSCLab, a clinical laboratory specializing in GMP production of cells for somatic cell therapy, was charged with developing a cell isolation procedure consistent with FDA standards for purity, potency, safety and identity that can be utilized in clinical trials.


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_____________________ Apply On-Line! _________________________

Go to www.pactgroup.net and select “Applications” for more information. The preliminary application is provided on-line along with informational documents to assist you in completing the application. Once a preliminary application has been approved following Steering Committee review, a full application is invited. The full application is also submitted on-line and is accessed using the same link to the Application Process page for the preliminary application.


Apply Now!


4

_____________________ Register to Receive PACT Updates _________________________

Receive early notification of PACT-sponsored Web Seminars and Workshops! Go to www.pactgroup.net and register. _________________________

Contact PACT _________________________






The University of Minnesota Contract Number: N01-HB-37164 The University of Pittsburgh Contract Number: N01-HB-37165


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NNNEEEWWWSSSLLLEEETTTTTTEEERRR Volume 4 No. 4 – December 2007



AAA YYYeeeaaarrr IIInnn RRReeevvviiieeewww 2007 has been a successful year for PACT. To date we have received over 55 application requests for manufacturing cell therapy products. Over 100 cell products have been administered to patients from seven separate approved applications. On the educational front we have conducted three web seminars and a workshop. Plans are to continue accepting applications and to grow our educational initiatives. _________________________ Educational Updates _________________________

Three Web Seminars were held in 2007. This brings a total of eight web seminars conducted since PACT’s inception.

February 22, 2007 - “Adverse Event Reporting” with Drs. Hanh Khuu (NIH) and Helen Heslop (Baylor

College of Medicine) as speakers July 19, 2007 - “Interpreting AABB and FACT Standards in Cell Therapy with Dr. Phyllis Warkentin (Univ. of

Nebraska Medical Center) and Doug Padley (Mayo Clinic, Rochester, MN) as speakers Over 300 attendees participated in the July web seminar. The Q & A session was transcribed is posted to the PACT website under Educational Material - PACT Web Seminars

October 11, 2007 - “Preparing of an FDA Inspection” with Drs. Adrian Gee (Baylor College of Medicine) and Nancy Collins (University of Toledo Medical Center) as speakers

Over 150 attendees participated in the October web seminar. The Q & A session is being transcribed and will be posted to the PACT website under Educational Material - PACT Web Seminars soon

April 10-11 2007 Workshop

A GMP training workshop was held in Minneapolis, MN. Presentation topics included database systems, product release criteria, cyropreservation, and IND submissions. CME/CE credits, through our collaboration with AABB, were provided to requesting attendees.

Additional Educational Resources Standard Operating Procedures

PACT has made available the following SOPs listed below to requesting individuals. Visit our website for information regarding this educational resource.



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_________________________ Educational Updates continued _________________________

Cytokine and Antibody List PACT has provided an abridged list of commercially available cytokines and antibodies on the PACT website under the Resources link. (Disclaimer: The lists of antibody and cytokine products and their corresponding vendors are for collaborative research and informational purposes only. This list was generated after polling cell-processing facilities regarding cytokine/antibody use. This is not and should not be considered a comprehensive listing of all commercially available cellular therapy products. The NHLBI and entities of PACT neither support nor endorse the vendors and products listed).

________________________________ PACT - attended Meetings ________________________________

Hematopoietic Growth Factors – Use in Normal Blood and Stem Cell Donors: Clinical and Ethical Issues March 15-16, 2007/Bethesda, MD PACT representatives attended a program on “Hematopoietic Growth Factors”

AABB Spring Conference on Cellular Therapy March 23-25 2007/San Diego, CA (Supported in part by PACT) Representatives from the PACT facilities presented on PACT- manufactured cell therapy products and initiatives

6th Cell Therapy Liaison Meeting with the FDA June 7, 2007Bethesda, MD PACT members attended the Cell Therapy Liaison meeting

13th Annual Meeting of the International Society for Cellular Therapy (ISCT) June 24-27, 2007/Sydney,Australia (Abstract poster presentations)

7th Annual Somatic Cell Therapy (SCT) Symposium 2007 (Supported in part by PACT) September 26-28, 2007/Bethesda, MD PACT members attended the Somatic Cell Therapy (SCT) Annual Meeting. Posters were displayed at the SCT symposium that further described PACT’s involvement in cell therapy research. In addition, PACT provided an electronic survey for symposium attendees to answer in order to capture information about the attendees and the overall needs of the cell therapy community.

36th Annual Scientific Meeting of the International Society for Experimental Hematology (ISEH) September 28-30, 2007/Hamburg, Germany A PACT representative from Minnesota attended the Annual Meeting of the International Society for Experimental Hematology

American Association of Blood Banks (AABB) Annual Meeting & TXPO 2007 October 20-23, 2007/Anaheim, CA A PACT session was held on Tuesday, October 23rd from 2:00pm - 5:00pm titled: “PACT - Cell Therapy Challenges: Product Characterization, Regulatory Compliance and Lessons Learned”. Speakers from the three PACT facilities and from Cedars Sinai Medical Center in Los Angeles, CA presented on:

Methods for constructing a product development plan

Alternatives in phases of assay development and establishing release criteria

Translating cell-manufacturing activities from one laboratory to another

PACT had an exhibit booth, which displayed our services that we provide such as education, expertise in regulatory affairs, and production assistance to the cell therapy community.


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________________________________ PACT - attended Meetings continued ________________________________

AABB Audio conferences PACT AC and facility representatives attended AABB audioconferences related to cell therapy at the AABB office in Bethesda, MD

American Heart Association Scientific Sessions 2007 November 4-7, 2007/Orlando, FL PACT representatives attended the meeting and shared an exhibit booth with NHLBI

American Society of Hematology - 49th Annual Meeting December 8-11, 2007/Atlanta, GA

________________________________ PACT Projects ________________________________

PACT is involved in the development of a Cell Therapy book. Draft chapters have been submitted and are currently under review. The purpose of this book is to provide the cell therapy community with practical aspects of cellular therapy surrounding the implementation of GMP/GTP regulations. We anticipate making the book available electronically and to provide supplements and updates to the book on a regular basis.

A draft publication based on our findings in evaluating the Charles River Laboratories’ Endosafe®

Portable Test System (PTSTM) for the rapid detection of endotoxin in cell therapy products is completed and will be submitted for publication by years end.

PACT has drafted a manuscript about its four-year experience as a federally funded contract

manufacturing and educational resource to the cell therapy community.

PACT has been involved in validating a cell separation system using small volumes of bone marrow at one of our PACT centers. Phase I of this study is completed and analysis of the data has been conducted. Phase II will commence in first quarter 2008 with the three PACT manufacturing centers participating in the evaluation of this cell separation system.

_________________________________________ 2007 PACT Publications/Abstracts _________________________________________

Publications

McKenna D, Sumstad D, Bostrum, N et al. GMP-production of natural killer cells for immunotherapy: A six-year single institution experience. Transfusion 2007; 47 (3): 520-528

Cooley S, McKenna, D, and Miller J. NK Cell Immunotherapy. Principles of Cell Therapy, eds. Horowitz E and Keating A, Cambridge University Press (submitted for publication)

Kennedy-Nasser, A, and CM Bollard. T Cells and Stem Cell Transplant. Bone Marrow Transplant. 2007 May14; [Epub ahead of print]


Abstracts

David McKenna, Jr., Darin Sumstad, Nancy Bostrom, et al. Good manufacturing practices production of natural killer cells for immunotherapy: a six year single institutional experience. Transfusion March 2007 vol 47, pgs. 520-528.

Bollard CM, Myers GD, et al. The Clinical Use of Donor-Derived Adenovirus- Specific Cytotoxic T Lymphocytes. Biology of Blood and Marrow Transplantation 2007 vol 13, suppl 2 page 1

William F. Reed, MD et. al for the PACT Group PRODUCTION ASSISTANCE FOR CELLULAR THERAPIES (PACT): 3-YEAR EXPERIENCE FROM THE US NATIONAL HEART LUNG AND BLOOD INSTITUTE (NHLBI) CONTRACT RESEARCH PROGRAM

Griffin Deborah L, McNeil Melissa, Donnenberg Albert D, Kiss Joseph E, Whiteside Teresa L, Donovan Maryann DEVELOPMENT OF A CURRENT GOOD MANUFACTURING PRACTICE (CGMP) TRAINING PROGRAM FOR THE CELLULAR THERAPIES LABORATORIES AT THE UNIVERSITY OF PITTSBURGH CANCER INSTITUTE

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April 2008 Workshop PACT will be conducting a third workshop in Pittsburgh, PA in early May 2008 and will include

actual hands on cell processing training. Visit our newly designed website and sign up for notification regarding additional details on workshop objectives and registration.

Four Web Seminars will be held in 2008 “Cryopreservation of Cell Therapy Products” with Allison Hubel (Univ. of Minnesota)

“Validation Processes” – speakers TBD

“NHLBI Funding and Training Opportunities” - speakers TBD

“Train the Trainer” with professional trainer Larry Midgett (National Seminars Group) and Diane Kadidlo (University of Minnesota) as speakers


Apply Now!

_________________________ Apply On-Line! _________________________ Go to www.pactgroup.net and select “Application Process” for more information. The preliminary application is provided on-line along with informational documents to assist you in completing the application. Once a preliminary application has been approved following steering committee review, a full application is invited. The full application can now be submitted on-line and is accessed using the same link to the Application Process page for the preliminary application.



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_________________________ Register to Receive PACT Updates _________________________ Receive early notification of PACT-sponsored Web Seminars and Workshops! Go to www.pactgroup.net and register. _________________________ Contact PACT _________________________ PACT Administrative Center Contact Person(s): Jamie Winestone or Debbie Wood Address: The EMMES Corporation Telephone: 301.251.1611




-PACT Manufacturing Facilities-

Baylor College of Medicine Contract Number: N01-HB-37163 The University of Minnesota Contract Number: N01-HB-37164 The University of Pittsburgh Contract Number: N01-HB-37165





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NNNEEEWWWSSSLLLEEETTTTTTEEERRR Volume 4 No. 3 – September 2007 _____________________________________________

AABB Annual Meeting: PACT Session _____________________________________________

American Association of Blood Banks (AABB) Annual Meeting & TXPO 2007 October 20-23, 2007

PACT will be conducting a PACT session on Tuesday, October 23rd from 2:00pm - 5:00pm titled: PACT-Cell Therapy Challenges: Product Characterization, Regulatory Compliance and Lessons. Speakers from the three PACT facilities and from Cedars Sinai Medical Center in Los Angeles, CA will be presenting on:

Methods for constructing a product development plan Alternatives in phases of assay development and establishing release criteria Translating cell-manufacturing activities from one laboratory to another

A Q & A session member panel, comprised of the 5-speakers will be included in the session. We will have a PACT exhibit booth to display our services that we provide such as education, expertise in regulatory affairs, and production assistance to the cell therapy community. Please stop by and visit our booth and attend our session. _________________________

Educational Updates _________________________

July 19, 2007 Web Seminar A web seminar on “Interpreting AABB and FACT Cell Therapy Standards” with Dr. Phyllis Warkentin (Univ. of Nebraska Medical Center) and Doug Padley (Mayo Clinic) as speakers, was held on July 19, 2007. Over 300 attendees participated in the PACT-sponsored web seminar held on July 19, 2007. The participants completed a survey that was designed to collect data on the experience and current position of the participants, overall organization of the current web seminar, obtain suggestions on how to improve future web seminars, and provide feedback on speaker performance. One hundred seventy-nine web seminar participants responded to the survey. General responses ranged from good to excellent 88%-97%. It is noteworthy that 72% of respondents indicated a likely impact on practice, based upon this educational web seminar. Individuals who participated in the survey also provided feedback on anticipated future web seminar topics. Majority of the participants indicated that they would be interested in having a web seminar on preparing for an FDA Inspection. The Q & A session has been transcribed and is posted to the PACT website under Educational Material - PACT Web Seminars. October 11, 2007 Web Seminar A web seminar on “Preparing for an FDA Inspection” with Drs. Adrian Gee (Baylor College of Medicine) and Nancy Collins (Univ. of Toledo Medical Center) as speakers will be held on October 11, 2007. Objectives for this web seminar include: Learning the steps to follow when preparing for a facility inspection, learning what and what not to do during an inspection, and learn and understand what inspectors focus on during an inspection. To register and for additional educational information, please visit our website and click on the Educational Material link.




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Standard Operating Procedures PACT has made available the following SOPs listed below to requesting individuals. Visit our website for information regarding this educational resource.


PACT Discussion Board Plans are underway to support a Discussion Board to provide cell therapy processing laboratories with an easily accessible venue to communicate and share information. Check our website for an update.

________________________________

PACT - attended Meetings ________________________________

6th Cell Therapy Liaison Meeting, June 7, 2007 PACT representatives attended the meeting to discuss the FDA Cord Blood Guidance document issued in December 2006.

PACT Steering Committee Meeting PACT members gathered for their bi-annual PACT Steering Committee meeting on September 25, 2007 in Bethesda, MD. PACT members held an Education and Working Group meeting at the EMMES Corporation on September 24, 2007 to discuss PACT educational and resource initiatives.

7th Annual Somatic Cell Therapy (SCT) Symposium 2007(Supported in part by PACT) PACT members attended the Somatic Cell Therapy (SCT) Annual Meeting on September 26-28, 2007 in Bethesda, MD. Posters were displayed at the SCT symposium that further described PACT’s involvement in cell therapy research. In addition, PACT had an electronic survey for symposium attendees to answer in order to capture information about the attendees and the overall needs of the cell therapy community.

36th Annual Scientific Meeting of the International Society for Experimental Hematology (ISEH) A PACT representative from Minnesota attended the Annual Meeting of the International Society for Experimental Hematology on September 28-30, 2007 in Hamburg, Germany.

AABB Audioconferences PACT AC and facility representatives continue to attend AABB audioconferences related to cell therapy at the AABB office in Bethesda, MD

PACT representatives will be attending the following October and November 2007 meetings:

Symposium on Cardiovascular Regenerative Medicine October 1-2, 2007 Natcher Conference Center (NIH) Bethesda, MD

American Heart Association (AHA) Scientific Sessions November 4-7, 2007 Orange County Convention Center Orlando, FL


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_________________________

Apply On-Line! _________________________ Go to www.pactgroup.net and select “Application Process” for more information. The preliminary application is provided on-line along with informational documents to assist you in completing the application. Once a preliminary application has been approved following steering committee review, a full application is invited. The full application can now be submitted on-line and is accessed using the same link to the Application Process page for the preliminary application. _________________________

Register to Receive PACT Updates _________________________ Receive early notification of PACT-sponsored Web Seminars and Workshops! Go to www.pactgroup.net and register. _________________________

Contact PACT _________________________ PACT Administrative Center Contact Person(s): Jamie Winestone or Debbie Wood Address: The EMMES Corporation Telephone: 301.251.1611




-PACT Facilities-

Baylor College of Medicine Contract Number: N01-HB-37163 The University of Minnesota Contract Number: N01-HB-37164 The University of Pittsburgh Contract Number: N01-HB-37165



Apply Now!

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NNNEEEWWWSSSLLLEEETTTTTTEEERRRVolume 4 No. 2 – June 2007

_________________________PACT Projects_________________________

PACT is currently involved in the development of a Cell Therapy book. The purpose of this book is to providethe cell therapy community with practical aspects of cellular therapy surrounding the implementation ofGMP/GTP regulations. We anticipate making the book available electronically and to provide supplements andupdates to the book on a regular basis. Several individuals, external to PACT and from the EU, have graciouslyaccepted our invitation to contribute to this publication. We would like to take this opportunity to thank thosewho contributed their time and expertise in writing chapters for this book.

A draft publication based on our findings in evaluating the Charles River Laboratories’ Endosafe® Portable TestSystem (PTSTM) for the rapid detection of endotoxin in cell therapy products is near completion. This paper isbeing published jointly with Charles River.

PACT is in the process of writing a paper about its three-year experience as a federally-funded contractmanufacturing and educational resource to the cell therapy community.

PACT has been involved in validating a cell separation system using small volumes of bone marrow at one of ourPACT centers. Phase I of this study is nearing completion and analysis of the data is in progress. Following thecompletion of Phase I, Phase II will commence and the remaining two manufacturing centers will participate inthe evaluation this cell separation system.

_________________________April 2007Workshop Update_________________________

Forty-three participants attended the Design and Operation of a GMP Cell Therapy Facility workshop hosted by TheUniversity of Minnesota on April 10-11, 2007. Many of the participants included medical directors, laboratory supervisors,and medical technologists. A variety of specialty areas such as QA/QC, research and development, and education andtraining were represented. Interesting topics such as cryopreservation, product development, lot release criteria, andmaterials management were presented. CME/CE credits, through our collaboration with AABB, were provided torequesting attendees. The responses to the workshop survey were very positive and provided valuable feedback onadditional topics for our next workshop. Plans are for the University of Pittsburgh to host PACT’s third workshop in latespring 2008.

PACT offers scale-up capability and expertise in the translational developmentneeded to produce cell therapy products for use in clinical trials under



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_________________________Educational Updates_________________________

July 2007 Web SeminarOur next Educational Web Seminar is scheduled for July 19, 2007. Speakers from the Mayo Clinic and the University ofNebraska Medical Center will be presenting “Interpreting AABB and FACT Standards in Cell Therapy.” To register visit ourwebsite at www.pactgroup.net. A web seminar on developing a GMP training curriculum is scheduled for October 2007.

February 2007 Web Seminar was a successA web seminar on “Adverse Event Reporting” with Drs. Hanh Khuu (NIH) and Helen Heslop (Baylor) as speakers, washeld on February 22, 2007 and a PDF copy of each presentation is now available on the website under EducationalMaterial - PACT Web Seminars. Objectives for this web seminar included: assessing adverse events, documentation, andexpedited reporting requirements and forms. For additional educational information, please visit our website and click onthe Educational Material link.


Standard Operating ProceduresPACT will make available the following SOPs listed below to requesting individuals. Visit our website forinformation regarding this educational resource. Environmental Monitoring Facility Cleaning SOP on Writing SOPs Staff Training (general facility orientation and prospective/retrospective training checklists)

Cytokine and Antibody ListPACT has provided an abridged list of commercially available cytokines and antibodies on the PACT website underthe Resources link. (Disclaimer: The lists of antibody and cytokine products and their corresponding vendors are forcollaborative research and informational purposes only. This list was generated after polling cell-processing facilities regardingcytokine/antibody use. This is not and should not be considered a comprehensive listing of all commercially available cellulartherapy products. The NHLBI and entities of PACT neither support nor endorse the vendors and products listed).

PACT-sponsored Discussion BoardPACT will soon be hosting a web-based discussion board to provide cell therapy processing laboratories with aneasily accessible venue to communicate and share information. No membership is required and there are Nopasswords to remember! Subscription to the discussion board will be by request or invitation only. Subscribers willbe allowed to view and post messages via email or through the discussion board web page, upload documents to thediscussion board web page and even set their own message delivery preferences. Visit our website in the comingmonths for more details about this valuable resource.

_________________________Cell Therapy Forum_________________________

PACT is pleased to announce that two abstracts have been accepted for poster presentations at the 13th Annual ISCTMeeting in Sydney, Australia on June 24 - 27, 2007.

PRODUCTION ASSISTANCE FOR CELLULAR THERAPIES (PACT): 3-YEAR EXPERIENCE FROMTHE US NATIONAL HEART LUNG AND BLOOD INSTITUTE (NHLBI) CONTRACT RESEARCHPROGRAM

William F. Reed, MD et. al for the PACT Group**Stephen J. Noga, MD, PhD and William F. Reed, MD, PACT Steering Committee Chairs, Adrian P. Gee,M.I.Biol, PhD and Cliona Rooney, PhD, Baylor College of Medicine, David McKenna, MD and John E.Wagner, MD, University of Minnesota, Albert D. Donnenberg, PhD and Theresa L. Whiteside, PhD, Universityof Pittsburgh



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DEVELOPMENT OF A CURRENT GOOD MANUFACTURING PRACTICE (CGMP) TRAININGPROGRAM FOR THE CELLULAR THERAPIES LABORATORIES AT THE UNIVERSITY OFPITTSBURGH CANCER INSTITUTE

Griffin Deborah L, McNeil Melissa, Donnenberg Albert D, Kiss Joseph E, Whiteside Teresa L, Donovan Maryann

Theses activities have been funded in whole or in part with Federal funds from the NHLBI NIH._________________________PACT - attended Meetings_________________________

PACT Attendance

Hematopoietic Growth Factors – Use in Normal Blood and Stem Cell Donors: Clinical and EthicalIssuesPACT representatives attended a program on ‘Hematopoietic Growth Factors’ March 15-16, 2007 in Bethesda, MD

6th Cell Therapy Liaison Meeting with the FDAPACT members attended the Cell Therapy Liaison meeting on June 7, 2007 in Bethesda, MD

PACT Presentations

PACT members will be attending the following June meeting:

June 24 – 27, 2007 (abstract poster presentation)13th Annual Meeting of the International Society forCellular Therapy (ISCT)Sydney, Australiawww.celltherapysociety.org/


The Administrative Center at EMMES Corporation - Contract Number: N01-HB-37166

Baylor College of Medicine Contract Number: N01-HB-37163

The University of Minnesota Contract Number: N01-HB-37164

The University of Pittsburgh Contract Number: N01-HB-37165

National Heart Lungand Blood Institute

http://www.celltherapysociety.org/


_______Produ_______

To datecontinuThe cellproduce

_______Apply_______

Go toprovided

Once afull appprelimin

_______RegistPACT_______

ReceiveGo to w

_______Conta_______

PACT

Contact

Address

Website

PACT accepts applications on an ongoing basis for contract manufacturing ofcell therapy products

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__________________cts Delivered__________________

, PACT has delivered 63 cell therapy products from seven different applications for patient administration. We areing to receive applications requesting manufacturing support for a variety of products and clinical indications.processing facilities strive to produce a cellular product along with the assurance that it is clinical grade and is

d in a manner compliant with regulatory requirements.

__________________On-Line!

__________________

www.pactgroup.net and select “Application Process” for more information. The preliminary application ison-line along with informational documents to assist you in completing the application.

preliminary application has been approved following steering committee review, a full application is invited. Thelication can now be submitted on-line and is accessed using the same link to the Application Process page for theary application.

__________________er to ReceiveUpdates

__________________

early notification of PACT-sponsored Web Seminars and Workshops!ww.pactgroup.net and register.

__________________ct PACT__________________

Administrative Center

Person(s): Jamie Winestone or Debbie Wood

: The EMMES Corporation Telephone: 301.251.1611401 North Washington Street Fax: 301.251.1355Suite 700 Email: [email protected], Maryland 20850

: http://www.pactgroup.net/

Apply Now!





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NEWSLETTER VVVooollluuummmeee 444 NNNooo... 111 ––– MMMAAARRRCCCHHH 222000000777 _________________________ PACT Projects _________________________ PACT is in the process of publishing jointly with Charles River on our findings in evaluating the Charles River Laboratories’ Portable Test System (PTSTM) for the rapid detection of endotoxin in cell therapy products. PACT has been involved in establishing and validating shipping conditions for cell therapy products. These data were developed in response to an application submitted to PACT. Plans to publish a paper on our findings are currently underway. _________________________ April 2007 Workshop _________________________ Registration for the April 10-11, 2007 workshop hosted by the University of Minnesota in Minneapolis, MN is now closed. Please visit out website periodically for updates on future workshops. _________________________ Web Seminars _________________________ Educational Updates The interactive shared application feature from the web seminar on “Database Systems” by Darin Sumstad and Jeff Wilson held on October 26, 2006 is now available on the website under Educational Materials - PACT Audio Conferences. Objectives for this web seminar included: developing a database system, elements of a database system, and data capture of information. For more educational advancement and information, please visit the website. July 2007 Web Seminar Our next Educational Web Seminar is scheduled in July 2007. The topic will be on Cell Therapy Standards. Look on our websit e for details in the upcoming months. A web seminar on developing a GMP training curriculum is scheduled for this autumn.

The PACT Group provides education, regulatory and production assistance to the cell therapy community through contract manufacturing of

therapeutic cell products

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NNNEEEWWWSSSLLLEEETTTTTTEEERRR VVVooollluuummmeee 444 NNNooo... 111 ––– MMMAAARRRCCCHHH 222000000777 _________________________ Cell Therapy Forum _________________________ Published in TRANSFUSION 2007;47:520-528. Clinical-Scale Production of Natural Killer Cells for Immunotherapy: A Six Year Single Institutional Experience David H. McKenna, Jr., Darin Sumstad, Nancy Bostrom, Diane M. Kadidlo, Susan Fautsch, Sarah McNearney, Rose DeWaard, Phillip B. McGlave, Danie J. Weisdotf, John E. Wagner, Jeffrey McCullough, and Jeffrey S. Miller BACKGROUND: Natural killer (NK) cells, a subset oflymphocytes and part of the innate immune system, play a crucial role in defense against cancer and viral infection. Herein is a report on the experience of clinical-scale, good manufacturing practices (GMPs)production of NK cells to treat advanced cancer. STUDY DESIGN AND METHODS: Two types of NK cell enrichments were performed on nonmobilized peripheral blood mononuclear cell apheresis collections with a cell selection system (CliniMACS, Miltenyi): CD3 cell depletion to enrich for NK cells and CD3 cell depletion followed by CD56 cell selection to obtain a more pure NK cell product. After overnight incubation with interleukin-2 (IL-2), cells were washed, resuspended in 5 percent human serum albumin, and then released for infusion. RESULTS: A total of 70 NK cell therapy products have been manufactured for patient infusion since 2000. For the CD3 cell–depleted NK cell products, the mean purity, recovery, and viability were 38, 79, and 86 percent, respectively. For the CD3 cell–depleted/ CD56 cell–enriched NK cell products, the mean purity, recovery, and viability were 90, 19, and 85 percent, respectively. Gram stain, sterility, and endotoxin testing were all within acceptable limits for established lot release. Compared to the resting processed cells, IL-2 activation significantly increased the function of cells in cytotoxicity assays. CONCLUSION: Clinical-scale production of NK cells is efficient and can be performed under GMPs. The purified NK cell product results in high NK cell purity with minimal contamination by T cells, monocytes, and B cells, but it requires more time for processing and results in a lower NK cell recovery when compared to NK cell enrichment with CD3 cell depletion alone. Additional laboratory studies and results from clinical trials will identify the best source and type of NK cell product. Supported in part by the National Heart, Lung, and Blood Institute Contract N01-HB-47095 (Production Assistance for Cellular Therapies, or PACT).

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NNNEEEWWWSSSLLLEEETTTTTTEEERRR VVVooollluuummmeee 444 NNNooo... 111 ––– MMMAAARRRCCCHHH 222000000777 _______________________________ Cell Therapy Forum con’t. _______________________________ Published in Journal of Immunotherapy. 30(1): 96-107, January 2007 Abstract Contact-activated Monocytes: Efficient Antigen Presenting Cells for the Stimulation of Antigen-specific T cells Leen, Ann; Ratnayake, Maheshika; Foster, Aaron; Heym, Kenneth; Ahmed, Nabil; Rooney, Cliona M; Gottschalk, Steph en Mature dendritic cells (DCs) are potent antigen presenting cells (APCs) that have been used in vaccine studies and adoptive immunotherapy protocols. For many clinical studies DCs are derived from monocytes in the presence of cytokines, which are expensive and often unavailable for clinical use. Here we describe a cytokine independent method for the differentiation of monocytes into APCs for the reactivation of antigen-specific memory T cells from both healthy donors and cancer patients. Contact activation of monocytes resulted in secretion of proinflammatory cytokines, such as IL-8, and increased cell surface expression of costimulatory molecules. To determine if activated monocytes (actMo) like DC can reactivate antigen-specific CTL, they were transduced with adenoviral vectors encoding the subdominant Epstein Barr virus antigens, latent membrane proteins (LMP) 1 and 2, which are expressed in Epstein Barr virus-positive malignancies. Stimulation of peripheral blood mononuclear cells with LMP1- and LMP2-expressing actMo activated LMP1- and LMP2-specific T cells, which could be further expanded with LMP1 or LMP2 expressing lymphoblastoid cell lines. The use of actMo as APCs simplifies the production/manufacture of antigen-specific T cells for clinical trials. ______________________________ PACT- attended Meetings ______________________________ PACT Joint-Sponsorship March 23-25 2007 – PACT was pleased to be a joint sponsor of the AABB Spring Conference on Cellular Therapy at the San Diego Marriott Hotel and Marina in San Diego, California. Speakers from the PACT facilities presented on PACT-manufactured cell therapy products and initiatives. PACT Presentations May 2007 – PACT members will be presenting at the following meetings: May 18 – 22, 2007 The American Association of Immunologists (AAI) 94th Annual meeting Miami Beach, FL For more information, please visit www.immunology2007.org

May 30 – June 3, 2007 The American Society of Gene Therapy (ASGT) 10th Annual Meeting Seattle, WA For more information, please visit www.asgt.org/am07

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NNNEEEWWWSSSLLLEEETTTTTTEEERRR VVVooollluuummmeee 444 NNNooo... 111 ––– MMMAAARRRCCCHHH 222000000777

_____________________________ How to Apply? _____________________________ Go to www.pactgroup.net and select “Application Process” for more information. The preliminary application is provided on-line along with informational documents to assist you in completing the application. Once a preliminary application has been approved by a steering committee vote, a full application is invited. The full application can now be submitted on-line and is accessed using the same link to the Application Process page for the preliminary application. _____________________________ Products Delivered _____________________________ PACT has been busy this past quarter. We delivered several cell therapy products from four different applications for patient administration. We are continuing to receiv e applications requesting for a variety of products and indications. We are committed to bringing manufacturing requests to completion by providing a quality cell therapy product. ____________________________ Getting the Word Out! ____________________________ We want you to know more about PACT. Look for our ad regarding manufacturing support for cardiac indications in the American Journal of Cardiology March 15, 2007 edition. We periodically post updates in Cell Therapy News (CTN) and on our website. ________________________________________ Register to Receive PACT Updates ________________________________________ Receive early notification of Web Seminars and PACT-Sponsored Workshops! Go to www.pactgroup.net and register.

PACT is accepting applications for contract manufacturing of cell therapy products Apply Now!

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NNNEEEWWWSSSLLLEEETTTTTTEEERRR VVVooollluuummmeee 444 NNNooo... 111 ––– MMMAAARRRCCCHHH 222000000777 ____________________________ Contact PACT ____________________________ PACT Administrative Center Contact Person(s): Jamie Winestone or Debbie Wood Address: The EMMES Corporation Telephone: 301.251.1611

401 North Washington Street Fax: 301.251.1355 Suite 700 Email: mailto:[email protected] Rockville, Maryland 20850




Baylor College of Medicine Contract Number: - N01-HB-37163

The University of Minnesota Contract Number: - N01-HB-37164

The University of Pittsburgh Contract Number: - N01-HB-37165

National Heart Lung and Blood Institute

1

NEWSLETTER VVVooollluuummmeee 333 NNNooo... 444 ––– DDDEEECCCEEEMMMBBBEEERRR 222000000666

_______________________ PACT Projects _______________________ PACT has been involved in evaluating Charles River Laboratories’ Portable Test System (PTSTM) for the rapid detection of endotoxin in cell therapy products. PACT recently presented preliminary data at the September 2006 Annual Somatic Cell Therapy Symposium. Future plans include updates on rapid release testing validation processes at the AABB Spring Conference in March 2007. PACT and Charles River plan to jointly publish our findings of the multi center study, which has performed side by side testing with the PTS and gel and kinetic methods. Another PACT study currently underway involves establishing and validating shipping conditions for cell therapy products. Diane Kadidlo presented the Validation of Natural Killer Cell Activation During Long-Distance Shipping at the October 2006 AABB Annual meeting. These data were developed in response to an application submitted to PACT. The abstract is provided below under Cell Therapy Forum. _________________________ Feb 2007 Web Seminar _________________________ Our next Education Web Seminar is scheduled for Thursday, February 22, 2007. The topic will be Adverse Event Reporting from the patient/clinical and product perspectives. Look for our sponsorship ad in Cell Therapy News as well as our website for details early next year. _________________________ April 2007 Workshop _________________________ Due to the huge success of the April 2006 workshop, PACT will be sponsoring a second Cell Therapy Workshop scheduled for April 2007 at the University of Minnesota in Minneapolis, MN. A tour of the MMCT facility will be given. Updates regarding the workshop will be posted to our website as they are available.

The PACT manufacturing program, funded by the NHLBI, provides investigators with clinical grade cell therapy products. PACT consists of three GTP/GMP facilities, which

offer expertise in the translational development and manufacturing of cell therapy products

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NNNEEEWWWSSSLLLEEETTTTTTEEERRR VVVooollluuummmeee 333 NNNooo... 444 ––– DDDEEECCCEEEMMMBBBEEERRR 222000000666 _________________________ Cell Therapy Forum _________________________ Abstract published in Transfusion Vol.46 Supplement September 2006 Validation of Natural Killer Cell Activation During Long-Distance Shipping D M Kadidlo ([email protected]), N Bostrom, S Adams, S Fautsch, J McCullough, J E Wagner, D H McKenna Jr., University of Minnesota, Minneapolis/Saint Paul, MN Background: Many novel cell therapies must be administered as fresh products. Difficulties may arise when a clinical site is distant from the cell processing facility. Here we describe validation of shipping and in-transit activation of NK cells in preparation for a clinical trial at a distant transplant center. Methods: NK cells were prepared from non-mobilized peripheral blood mononuclear cell (MNC) apheresis collections using the Miltenyi CliniMACS Cell Selection System (CD3+ cell depletion). Cells were incubated in X-VIVO 15, without gentamicin and phenol red (Cambrex BioScience) supplemented with 10% human AB serum (Valley Biomedical) and 1000 U/mL IL-2 (Chiron Corporation) in VueLife Teflon bags (American Fluoroseal Corporation). Temperature stabilizing packs (brought to 33°C) were placed around the product to maintain approximate body temperature within the shipping container. Following round trip flight to Colombus, OH (AirNet), cells were washed and re-suspended prior to QC/lot release testing. Results: Two of three planned validation runs have been completed. Shipping temperatures (at nine hours) were maintained between 29.8°C and 32.0°C (run 1) and 32.4°C and 33.5°C (run 2). Final temperatures (at 15 hours) were 26.9°C (run 1) and 30.9°C (run 2). All lot release criteria were met with the exception of phenotype (run 1); only 18% of the final product was CD3-/CD56+. In this case, however, NK cell content of the starting MNC product was low at 6%. This low value was due to the known variability in starting NK cell numbers among donors and did not preclude successful activation of NK cells in-transit when tested after shipping in cytotoxicity assays (data to be shown). See table for complete lot release results. Conclusions: The need for some novel cell therapies to be infused as fresh products may be a limitation for their use. However, here we have shown that NK cells can be successfully shipped for use at distant clinical centers. This project has been funded in whole or in part by the National Heart, Lung, and Blood Institute, National Institutes of Health, under Contract No.N01-HB-47095 (PACT - Production Assistance for Cellular Therapies).

NK Cell Product Testing

Test Run 1 Run 2 Lot Release Specification

NK Cell Phenotype (% CD3-/CD56+) 17.61 33.42 >20

T (CD3+) Cell Dose (E+05/kg) 0.03 0.87 <5

TNC Dose (E+07/kg) 1.0 3.0 <3

Viability (7-AAD) 97.63 92.49 >70

Gram Stain No organisms seen No organisms seen No organisms seen

Endotoxin (LAL Method) <4.8 EU/kg <2.63 EU/kg <5 EU/kg

Bacterial/Fungal Culture (BacTec) No growth No growth No growth

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NNNEEEWWWSSSLLLEEETTTTTTEEERRR VVVooollluuummmeee 333 NNNooo... 444 ––– DDDEEECCCEEEMMMBBBEEERRR 222000000666 _________________________ Cell Therapy Forum con’t. _________________________ Abstract published in Nature Medicine Volume 12, Number 10 October 2006 Monoculture-derived T lymphocytes specific for multiple viruses expand and produce clinically relevant effects in immunocompromised individuals Ann M Leen1, 2, 8, G Doug Myers1, 2, 8, Uluhan Sili1, M Helen Huls1, Heidi Weiss4, Kathryn S Leung1, 2, George Carrum1, 4, Robert A Krance1, 2, 4, Chung-Che Chang6, Jeffrey J Molldrem7, Adrian P Gee1, 2, 4, Malcolm K Brenner1, 2, 4, Helen E Heslop1, 2, 4, Cliona M Rooney1, 2, 3, 5 & Catherine M Bollard1, 2, 3, 4

Immunocompromised individuals are at high risk for life-threatening diseases, especially those caused by cytomegalovirus (CMV), Epstein-Barr virus (EBV) and adenovirus. Conventional therapeutics are primarily active only against CMV, and resistance is frequent. Adoptive transfer of polyclonal cytotoxic T lymphocytes (CTLs) specific for CMV or EBV seems promising, but it is unclear whether this strategy can be extended to adenovirus, which comprises many serotypes. In addition, the preparation of a specific CTL line for each virus in every eligible individual would be impractical. Here we describe genetic modification of antigen-presenting cell lines to facilitate the production of CD4+ and CD8+ T lymphocytes specific for CMV, EBV and several serotypes of adenovirus from a single cell culture. When administered to immunocompromised individuals, the single T lymphocyte line expands into multiple discrete virus-specific populations that supply clinically measurable antiviral activity. Monoculture-derived multispecific CTL infusion could provide a safe and efficient means to restore virus-specific immunity in the immunocompromised host. 1 Center for Cell and Gene Therapy, Baylor College of Medicine, The Methodist Hospital and Texas Children's Hospital, Houston, Texas 77030, USA. 2 Department of Pediatrics, Baylor College of Medicine, The Methodist Hospital and Texas Children's Hospital, Houston, Texas 77030, USA. 3 Department of Immunology, Baylor College of Medicine, The Methodist Hospital and Texas Children's Hospital, Houston, Texas 77030, USA. 4 Department of Medicine, Baylor College of Medicine, The Methodist Hospital and Texas Children's Hospital, Houston, Texas 77030, USA. 5 Department of Virology, Baylor College of Medicine, The Methodist Hospital and Texas Children's Hospital, Houston, Texas 77030, USA. 6 Department of Pathology, Weill Medical College of Cornell University, TMHRI, The Methodist Hospital, Houston, Texas 77030, USA. 7 Department of Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA. 8 These authors contributed equally to this work. Correspondence should be addressed to Catherine M Bollard [email protected] _____________________________ PACT-Related Meeting _____________________________ Mark your calendars!

March 2007 – PACT is pleased to be a joint sponsor of the AABB Spring Conference on Cellular Therapy at the San Diego Marriott Hotel and Marina in San Diego, California.

March 23 - 25, 2007

For further meeting details, visit www.AABB.org Choose Meetings and Events =>National and Regional Conferences

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NNNEEEWWWSSSLLLEEETTTTTTEEERRR VVVooollluuummmeee 333 NNNooo... 444 ––– DDDEEECCCEEEMMMBBBEEERRR 222000000666

_____________________________ How to Apply? _____________________________ Go to www.pactgroup.net and select “Application Process” for more information. The Preliminary application is provided on-line along with informational documents to assist you in completing the application. _____________________________ FAQs _____________________________ If I don’t have my clinical trial funding in place, can I still submit an application to PACT? Yes, although please note that PACT does not provide funding to conduct clinical trials. You may submit your application to PACT for consideration while you are pursuing funding for your trial, allowing you to complete the PACT process in a timely manner before your start date for the trial. If your full application is approved, a contract will be developed. At that point, the manufacture of your PACT-provided product will be on hold pending demonstration of adequate funds to conduct your clinical trial. What does a proposed product fitting within the NHLBI scope mean? The National, Heart, Lung and Blood Institute is seeking product requests that support scientifically meritorious and innovative clinical research relevant to cardiac, lung and blood cell therapies. The product is required to support clinical trials with cardiac, lung or blood indications. The product itself is not required to originate from the above-mentioned sources. Applications will be reviewed on a case-by-case basis for relevance and scope. __________________________________ Register to Receive PACT Updates __________________________________ Receive early notification of Web Seminars and PACT-Sponsored Workshops! Go to www.pactgroup.net and register.

PACT is accepting applications for contract manufacturing of cell therapy products

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NNNEEEWWWSSSLLLEEETTTTTTEEERRR VVVooollluuummmeee 333 NNNooo... 444 ––– DDDEEECCCEEEMMMBBBEEERRR 222000000666 _________________________ Contact PACT _________________________ PACT Administrative Center Contact Person(s): Jamie Winestone or Debbie Wood Address: The EMMES Corporation Telephone: 301.251.1611





Baylor College of Medicine Contract Number: - N01-HB-37163

The University of Minnesota Contract Number: - N01-HB-37164

The University of Pittsburgh Contract Number: - N01-HB-37165

National Heart Lung and Blood Institute

1

NEWSLETTER

VVVooollluuummmeee 333 NNNooo... 333 ––– SSSEEEPPPTTTEEEMMMBBBEEERRR 222000000666

_________________________ Who Are We? _________________________

TThhee PPAACCTT GGrroouupp pprroovviiddeess eedduuccaatt iioonn,, lleeaaddeerrsshhiipp aanndd pprroodduuccttiioonn aassssiissttaannccee ttoo tthhee ccee llll

tthheerraappyy ccoommmmuunniittyy tthhrroouugghh ccoonnttrraacctt mmaannuuffaaccttuurriinngg ooff tthheerraappeeuuttiicc cceell ll pprroodduuccttss

_________________________ Educational Activity _________________________ PACT-Sponsored Education Web Seminar October 26, 2006 at Noon ET, Duration 1 hour Target Audience: Technologists, Managers/Supervisors In response to requests, the next PACT web seminar will feature Cell Therapy Data Management. This one topic-web seminar will explore the challenges faced as the field matures and facilities need to determine the best way to archive and retrieve relevant data. Speakers from the University of Minnesota and Baylor College of Medicine will present. As always, the web seminar offers real-time presentations and a Q & A session to encourage attendee-speaker interaction. We are pleased to announce that CME Credits will be available for participants through a partnership with AABB.

AABB is an approved, accredited provider (Provider number 0000381) by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. AABB designates this education activity for a maximum of 1 category 1 credits toward the AMA Physicians Recognition Award. Each physician should claim those credits that he/she actually spent in the activity.

The web seminar will be presented at 12:00 Noon Eastern Time on October 26, 2006. Presentation slides will be available to registered attendees for printing prior to the web seminar. For comments or future topic suggestions, email [email protected]. The web seminar is free. For registration and web seminar details, visit www.pactgroup.net.

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NNNEEEWWWSSSLLLEEETTTTTTEEERRR VVVooollluuummmeee 333 NNNooo... 333 ––– SSSEEEPPPTTTEEEMMMBBBEEERRR 222000000666 ___________________________ PACT Meeting Attendance ___________________________ September 2006 - The PACT AC Principal Investigator presented on regulatory aspects of cell therapies at the

Annual Somatic Cell Therapy meeting in Bethesda, MD. October 2006 - Visit our Exhibit Booth (#853) at the AABB Annual Meeting & TXPO at the Miami Beach

Convention Center in Miami, Florida. October 21 through 24, 2006

Go to www.AABB.org for meeting details _____________________________________ Online Application Submittal is Here _____________________________________ We’ve made it easier to submit your preliminary application using our new online system. You can still submit via email, but for the online system, all you need to do is register once, and then enter required items as they become available. When all sections have been completed, click Submit. Go to www.pactgroup.net and choose “Application Process” for more information.

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NNNEEEWWWSSSLLLEEETTTTTTEEERRR VVVooollluuummmeee 333 NNNooo... 333 ––– SSSEEEPPPTTTEEEMMMBBBEEERRR 222000000666 Submitted your Preliminary application? What’s next? Preliminary applications are reviewed by email and teleconference within a few weeks of submission to [email protected]. The PACT Steering Committee has scheduled monthly teleconferences and the dates are provided on the website. Applications should be submitted 2 weeks in advance of the next teleconference date if possible. Once a preliminary application has been accepted by a steering committee vote, a full application is invited. The review process is more detailed including outside reviewers and is then followed by a steering committee vote. Additional questions or clarifications may be generated by this review. The overall process may take 1-2 months depending on the timeliness of responses. If I don’t have my clinical trial funding in place, can I still submit to PACT? Yes, although please note that PACT does not provide funding to conduct clinical trials. You may submit your application to PACT for consideration while you are pursuing funding for your trial, allowing you to complete the PACT process in a timely manner before your start date for the trial. If your full application is approved, a contract will be developed. At that point, the manufacture of your PACT-provided product will be on hold pending demonstration of adequate funds to conduct your clinical trial. The steps are outlined below: Full Approval Process: Ø Receipt of preliminary application from Applicant Ø Evaluation by Steering Committee - Preliminary Approval Ø Submission of full application by Requesting Investigator (Online option is under development) Ø Application review Ø Applications require both Steering Committee and external review Ø An internal liaison will be appointed for communicating any questions to and from the Applicant and

Steering Committee Ø If approved, a Cell Manufacturing Facility will be designated Ø Signing of contract with designated Facility Ø Development of budget and timeline by designated Facility and Applicant Ø Approved by Steering Committee Ø Product manufacturing will begin once final approval of budget and timelines

______________________________________________ PACT Offers More than Manufacturing Support ______________________________________________ The field of Cellular Therapy is still growing. In addition to working with applications from the field, PACT is also looking at general challenges that apply to cell therapy as a whole. Several projects are currently underway to address concerns that cell therapy facilities encounter, such as product shipping, rapid release testing, and equipment validation procedures. _________________________ Register With PACT _________________________ You will receive early notification of Web Seminars and Hands-On Workshops! Go to www.pactgroup.net.

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NNNEEEWWWSSSLLLEEETTTTTTEEERRR VVVooollluuummmeee 333 NNNooo... 333 ––– SSSEEEPPPTTTEEEMMMBBBEEERRR 222000000666 _________________________ Contact PACT _________________________ PACT Administrative Center Contact Person(s): Jamie Winestone or Debbie Wood Address: The EMMES Corporation Telephone: 301.251.1611



The PACT GROUP

The Administrative Center at EMMES Corporation Contract Number: N01-HB-37166

Baylor College of Medicine Contract Number: N01-HB-37163

The University of Minnesota Contract Number: N01-HB-37164

The University of Pittsburgh Contract Number: N01-HB-37165


National Heart Lung and Blood

Institute

NEWSLETTER Volume 3 No. 2 – JUNE 2006 VVoolluummee 33

In preparation for an upcoming pilot clinical trial in patients with HIV-1 infection, a novel dendritic cell (DC)-based vaccine is being manufactured. The trial will test the hypothesis that isolated endogenous virus presented by DC serves as potent immunogen for activation of CD8+ and CD4+ T cells specific for a broad range of autologous HIV-1 antigens. The vaccine production under cGMP conditions involves: 1) autologous virus isolation; 2) superinfection of CD4+ T cells with the isolated virus; 3) preparation of the autologous DC product consisting of: inactivation of the virus in CD4+ T cells, T-cell apoptosis, co-incubation of DC with apoptotic T cells, and vaccine testing and release. To translate the production process to cGMP, endogenous virus was isolated from peripheral blood-derived CD4+ T cells of 3 HIV-1+ subjects by co-incubation with autologous OKT-3-stimulated CD4+ T cells. CD4+ T cell supernatants were tested for p24 levels by ELISA (>25ng/ml) and for TCID50 from 4,642 to 46,416/ml on day 19 of culture in a colorimetric assay with indicator TZM-bl cells. Autologous CD4+ T cells separated on Miltenyi immunobeads (>95% purity) and superinfected with the viral supernatant expressed p24 (28-54%) and had TCID50 of >500/ml on day 5. Virus inactivation with Psoralen (20µg/ml) and UVB (312nm) reduced TCID50 of viral supernatants from 199, 986 to 11 (99%). Apoptotic CD4+ T cells (7-AAD+) were fed to autologous DC generated using ELUTRA and Aastrom System, and flow analysis showed that DC loading was completed in 24h. Based on these translational results and experience with generating DC from HIV-1 patients in a previous clinical trial, the IND for clinical trial was submitted to FDA.

NNoo.. 22 –– JJUUNNEE 22000066 _____________________________ Cellular Therapy Forum _____________________________ Abstracts presented at the 12th Annual ISCT Meeting 4-7 May 2006 Autologous dendritic cell (DC)-based HIV-1 vaccine: Endogenous virus-superinfected apoptotic T cells fed to DC Whiteside TL, Piazza P, Connolly N, Riddler S, Rinaldo C

T Cell Immunotherapy for Adenoviral Infections of Stem Cell Transplant Recipients A.M. Leen, G.D. Myers, U. Sili, M.H. Huls, E. Buza, H. Weiss, A. Gee, K. Leung, G. Carrum, R.A. Krance, M.K. Brenner, C.M. Rooney, H.E. Heslop, and C.M. Bollard. Adenoviruses remain a major cause of mortality and morbidity in hematopoietic stem cell transplant (HSCT) recipients. To date, no effective anti-adenoviral treatment is available, presenting a potential role for adoptive T cell therapy, as an increased risk of infection can be correlated with lack of endogenous T cell immunity. Therefore the goal of this project was to generate adenovirus-specific cytotoxic T lymphocyte (CTL) lines for the prophylaxis and treatment of adenoviral infections post-HSCT. We have identified the hexon protein of adenovirus as providing immunodominant epitopes that are recognized by healthy donors, and hexon-specific T cells are routinely reactivated by stimulation of PBMC with adenovirus vectors in vitro. To test the hypothesis that hexon-specific T cells can provide protection against adenovirus infections in HSCT recipients, we produced adenovirus-specific CTL lines for infusion from the stem cell donors.

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NNNEEEWWWSSSLLLEEETTTTTTEEERRR VVVooollluuummmeee 333 NNNooo... 222 ––– JJJUUUNNNEEE 222000000666 To date we have initated two clinical trials to assess the safety and efficacy of these CTLs in vivo. The first trial involves the administration of EBV- and adenovirus-specific CTLs to CMV-seronegative recipients. We have enrolled 6 patients on the procurement phase of the study and we have generated 5 CTL lines for infusion. Characterization of the CTL lines by cytotoxicity and ELISPOT assay indicates that the lines are bi-virus specific, recognizing both EBV and adenovirus targets. Post-infusion, samples for immune monitoring will be analyzed by tetramer analysis and IFN-γ ELISPOT assays. In addition, extensive virologic monitoring for the presence of EBV and adenovirus pre- and post-infusion will also be performed. The second trial involves the infusion of CMV, EBV and adenovirus-specific CTLs for CMV-seropositive allogeneic transplant recipients. To date, we have treated 9 patients on this protocol. Administration of these tri-virus-specific CTLs has proven safe and we can detect in vivo expansion of individual virus-specific populations in the presence of the respective virus. _______________________ PACT Workshop _______________________ At Baylor College of Medicine - Houston, TX The PACT-Sponsored Two-Day Workshop on the "Design and Operation of GMP Cell Therapy Facilities" hosted at Baylor College of Medicine on April 4-5, 2006 was a huge success. Attendees represented a broad range of laboratory roles, from Laboratory Technologists to Lab Supervisors/Directors, each working in a wide variety of specialty areas such as Donor Recruitment/Testing, Regulatory and Quality Compliance. The workshop offered GMP compliance-related topics, including how to determine adequate environmental monitoring, manage cell product-related databases, properly document activities, and maintain manufacturing records. Participants provided positive feedback regarding the workshop's organization and relevant subject matter. The tours of the Baylor and MD Anderson facilities were well attended and were found to be very useful. Suggestions for future workshops included exploring research and regulatory topics and specialized issues such as cord blood collection. The PACT group came away from the workshop with many good ideas for the next PACT-sponsored workshop, scheduled for spring of 2007. _______________________________________________ PACT Sponsored Education Web Seminar _______________________________________________ July 20, 2006 at Noon ET, Duration 1 hour Target Audience: Technologists, Managers/Supervisors Facility master files, standard operating procedures development, and deviation management systems will be the topics discussed on the next PACT web seminar. These topics are relevant to the process of manufacturing therapeutic cell products as well as the management of a cell therapy manufacturing facility. Speakers from the Universities of Minnesota and Pittsburgh, and Baylor College of Medicine will present these Good Manufacturing Practice topics. The format of the web seminar offers real-time presentations and a Q & A session to encourage attendee-speaker interaction. We are pleased to announce that CME Credits will be available for participants. The web seminar will be presented at 12:00 Noon Eastern Time on the July 20, 2006. Presentation slides will be available to registered attendees for printing prior to the web seminar. For comments or future topic suggestions, email [email protected]. The web seminar is free. For registration and details, go to http://www.pactgroup.net/webinar/webinar.htm.

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_ NEWSLET ER Volume 3 No. 2 – JUNE 2006 NNEEWWSSLLEETTTTTEERR VVoolluummee 33 NNoo.. 22 –– JJUUNNEE 22000066 ____________________________________ Product Manufacturing Requests ____________________________________ An invitation to apply PACT is currently accepting applications for manufacture of clinical or translational cell therapy products. PACT encourages submission of applications from investigators with a funded clinical trial who are seeking support for manufacturing and/or product development. Since PACT is funded by NHLBI, applications should have relevant scope. For more information, visit the Application Process area of our website, www.pactgroup.net. Refer to the figure below for some of the cell product types being manufactured at our PACT facilities. Figure 1. Cell Product Types

Allogeneic NK Cells Dendritic Cells/Tumor Cell

Hybrid Vaccine Hematopoietic Cells: Umbilical

Cord Blood NK Cells

Allogeneic Leukapheresis NK Cells Endothelial Stem Cells Mesenchymal Stem Cells

B95-8 EBV Virus Supernatants Hematopoietic Cells: Bone Marrow Neural Stem Cells

CD34 Selection Hematopoietic Cells: Peripheral Blood

NK Cells Pancreatic Cells

CD4+/CD25+ T Reg Cells Hematopoietic Cells: Peripheral Blood

Derived T Reg Cells Progenitor Cells

CMV (pp65) Specific CTLs Hematopoietic Cells: Umbilical

Cord Blood T Reg Cells Skeletal Myoblast

The turnaround time for the decision on the preliminary application is generally 2-3 weeks. If approved, the applicant will be invited to submit a full clinical or translational application. The review process for the full application is more detailed including outside reviewers as well as steering committee review and vote. The average process time for a decision is approximately 3 months, depending on the timeliness of responses. The PACT group has experience with IND submissions particularly with developing the Chemistry, Manufacturing, and Controls section of INDs. PACT can provide you with the regulatory support you need. PACT is now offering applicants the ability to apply online; visit the official PACT website. For more information on how to apply or access to the online preliminary application, please visit www.pactgroup.net. ____________________ Contact PACT ____________________ PACT Administrative Center Contact Person(s): Jamie Winestone or Debbie Wood Address: The EMMES Corporation Telephone: 301.251.1611



This project has been funded in whole or in part with Federal funds from the NHLBI, NIH under Contract No. N01-HB-37166.

http://www.pactgroup.net/products/products.htm

http://www.pactgroup.net/products/products.htm

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NEWSLETTER VVVooollluuummmeee 333 NNNooo... 111 ––– MMMAAARRRCCCHHH 222000000666 _____________________________ Cellular Therapy Forum _____________________________ Defense Against Malignancy Dr. David McKenna, University of Minnesota Natural killer (NK) cells lyse targets in an MHC-unrestricted fashion, and recognition of self-MHC on cell surfaces by inhibitory NK cell receptors [e.g., killer immunoglobulin-like receptors (KIR)] protect against cytolysis. NK cells are particularly active in the settings of malignancy and viral infection. While cytotoxic T lymphocyte activity is hampered secondary to down-regulation of MHC class I in transformed or infected cells, NK cell activity may increase when MHC is down-regulated or by strategies aimed to avoid interaction with inhibitory KIR. Several studies have demonstrated the importance of NK cells in the defense against malignancy,1-3 and some have indicated the potential utility of NK cells in hematopoietic stem cell (HSC) transplantation.4,5 Researchers have begun to exploit known mechanisms of NK cell function in efforts to augment anti-tumor activity.6 In a study by Ruggeri, et al.,5 none of 20 AML patients receiving haploidentical T cell-depleted HSC grafts experienced relapse when KIR ligand incompatibility in the graft-versus-host direction was present. Additionally, studies in mice4,5 have suggested that the pre-transplant infusion of allo-reactive NK cells may obviate the need for high-intensity conditioning as well as reduce graft-versus-host disease (GVHD). The University of Minnesota team, led by Dr. Jeffrey Miller and Dr. Daniel Weisdorf, has been engaged in NK cell research, including human clinical trials for several years. The latest trial involving NK cells is sponsored by PACT. This trial will test the hypothesis that administration of allogeneic (haploidentical) NK cells in conjunction with an HSC graft from the same donor will be efficacious in the prevention of relapse of disease (high risk myeloid malignancies) and in the reduction of GVHD. Allogeneic NK cells derived from a non-G-CSF stimulated apheresis collection will be infused prior to a non-myeloablative PBSC (CD34+ cell selected) transplant from the same haploidentical donor. The trial is open, and three patients have been enrolled and treated thus far. _____________________ Web Seminar 3 _____________________ Sign up for future events

The education program started off with the web seminar on Jan 19th with excellent response. To get information as early as possible, we encourage interested parties to sign up at the PACT website ahead of time to receive notices regarding upcoming seminars and workshops. Go to www.pactgroup.net and click on sign-up link under Education Sessions.

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NNNEEEWWWSSSLLLEEETTTTTTEEERRR VVVooollluuummmeee 333 NNNooo... 111 ––– MMMAAARRRCCCHHH 222000000666 _______________________________________________________________ ISCT 12th Annual Meeting, 4th - 7th May 2006, Berlin, Germany _______________________________________________________________ Presentation Topics T Cell Immunotherapy for Adenoviral Infections of Stem Cell Transplant Recipients Ann M. Leen Baylor College of Medicine Autologous dendritic cell (DC)-based HIV-1 vaccine: Endogenous virus-superinfected apoptotic T cells fed to DC Theresa L. Whiteside, Paolo Piazza, Nancy Connolly, Sharon Riddler, Charles R. Rinaldo University of Pittsburgh School of Medicine and Graduate School of Public Health ____________________ Contact PACT ____________________ PACT Administrative Center Contact Person(s): Jamie Winestone or Debbie Wood Address: The EMMES Corporation Telephone: 301.251.1611


Website: www.pactgroup.net __________________________ References for article __________________________

1.) Imai K, Matsuyama S, Miyake S, et al. Natural cytotoxic activity of peripheral blood lymphocytes and cancer incidence: an 11-year follow-up study of a general population. Lancet (2000); 356:1795-1799. 2.) Ishigami S, Natsugoe S, Tokuda K, et al. Prognostic value of intratumoral natural killer cells in gastric carcinoma. Cancer (2000); 88:577-583. 3.) Coca S, Perez-Piqueras J, Martinez D, et al. The prognostic significance of intratumoral natural killer cells in patients with colorectal carcinoma. Cancer (1997); 79:2320-2328. 4.) Hirayama M, Genyea C, Brownell A, et al. IL-2-activated murine newborn liver NK cells enhance engraftment of hematopoietic stem cells in MHC-mismatched recipients. Bone Marrow Transplantation (1998); 21:1245-1252. 5.) Ruggeri L, Capanni M, Urbani E, et al. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science (2002); 295:2097-2100. 6.) Koh CY, Blazar BR, George T, et al. Augmentation of antitumor effects by NK cell inhibitory receptor blockade in vitro and in vivo. Blood (2001); 97(10):3132-3137.


NEWSLETTER Vo ume 2 No 2 - DECEMBER 2005 VVoo

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B) The yield of product is one half of that normally obtained by the processing procedure.

lluummee 22 NNoo.. 22 -- DDEECCEEMMBBEERR 22000055 ________________________________________ Web Seminar Education Forum ________________________________________ Biological Product Deviation Reporting Biological Product Deviation under current Good Tissue Practice refers to the transmission of communicable disease from biological products. Deviation from the applicable standards or specifications as well as unexpected events that may relate to the transmission of communicable diseases are defined in 21 CFR1271.3(dd). Familiarizing with the deviation and product codes can be helpful for the reporting. It is important to distinguished between Adverse Event Reporting and Biological Deviation Reporting. Review the presentation on Adverse Event Reporting and Biological Deviation Reporting covered by Deborah Griffin from the University of Pittsburgh PACT facility at http://www.pactgroup.net/education/education.htm. Here are a couple of case study questions for review and discussion. The answers are provided at the end of this newsletter.

1) Which of the following would require a Biological Product Deviation Report?

A) The product is infused without infectious disease test results on the donor. The day after infusion the results are obtained and show a positive test for HTLV I/II.

C) Donor screening for an autologous product reveals that the donor lived in Europe the whole of the year before product collection. The product has been infused.

D) During processing, an incubation step was performed at the wrong temperature. The product met release criteria and was infused.

E) All of the above.

2) You receive an allogeneic marrow from a European NMDP donor, minimal processing goes smoothly,

and the recipient recovers without incident. What action is required by the facility that made the product available for infusion?

A) None

B) An Adverse Reaction Report

C) A Biological Product Deviation Report

D) A report to the Institutional Review Board

E) B & C only

http://www.pactgroup.net/education/education.htm

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_______________________ Web Seminar 3 _______________________ New educational web seminar starts off 2006 With overwhelming responses since the premier of the web seminar, PACT is excited to offer more exciting web seminars. To begin the new year, the first seminar in the series will take place on 19th January. Presentation topics include Rapid Release Testing, Product Transportation and Work Flow Analysis: Handling Multiple Specimens. These topics offer technical discussions and insight to managing a cellular product therapy manufacturing laboratory and handling of cell products for human use more efficiently. Technical and management staff is encouraged to participate in this seminar. Register at the website now! www.pactgroup.net _________________________________________________________ ASH Meeting 10 – 13 December 2005 (Atlanta) _________________________________________________________ Presentation topics Spotlight on Cellular Therapy: Graft Engineering and Clinica Applications Adrian P. Gee, MIBiol, PhD, Baylor College of Medicine, Houston, TX Cellular Processing Techniques for Graft Engineering Ethical and Clinical Controversies in Hematology John E. Wagner, MD, University of Minnesota, Minneapolis, MN Practical and Ethical Issues with Genetic Screening ______________________ Contact PACT ______________________ PACT Administrative Center Contact Person(s): Jamie Winestone or Debbie Wood Address: The EMMES Corporation Telephone: 301.251.1611



__________________________ Answer Key To Quiz __________________________ 1. A 2. A


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PACT NEWSLETTER

VVVooollluuummmeee 222 NNNooo... 111 ——— SSSEEEPPPTTTEEEMMMBBBEEERRR 222000000555 Web Seminar Education Forum CMC writing for IND Applications Report from the July 14th 2005 web seminar Dr. McKenna, from the PACT-University of Minnesota facility presented on the chemistry, manufacturing and controls (CMC) for IND application. Required in section 7 of the IND, the CMC writing is a critical component in the IND submission. Submission must include product manufacturing and characterization, lot release testing, stability information, labeling and tracking. The amount of information submitted may vary with the phase or proposed duration of the study, dosage form, and the amount of information otherwise available. Emphasis in submission should be placed on providing information to allow proper evaluation of subject safety. Sufficient information should be submitted to assure proper identification, quality, purity, and strength of investigational product. If the planned study utilizing cryopreserved product is brief or the cell therapy will be administered as a fresh product, supporting stability testing may be commensurately limited. The complete presentation can be found at the PACT website www.pactgroup.net Product Applications New applications and product list As of September 2005, PACT has evaluated eighteen applications for cell manufacturing ranging from skeletal myoblasts, human dendritic cells, allogeneic natural killer cells and cytotoxic T-lymphocytes. Six applications have received budget and timeline approval and manufacturing or translational development has begun. PACT continues to encourage submission of applications from investigators seeking support for manufacturing and/or product development. Details of application criteria and forms are found on the PACT website. There are a wide variety of cell therapy products PACT is considering for manufacturing: Table of Product List.

Progenitor Cells T-Cell Depletion Donor Leukocytes

Hematopoietic Cells: Bone Marrow, Peripheral Blood, Umbilical Blood, Umbilical

Placenta Cord Blood Bone Marrow/Peripheral Blood Leukocytes Unmodified

Hepatic Progenitor Cells CD34 Selection Alloreactive T-cell depleted

Cardiac Progenitor Cells CD3 Depletion

Multipotent Adult Progenitor Cells CD34+/-CD3-

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PPPAAACCCTTT NNNEEEWWWSSSLLLEEETTTTTTEEERRR VVVooollluuummmeee 222 NNNooo... 111 ——— SSSEEEPPPTTTEEEMMMBBBEEERRR 222000000555

Genetically Modified Cells Lymphocytes Dendritic Cells

Tumor Cells Lymph Node Lymphocytes Tumor Cell Hybrid Vaccine

Fibroblasts Tumor Infiltrating Lymphocytes Peptide

Synviocytes Adenovirus Specific CTLs Apoptotic Tumor Cell

Gene-Modified Tumor Vaccines CMV (pp65) Specific CTLs Tumor Lysate

Gene-Modified Dendritic Cells Antigen (LMP2) Specific CTLs Tumor-DC Hybrids

Gene-Modified CTLs HSV-TK Modified Allogeneic T-cells HIV-1 Peptides

Gene-Modified LCLs CD4/CD25 Regulatory Cells Gene-modified adenovector

______________________ Education Initiative ______________________ Second web seminar A total of 74 attendees, participated in the second web seminar conducted on July 14, 2005. They represented 59 different organizations. The participants completed a survey after the web seminar and the feedback was valuable to PACT in improving future seminars. One commented, ‘I think it would be helpful to cover each aspect of the cGTPs and see how various institutions are implementing them and what issues are practically challenging. For example, now that we have been dealing with the donor eligibility rule for two months, what are some of the problem areas, how are various institutions handling this information, the forms, and etc.’. A third web seminar is anticipated in January 2006. Details of registration will be provided on the PACT website. ________________________ Cell Therapy Survey ________________________ Focus going forward A survey of the cell therapy community was conducted in order to collect information about and recommendations from this group of professionals. The survey was circulated in an issue of Cell Therapy News (March 28, 2005), included in additional issues of Cell Therapy News, a press release, and at PACT’s Educational Web Seminar (March 31, 2005). The survey was designed to collect data on the cell therapy community’s familiarity with and knowledge of PACT, determine the demographics of the cell therapy community, and make an effort to determine how the participants might utilize PACT’s services. The survey demonstrates that there is a need for PACT within the Cell Therapy community to support contracted manufacturing and to provide educational materials to further the field of cellular product development for clinical studies.

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PPPAAACCCTTT NNNEEEWWWSSSLLLEEETTTTTTEEERRR VVVooollluuummmeee 222 NNNooo... 111 ——— SSSEEEPPPTTTEEEMMMBBBEEERRR 222000000555 _______________ Events ________________ PACT will be there

At the AABB annual meeting, Dr. Reed from PACT will be presenting a scientific overview of the PACT program and regulatory specialist Debbie Wood will go through the process of a proposal for an application. PACT representatives Dr. Bollard, Dr. Kiss and Dr. McKenna from the three facilities will discuss methods and protocols that are presently active at the manufacturing sites. Also, look for PACT’s attendance at the ASH Annual Meeting.

Table of Meeting Locations.

________________ Contact PACT ________________ By E-mail, phone or mail PACT Administrative Center Jamie Winestone or Debbie Wood The EMMES Corporation 401 North Washington Street Suite 700 Rockville, Maryland 20850 301.251.1611 Email: [email protected] Internet: www.pactgroup.net

This project has been funded in whole or in part with Federal funds from the NHLBI, NIH under Contract No. NO1-HB37166.

American Society for Hematology 47th Annual Meeting and Exposition December 10-13, 2005 Georgia World Congress Center Atlanta, Georgia

AABB Annual Meeting and TXPO 2005 October 15 – 18, 2005 Washington State Convention and Trade Center Seattle, Washington

PACT Newsletter PACT Newsletter PACT Newsletter PACT Newsletter

December 2004 Volume 1, Number 4

PACT Application Status

As of December 2004, the PACT group has evaluated 12 product applications

and has approved five products for manufacture. All five applications have

received budget and timeline approval and manufacturing/translational

development has begun. PACT continues to encourage submission of

applications from investigators seeking support for manufacturing and/or

product development.

Website Development

Efforts are being made to increase search engine ranking for the PACT website

and enhance the public home page appearance.

Newsletters/Articles

A Letter to the Editor titled “Production assistance for cellular therapies” was

authored by PACT members and published in Transfusion in December 2004.

PACT has recently provided an editorial to the BioProcessing Journal detailing

our initiatives, product application process, and product status to be published

in the journal’s Jan\Feb 2005 issue.

Education Training Committee

The PACT Education Committee is developing training presentations to be

delivered in a web cast format. The committee anticipates conducting its first

web cast during the first quarter of this year. The web casts will be offered at

no charge and are intended for those interested in instituting cGMP and cGTP

guidelines at their facilities. Details about topic content and registration will be

provided on the PACT website as soon as they are made available.

PACT Administrative Center

The EMMES Corporation 401 N. Washington Street – Suite 700 Rockville, MD 20850 Phone: (301) 251-1161 Fax: (301) 251-1355 E-mail: [email protected] We’re on the Web! www.pactgroup.net

Meetings

The Steering Committee met in October 2004 to discuss the progress of the

five recently approved products for manufacturing. Recommendations from

the External Review Panel (ERP) to improve the overall success of PACT were

reviewed and are being implemented.

Members of PACT attended and participated in the December 2004 American

Society of Hematology (ASH) meeting held in San Diego, CA. PACT was given

an opportunity via the NHLBI booth to have materials highlighting its

objectives, services, and accomplishments presented.

The NHLBI attended the American Heart Association (AHA) meeting in

November 2004 and was able to provide AHA members information about

PACT. There are plans for the NHLBI to attend the American College of

Cardiology conference in March 2005 and distribute information about PACT.

PACT representatives are looking forward to attending the May 2005

International Society for Cellular Therapy (ISCT) 11th Annual meeting being

held in Vancouver, British Columbia.

PACT brochures will be made available to all interested parties at these

meetings. You can also request a brochure by contacting us at

[email protected].

PACT Newsletter

October 2004 Volume 1, Number 3 PACT Application Status As of October 2004, the PACT group has approved 4 applications. These four applications have received budget and timeline approval and we are pleased to announce that two products have entered into the manufacturing and reporting phase. PACT is continuing to accept applications with reviews occurring on an ongoing basis and encourages investigators outside of the 3 PACT facilities to apply.

Website Development The Clinical Supply Agreement template has been finalized and can be accessed publicly on the PACT web site by potential applicants. The purpose of this template is to provide a basis for quicker approval of a finalized contract between an approved applicant and the manufacturing facility. Any questions regarding the agreement can be forwarded to [email protected].

Newsletters/Articles/Brochure A brief description of PACT titled “New NHLBI Program for Somatic Cell Manufacturing Funding” was published in the E-Newsletter of the American Society of Hematology” in August.

A color brochure has been printed which describes PACT’s role in process development, product scale-up & manufacturing support of cellular therapies for clinical trials. Contact and web site information is included in the brochure. The brochures will be available at the NHLBI booth during the American Society of Hematology (ASH) meeting in December 2004.

Education Training Committee The first PACT Education Committee teleconference was held in July 2004. A mission statement was developed which describes the group’s goal of providing training to those entering the field of cell processing. Existing educational/training materials are being provided from the three manufacturing facilities in order to establish a central resource database. The course material will focus on cGMP and cGTP, Translational and Clinical issues, QA and Regulatory issues. The committee is researching various interactive presentation software packages in order to deliver effective training. The presentation duration and format will be tailored for different audiences as well.

PACT Administrative Center The EMMES Corporation 401 N. Washington Street – Suite 700 Rockville, MD 20850 Phone: (301) 251-1161 Fax: (301) 51-1355 E-mail: [email protected] We’re on the Web! www.pactgroup.net

Meetings The NHLBI met in September with the External Review Panel (ERP) to discuss the progress that PACT has made over the past year and reviewed new initiatives that the group would like to pursue. The ERP is comprised of five highly experienced scientists representing disciplines supported by the NHLBI, and act as an advisory body for the project. The ERP expressed that PACT has the potential for providing the scientific community with a much-needed resource for advancing the cellular therapy field. The panel acknowledged the crucial need for continuing education and fully supported the idea of an educational training program. NHLBI will continue to meet annually with the ERP and provide the ERP with status reports throughout the year.

PACT Newsletter

July 2004 Volume 1, Number 2 PACT Application Status As of July 2004, the PACT group has received and is in the process of reviewing nine requests to manufacture cell therapy products. The proposed products have been innovative and potentially beneficial to furthering cellular therapy research to the clinical phase. Final approval will be contingent upon an approved budget and timeline. Once approved, contract negotiations, if applicable, will be initiated. Product manufacturing will begin once both parties are in contract accordance. A standard contract template between the designated manufacturing facility and the applicant investigator’s institution has been developed and is undergoing minor modifications before it is implemented.

Website Development Efforts have been made to expand the utility of and the information provided on the web site. The PACT website provides easy public access to the Preliminary Application and guidance documents for filling out the application, PACT facility lists of products that have been produced, links to FDA regulatory guidance information, related organizations, the supporting institution (NHLBI), PACT facility web sites, and the PACT Newsletter.

New Committees An education committee has been created to address training issues.

Newsletters/Articles Since its formation, PACT has had a newsletter article written and published by ISCT in the Winter 2003/2004 edition, an article by the Managing Editor for the AABB Weekly Report in June and a Letter to the Editor for Transfusion Medicine. Another article will soon be published in the ISCT Telegraft. These updates have focused on our mission, product application status, and facility expertise in manufacturing cellular products.

PACT Steering Committee Steering Committee Conference calls continue to occur monthly to solicit the review and approval of product applications and PACT related documents. Working group calls dedicated to PACT policies and procedures continue to be conducted monthly as well.

Each manufacturing facility will provide periodic updates regarding production status to the PACT group. This information will be confidential to the investigator who requested the product.

The second PACT Steering Committee was held on June 7, 2004. Principal Investigators from Baylor College of Medicine, the University of Minnesota, the University of Pittsburgh, the NHLBI, the Steering Committee Chair and Co-chair, the AC, a representative of the Division of Blood Diseases and Resources, as well as other members of the PACT group attended the meeting.

Some of the topics discussed during the meeting were:

♦ Further standardizing the process for reviewing product applications.

♦ Training forum to educate targeted audiences on regulatory and other guidance.

♦ Facility collaboration to increase capabilities and efficiencies.

♦ Establishing priorities, capabilities, budgets, funds available for products and anticipating the number of products that can be supported.

♦ Options for positioning and promoting PACT as a resource in cell therapy.

The next Steering Committee meeting is scheduled for October 29, 2004.


Other Meetings The PACT AC continues to attend meetings to further advance the group’s knowledge on regulatory issues concerning cellular therapies. PACT members attending the May ISCT meeting that was held in Dublin, Ireland distributed an information sheet highlighting PACT initiatives and goals.

In May and June of this year representatives from the AC as well as from PACT manufacturing facilities attended RFA pre-submission meetings on Specialized Centers for Cell-Based Therapy (SCCT) for Heart, Lung, and Blood Diseases and Data and Coordinating Center (DCC). It was an opportunity to provide the attendees with information regarding the PACT mission and objectives. PACT representatives expressed what PACT could offer investigators in terms of manufacturing their cellular products, as well as, providing regulatory support. Investigators were encouraged to apply for support but it was emphasized that PACT would follow it’s standard criteria and approval process. PACT encourages investigators to seek supplemental funding from diversified sources.

PACT Newsletter

April 2004 Volume 1, Number 1

Background/History The ISCT (International Society for Cellular Therapy) Telegraft announced in its Winter 2003/2004 quarterly newsletter, the inception of what is officially titled the PACT (Production Assistance for Cellular Therapies) project. This is a five-year endeavor supported by NHLBI that will focus on further development cellular immune therapies.

On September 30, 2003, The Baylor College of Medicine, the University of Minnesota, and the University of Pittsburgh were each awarded a five-year contract by the National Institutes of Health (NIH), National Heart, Lung and Blood Institute (NHLBI) as designated PACT cell processing facilities for the manufacturing of cellular products. The EMMES Corporation was awarded a five-year contract as the Administrative Coordinating Center for the PACT Project by NHLBI.

The first PACT Group Steering Committee meeting was held on January 7, 2004 in Bethesda, MD.

Representatives from the Baylor College of Medicine, the University of Minnesota, the University of Pittsburgh, NHLBI, The EMMES Corporation, the Steering Committee Chair and Chair-elect attended the January meeting. The meeting opened with a brief summary of the history behind this initiative to support novel somatic cellular therapies. Several items were addressed and timelines for projects were created.

The first quarter 2004 was dedicated to developing the PACT web site, documents pertaining to PACT project goals and expectations, proposal evaluation criteria, and standardizing the preliminary and full application templates, all of which will be utilized for streamlining the application review process. Monthly Steering Committee teleconferences have been held to approve general policies and procedures for the project as well as address the review and approval process for product application requests. Weekly teleconferences with the PACT Working Group have contributed to achieving several goals, which include establishing the on-going communication among the members of the PACT project to review and expedite the approval of critical steps involved in launching this initiative.


Website Development Public access to the PACT website home page was granted on February 12, 2004. The project logo, which incorporates the PACT name, was placed on the PACT website in March. On April 30, 2004, the template for the Preliminary Application (Preliminary Request to Manufacture a Cellular Product) along with information and instruction documents regarding the review process and a table listing the PACT Cell Processing Facilities Products, were approved and will be made available publicly on the PACT website under the Product Requests link. Links to each facility’s website along with NHLBI will be made readily available on the PACT website.

Additional Meetings In March, the Health Scientist Administrator from the NHLBI and the Project Director from the Administrative Center met with the AABB for discussions concerning the PACT project objectives and its potential of being involved in publications and journals related to the AABB.

The Administrative Center also met with the NHLBI repository, BBI Biotech, to tour their facilities and initiate discussions regarding their role in the PACT project.

Representatives from the Administrative Center attended Biological Modifiers Advisory Committee meetings to gain additional knowledge of regulatory and scientific issues related to cell therapies.

The next PACT Steering Committee meeting will be held on June 7, 2004.

Documents

Volume 6 No. 3 – September 2009 The PACT Group continues to … · A poster presentation highlighting the last six years of the PACT project will be on display. The poster will