Research Donor Collections

for Cell-Based Therapies:

How do you Build this into

your Busy Practice?

Michael Linenberger, MD

Medical Director, Apheresis & Cellular Therapy

Cancer Care Alliance/Fred Hutchinson Cancer Research Center/Seattle

ASFA Annual Meeting May 5, 2017

Disclosure Information Michael Linenberger, MD

I have no financial relationships to disclose

Other

• I am a current member of the Hematology Board Exam

Committee of American Board of Internal Medicine (ABIM)

• No exam questions will be disclosed in my presentation

Objectives

• Highlight cell-based therapies derived from

donor/patient MNC(A) & HPC(A) products

• Discuss product quality & potential impact

on manufacturing, potency & performance

• Review the key elements of process

development, operations, administrative

support, clinical management, QA systems,

regulatory oversight & laboratory interface

needed for a successful Apheresis program

Cell-Based Therapies from

MNC(A) or HPC(A) Products

- Chimeric antigen receptor (CAR)

- T cells

- NK cells

- Adoptive T-cells, NK cells

- Dendritic cell vaccines

- Gene-modified HPCs

December 2013

Derived from peripheral blood

Selected – activated – expanded

± Gene-modified

Cancer – Immunity Cycle Mellman I et al. Nature 2011;480:480

Rapid Growth in Clinical Research

www.celltrials.org; celltrials.info (accessed 02/19/2017)

ClinicalTrials.gov (March 2017): 1300 cell-based Immunotherapy trials

Patients as Consumers: A Global

Perspective of “Stem Cell” Therapy

Turner L & Knoepfler P. Cell Stem Cell. 2016;19:154

Apheresis Centers play a large

and ever-increasing role in

providing the “raw materials” for

innovative stem cell treatments

and cell-based immunotherapies

How do we do this?

HPC(A)

Isolate & gene-

modify CD34+

stem cells

Nagree MS et al. World J Stem Cells 2015;7:1233-50

http://www.hu-clinic.com/lp/

MNC(A) Isolate &

manufacture T cells,

NK cells, dendritic

cells

MNC(A) collection

Fesnak AD et al. Nat Rev Cancer 2016;16:566

Levine B et al. Mol Therapy: Methods & Clinic Develop 2017;4:92

PBMNC Manufacture: Open System

Prior Treatments Can Affect Peripheral

Blood T-Cells & Prevent Ex Vivo Expansion

Singh N et al. Sci Transl Med 2016;8(320):320ra3 [U Penn experience with pediatric ALL and NHL]

- PB T-cells are reduced

by disease (NHL > ALL)

- Initial Tx improves cts

- Continued Tx reduces

T-cells again

- Compromised ability to

grow T-cells in “test

expansion” cultures

- Poor success with “test

expansion” of NHL

- Addition of IL-7 + IL-15

to culture improves ex

vivo expansion

Fred Hutch Process Development: T Cell

Subsets Derived from MNC(A) Products

Sommermeyer D et al. Leukemia 2016;30:492

Preclinical studies showed

that CD8+ TN & TCM plus

CD4+ CD19 CAR-T cells

were most proliferative,

potent & persistent in vivo

Normal donors

Patients with

B-cell malignancies

Fred Hutch CAR-T Cell Production

Turtle C et al. Curr Opin Immunol 2012;24:633 http://slideplayer.com/slide/10464756/

BLOOD TRANSFUSION Prof. Dr. Sabri KEMAHLI

Professor of Pediatrics/Hematology

Alfaisal University College of Medicine

Apheresis Separation Chamber Interface

Fesnak AD et al. Transfus Med Rev 2016;30:139

Antibody-bead conjugate selection

CD8+ TCM CD4+ T

Fred Hutch Clinical Studies: Autologous

CD19 CAR-T Cells for Refractory ALL

Turtle C et al. J Clin Invest 2016;126:2123

• All patients collected adequate (selected) T cells, regardless of

circulating ALL blast count or absolute lymph count

• CD4+ & CD8+ TCM subsets selected to manufacture CAR-T cells

• Goal – Infuse a 1:1 ratio of CD4+:CD8+ TCM CAR-T cells

• Blood CD8+ & CD4+ T cell #’s are lower in patients with ALL

CD8+ T cells Patients

■ Healthy

CD4+ T cells

Fred Hutch Clinical Studies: Autologous

CD19 CAR-T Cells for Refractory ALL

Turtle C et al. J Clin Invest 2016;126:2123

Remission rate: 93%

MRD (–) rate: 86%

Mock U et al. Cytotherapy 2016;18:1002

The Future: Automated

Manufacturing in Closed Systems Closed System for:

Activation

Transduction

Expansion

Bring This to Your Busy Practice?

Be prepared

https://managementstudyguide.com/capacity-planning.htm

http://phase2foryou.com/blog/sometimes-it-takes-a-village/

It takes a village

https://www.pinterest.com/explore/registered-nursing-humor/

Maintain a good

sense of humor!

By Keith Simmons, USA TODAY.

Build infra-structure

Build expertise

In-House Protocols

Performance

Sites

Order sets

Billing

Equipment

Nursing/

Staffing

Submit “Concept Sheet” (Research Implementation Office)

Clinical Trial Activity Summary

Protocol / synopsis

Consents

Investigator Brochure

Pricing Request Table

Scientific Review Committee

Institutional Review Office

Clinical Investigator’s Meeting

Contracts & agreements – Legal

Budgets – financing – cost recovery

Protocol Implementation Committee

Clinical

Lab

Clinics

Apheresis

Unit

Pharmacy

Procedure

Suite (CVC)

Cellular

Therapy Lab

Materials

Mgmt

QA/

Document Control

Regulatory

Donor

Mgmt

Courier

Apheresis Roles & Responsibilities

Process Step Staff Member

Responsible

Estimated

Hrs/Week Justifications/Comments

Review protocols sent from

RIO (PIM and CTI) for APH

Involvement

Emily 1-2 APH involvement can be easily determined. CTS

ownership of this step will save RN time.

Review APH service

requests from outside

entities; determine

appropriate regulatory and

legal involvement; initiate

discussions, meetings, etc.

Emily + Lynn TBD

As CTS is currently the pivot-point between APH,

CTL and QA, they remain the most appropriate

party to assume this responsibility.

Review protocols sent from

RIO for PIM/CTI review

meetings

Emily +

Sherry 1-2 ea

CTS can review from an operational perspective,

and APH RN can review from both an operational

and clinical perspective. Questions/comments can

be combined for review at PIM/CTI meetings.

Review draft collection

orders for content, and/or

assist the study

coordinator in developing

paper orders or

Powerplans

Sherry w/

support from Ally

and Emily

1

SME RN preparation of order content, or

assistance in creation of orders, minimizes risk to

patient and study.

SME RN most familiar with protocols,

Review draft collection

orders, ensure they are

complete, in correct

format, and present to

Standard Practice

Committee

Ally with CPOE

Analyst support 2

APH Standard Practice Coordinator reviews final

draft orders, provides oversight of content and

format and presents final draft to SPC . Important

to ensure harmony between protocol orders and

all related documents such as APH SOPS & STPs,

SCCA APOPs and Nursing Policy, SPM Guidelines,

etc. Must also be within Joint Commission, DOH,

FACT, FDA regulations.

Add protocol to APH

Protocol Tracking table

(Sharepoint)

Emily 0.25

Complete pricing request

table, if necessary Emily 0.5

Attend PIM/CTI review

meetings Sherry 1-3

Department representatives at these meetings are

true SME’s, and are able to effectively participate

in discussions and answer clinical and operational

questions. Suggest that APH RN have

Wednesdays dedicated to protocol

implementation, as both PMI and CTI meetings are

scheduled for this day, and APH staff schedule

tends to be inflated for staff meeting attendance.

Process Step Staff Member

Responsible

Estimated

Hrs/Week Justifications/Comments

Follow up with Study

Coordinator on any

remaining

questions/issues

Sherry

+ Emily 1

CTS currently acts as the middle man in these

types of discussions, which is not an efficient use

of anyone’s time. APH RN SME would be the

most effective person to participate in these Q&A

discussions, with CTS input from an operational

perspective.

Determine level of

documentation required

for protocol (Process

Guideline, STP, SOP,

Reports)

Emily +

Sherry 0.25

CTS can consult with APH RN SME when level of

required documentation is not clear.

Develop APH Process

Guideline

Emily w/

Sherry’s support 2-4

If all relevant questions and issues have been

addressed upstream by the APH RN SME,

development of Process Guidelines using the

established template should be relatively easy.

Develop supporting

documentation (STP, SOP,

Reports), if necessary

Sherry w/

Emily’s support 2-4

CTS: usher documents through CTP DC system,

creation of initial draft documents based on

established documents.

APH: Review and fine-tuning of draft documents,

act as SME for approver review

questions/comments and qualification

questions/comments.

Review Process Guideline

and/or supporting

documentation prior to

implementation

Emily +

Sherry 1

With appropriate APH RN SME involvement, this

should serve as a final review, with very few

outstanding questions/issues that require follow-

up prior to implementation.

Train APH staff on Process

Guideline and/or

supporting documentation

Sherry + Emily 0.5-1

Training should be a joint effort. APH RN SME will

be available to answer questions/concerns from

APH RNs and Medical Directors that CTS is not

equipped to answer.

Create study billing labels,

if necessary

Emily

w/ support from

John/Kathy

0.25

These are now filed with the Process Guidelines,

therefore it makes sense that these fall under the

same umbrella of responsibility. Supply can be

maintained by John/Kathy.

Scheduling of

donors/patients John/Kathy 5

Recommend scheduling process be examined to

identify why this is such a burden. CPI project,

perhaps? As scheduling currently falls within the

scope of the APH Program Assistant, this

responsibility should stay with the APH Program

Assistant.

Process Step Staff Member

Responsible

Estimated

Hrs/Week Justifications/Comments

Track scheduling of

patients for specific

protocols

Emily 0.5

Need to fill gaps in knowledge about who is

requesting scheduling for which types of

protocols, and develop a strategy to ensure

appropriate notification.

Ensure all necessary

requirements for APH

research

donors/patients have

been met prior to

collection, and that all

requisite documentation

has been completed.

This includes: donor

screening & evaluation,

virology testing, and CBC

levels.

Sherry 1-2

A dedicated RN will be aware of which

patients are scheduled for which protocols,

as well as the requirements of each protocol.

It has been suggested that CTS take on this

role, but it would be more efficient for

someone who works in APH to have this

responsibility. Additionally, the APH RN SME

would possess the clinical and operational

knowledge to ensure all requirements have

been met and clinical considerations are

acceptable.

Review Process

Guideline and/or

supporting

documentation with RN

prior to collection

Emily w/

Sherry’s support 1

APH RN SME support will ensure any

outstanding clinical or operational

issues/questions will be appropriately

addressed.

Review protocols sent

from RIO (PIM & CRS) for

Apheresis involvement

Review draft collection

orders for content &

develop Powerplans

Complete pricing

request table

Determine level of

documentation (SOPs,

STPs, support docs) Scheduling &

tracking of

donors/patients

Apheresis Training:

Procedure; billing;

documentation;

labeling; shipping

? Validation runs ?

Develop Protocol

Implementation Checklist:

Screening, evaluation,

testing, pharmacy, billing

Create Process

Guidelines 19 Steps!

Training & Proficiency for Apheresis Staff

Celluzzi C et al.

HPC(A) Competency Assessment Frequency

P

erc

ent

of re

sponses p

er

cate

gory

Not

performed

at all

Performed

but not

specified

Every 2

years

Yearly Every 6

months

As

needed

https://www.saftpak.com/stppack/ProductDetail.aspx?ID=459

Labeling, packing, shipping, tracking

http://www.sensitech.com/en/

17 Steps!

Protocol Implementation Checklist

Review protocol for

Protocol Implementation

Meeting (PIM) – review draft

orders & Powerplans

Communicate

common Apheresis

concerns to PI

Determine level of docu-

mentation required – STPs,

Process Guideline, reports,

labels, study billing stickers

Draft: - Process Guideline

- Protocol fact sheet

- Study synopsis

- Flow analysis

- Copies of orders

Attend PIM & Clinical

Research Support

meetings

Determine level of

support needed from IDS

Pharmacy & study billing

Apheresis/Collection Flow Diagrams

20 Steps!

Apheresis Process Guideline

Standard Treatment Plans

Orders & Powerplans

Product: Clinical vs non-clinical

Patient / donor Info (paid, volunteer)

Product labels Chart / Cover Sheet

Evaluation of Donor / Patient

- Research Coordinator screen

- Donor Health Questionnaire

- Donor eligibility determination

- H & P; suitability; consenting

- Vein / line assessment

- Labs tests, timing, by whom

Collection Guidelines

- Standard vs special protocol

- Collection goal / parameters

- Pre- & post-collection labs

- Research lab samples/requisitions

Collection Reports / Forms

- Apheresis Procedure flow sheet

- Product Tracking Invoice

- Laboratory requisitions

- Summary of Rrecords

- Supplies Form; Billing Form

Disposition: Courier or Study Coordinator

Allo

HPC

Allo

MNC

Auto

HPC

Auto

MNC

Clinical MNC

(Feeder Cells)

Non-Clinical

HPC

Non-Clinical

MNC

Orders Min 24 hrs prior to

collection.

Min 24 hrs prior to

collection.

Min 24 hrs prior to

collection.

Written by outside

physician – requires

APH MD/D

review/approval.

Min 24 hrs prior to

collection.

Written by outside

physician – requires

APH MD/D

review/approval.

Min 24 hrs prior to

collection.

Min 24 hrs prior to

collection.

Min 24 hrs prior to

collection.

Consent CST055, “Special Consent for Procedural Treatment – Collection of Peripheral Blood Hematopoietic Progenitor Cells or Mononuclear Cells – required for all

H&P 30 calendar days 30 calendar days 30 calendar days 30 calendar days w/in 15 calendar day 15 calendar days N/A?

Updated

H&P 5 working days 5 working days

5 working days.

Outside patients

require REP085, and

must be approved

by APH MD/D

5 working days.

Outside patients

require REP085, and

must be approved

by APH MD/D

N/A 5 working days

N/A

IDM 30 calendar days 7 calendar days 30 calendar days* 7 calendar days w/in 7 calendar days

(day of draw is d1)

If ordered, 30

calendar days

If ordered, 30

calendar days

DHQ 30 calendar days 7 calendar days N/A N/A URD DHQ (REP315)

7 calendar days

30 calendar days

(REP122)

30 calendar days

(REP122)

CBC w/ in 24 hours of

collection

w/ in 24 hours of

collection

w/ in 24 hours of

collection

w/ in 24 hours of

collection

15 calendar days

(will be used as

baseline for

procedure)

30 calendar days

30 calendar days

(if w/in 15 days, also

counts as baseline

for procedure)

ABO Every day of

collection

Every day of

collection

Every day of

collection

Every day of

collection

Every day of

collection N/A N/A

Pregnancy

w/ in 7 calendar

days of collection

(prior to start of

recipient

conditioning)

w/ in 7 calendar

days of collection

(prior to start of

recipient

conditioning)

w/ in 7 calendar

days of collection

(prior to start of

conditioning)

N/A N/A w/ in 7 calendar

days N/A

Screening, Scheduling, Timelines

Immune Effector Cells: Cells used to

modulate, elicit, or mitigate an immune response

for therapeutic intent (dendritic, NK, T or B cells)

Clinical Standards, Process

and Product Control

Maus M & Nikiforow S. J Immunother Cancer 2017;5:36

Transfus Med 2015;25:57-78

Patient/Donor Care: UK Guidelines

Product Manufacturing: Near vs Far

Commercial manufacturing – Clinic & Mfg. physically separate

Schedule according to

manufacturing site

capabilities no storage

Order/prescription

(100s of sites)

< hours

< 1 day

Schedule patient

when finished

Schedule patient

when finished

(100s of sites)

< 1 day

< hours

Same Academic Center – Close interaction possible

Adapted from: Levine B et al. Mol Therapy: Methods & Clinic Dev 2017;4:92

MNC(A) Quality & Post-

Collection Processing:

Performance & Potency

• Separation/isolation methods

must be validated for products

• Products may need to be

collected in ACDA (no heparin)

&/or have additional plasma

• Target cell isolation may be

compromised by clumping from

PMNs (DNA slime), platelets,

monocytes, plasma proteins

• RBCs &/or platelets may interfere

with flow cytometry (Hct ≤ 2%)

• Cells/solute can affect expansion

or effector cell function Fesnak AD et al. Transfus Med Rev 2016;30:139

Commercial manufacturing – Clinic & Mfg. physically separate

Schedule according to

manufacturing site

capabilities no storage

Order/prescription

(100s of sites)

< hours

< 1 day

Schedule patient

when finished

Schedule patient

when finished

(100s of sites)

< 1 day

< hours

Same Academic Center – Close interaction possible

Adapted from: Levine B et al. Mol Therapy: Methods & Clinic Dev 2017;4:92

Important Considerations (Christine Fernandez, RN, MSN/Ed, OCN)

(1) Ideally: Company has apheresis experience (“they don’t know what they don’t know”);

understands FACT; provides feedback to Apheresis on product quality & efficiency

(2) Apheresis: Be proactive about rationale, details, training/roles & goals of protocol details

(3) Understand impact of dx & condition on mfg – GET FEEDBACK on product yield/quality

Details in “Apheresis Manual”

Ready to Collect!

Take-Home Messages

Project Management

https://managementstudyguide.com/capacity-planning.htm

http://phase2foryou.com/blog/sometimes-it-takes-a-village/

Organizational

Commitment

By Keith Simmons, USA TODAY.

Flexibility & collaboration

Seamless communication

Schoolfeed.classmates.com/

Maintain a good

sense of humor!

Summary

• Cell-based therapies derived from HPC(A) &

MNC(A) are rapidly advancing toward approval

for selected malignant & hereditary diseases

• Special collection techniques & product

parameters may be required to optimize mfg.

of immune effector & engineered stem cells

• Apheresis operational support for cell-based

therapies requires dedicated resources, infra-

structure & institutional/industry collaboration

Acknowledgments

• Laura Connelly-Smith, MBBCh, DM

• Michelle Flores, RN

• Lindsay Palomino, BSN RN HP

• Emily Johnson

• Jennifer Adrian

• Christine Fernandez, RN, MSN/Ed, OCN