Old problems, new directions - Home - ESMO - European Society for

Old problems, new directionsEli Gilboa

ESMO International Symposium on ImmunologyNov 15-17, 2007Athens, Greece

Cancer immunotherapy with mRNA transfected dendritic cellsA personalized form of cell therapy

IL-1IL-1, IL-6, TNF-, IL-6, TNF-, PGE, PGE22

Antigen-LoadedAntigen-LoadedMature DCMature DC

DC maturationDC maturation

CryopreservedCryopreservedDC VaccineDC Vaccine

LeukapheresisLeukapheresis

Immature Immature DCDC MonocyteMonocyte

ss

GM-CSF, IL-4GM-CSF, IL-4

Tumor Tumor BiopsyBiopsy

Tumor antigensTumor antigens(mRNA)(mRNA)

Antigen LoadingAntigen Loading(mRNA transfection)(mRNA transfection)

The underlying premise of developing patient-specific vaccination protocols

Added complexity and cost associated with such interventions will be offset by a substantial added benefit to the patient.

Clinical benefit is minimal, if any.

“Promising” vaccination strategies

• DNA vaccines

• Poxvirus vector-based vaccines

• GM-CSF transduced tumor vaccines

• Idiotype + GM-CSF

• gp96-secreting tumor vaccines

• Dendritic cell vaccines

• Listeria vector-based vaccines

Preclinical murine studies- Antitumor effects in murine models- No toxicity

Clinical trials- Immune responses- Hints of clinical impact



• DNA vaccines






• Listeria vector-based vaccines• NDV-infected autologous tumor vaccines (Schirrmacher & colleagues)



Immunological control of cancer

Where are we going from here



• DNA vaccines






• Listeria vector-based vaccines• NDV-infected autologous tumor vaccines (Schirrmacher & colleagues)



Specific Active Immunotherapy of Cancer

Cancer Vaccines

To engender protective immunity in the cancer patientthat will negatively impact on tumor progression.

Induction of immunity

Persistence of immunity

+Immune suppression

Immune escape

A multi pronged approach to cancer immunotherapy



+Immune suppression

Immune escape


Why is a tumor growing in an immune competent patient not eliminated by an immune response?

Lack of immunogenicity

The immune system is not activatedin response to the growing tumor - “tumor is not sufficiently distinct from normal tissue”




Immune suppression

Tumors activate mechanisms which suppress the differentiation and/or function of an otherwise effective antitumor response

+




Immune suppression


+




Immune suppression


+

Tumor-induced immune suppression

Immune suppressiveCell types

Immune suppressiveproducts

Regulatory T cellsIL-13 secreting NKT cellsImmature myeloid cells (ImC)Tolergenic DC (“iDC”, pDC)“Alternatively activated” M (AAMs)…and other

Cox-2 generated prostanoidsB7H1TGFIL-10Decoy receptor 3 (DcR3)STAT3cAMPAdenosineVEGFIndoleamine deoxygenase (IDO)…and more

...and more evidence

• Immune mediated tumor rejection in the absence of vaccination, e.g., blocking TGF signaling in T cells (Gorelik & Flavell, Nat. Med. 2001, 7:1118)

• Tumor induced immune suppression, not lack of inherent immunogenicity, the main reason for tumor outgowth - in a highly relevant spontaneous tumor model where tumors are heterogenous, multifocal exhibiting different biologies. (G. Willimsky & T. Blankenstein. Nature, 2005, 437, 141-146 )

• Vigorous premalignancy-specific effector T cell response in the bone marrow of patients with monoclonal gammopathy. Dhodapkar et al., Exp Med, 2003, 198:1753

• Inverse correlation between tumor progression in ovarian and colorectal cancer patients and immune infiltrate (Zhang et al., N. Engl. J. Med., 2003, 348:203; Galon et al., Science, 2006, 313:1960)

• Immune-mediated control of subclinical cancer in murine models (Schreiber, Smyth and colleagues, CRI meeting, Manhattan, NYC, October 2006)

• Inherent immunogenicity of human cancer – Frequent induction of immune responses which are occasionally associated with better prognosis but ultimately fail to reverse disease course (reviewed by Hodi & Dranoff, Adv. Immunol., 2006, 90:341)

Cancer despite immunosurveillance: immunoselection and immunosubversion. Zitvogel, L., Tesniere, A. and G. Kroemer. Can. Rev., Immunol., 2006, 6:715

“The seventh hallmark of cancer”




Regulatory T cellsIL-13 secreting NKT cellsImmature myeloid cells (ImC)Tolergenic DC (“iDC”, pDC)“Alternatively activated” M (AAMs)…and other

Cox-2 generated prostanoidsB7H1TGFIL-10Decoy receptor 3 (DcR3)STAT3cAMPAdenosineVEGFIndoleamine deoxygenase (IDO)…and more

Naturally occuring CD4+CD25+ regulatory T cells

• A distinct lineage of thymic origin, comprise 3-10% of the CD4+ T cell population

• Immune suppressive - inhibit CD4+ & CD8+ T cell responses

• Function - Preventing autoimmunity by keeping autoreactive T cells in

check.

• Depletion of Treg in mice with CD25 antibodies:

– Induces or exacerbates autoimmune pathology

– Potentiates tumor immunity, especially in conjunction with vaccination.

Elimination of TElimination of Tregreg using a diphteria toxin-IL-2 conjugate (ONTAK using a diphteria toxin-IL-2 conjugate (ONTAK®®) in ) in

RCC patients vaccinated with tumor RNA transfected DCRCC patients vaccinated with tumor RNA transfected DC

Follow-up

Treatment Phase Follow-upPost-Surgery

Week 2 Week 6Week 0Week -4

ONTAKØ +RCC RNA loaded DC

RCC RNA loaded DC

Nephrectomy

EligibilityAssessment

Dosing Schedule: 3 cycles of 1x107 cells i.d per cycle

Leu

kaph

eres

is

InformedConsent

Leu

kaph

eres

is

RA

ND

OM

IZE

750

500

250

0IFN

/105

CD

8+ T

cel

ls

ONTAK® - +n=4 n=6

p=0.019

Dannull et al., J. Clin. Invest., 2005, 115:3623

A. RCC RNA + ONTAK®

B. RCC RNA

3737

RCC PBMCRCC PBMCPBMCRCC PBMCPBMCRCC PBMCPBMC0

250

500

750

1000

RCC RERCC RERERCC RERERCC RERE

0202 --RCCRCC --DABDAB0101 --RCCRCC --DABDAB

597597

7272

900900

64646565

RCC PBMC

0404 --RCCRCC --DABDAB

RCC PBMC


RCC PBMC


480480 501501

3535

280280

IFN

/10

5 C

D8+

T c

ells

1515

RCCRCC PBMC RCC PBMC RCC PBMC RCC PBMC

0808 --RCCRCC 0909 --RCCRCC 1010 --RCCRCC 1111 --RCCRCC

4040 56569797

3030

286286

38387979

IFN

/10

5 C

D8+

T c

ells

0

250

500

750

1000

Limitation to targeting CD25 for Treg depletion

• CD25, a component of the IL-2 receptor complex, is also upregulated on conventional activated (vaccine-induced) T cells.

1. Treg rebound with time

2. The tumor and the vaccination itself can generate Treg

3. Interfere with an ongoing protective immune response against subclinical levels of pathogenic infection

• A significant fraction of Treg (10-30%), especially recently activated Treg, have downregulated CD25.

• Depletion is global - risk of autoimmune pathology

• CD25 depletion constitutes an additional intervention and a reagent not always readily available for clinical testing.

Other Treg-specific markers

GITR, Lag-3, CTLA-4, CD103 - expressed on the cell surface but, like CD25, not specific.

Foxp3• Member of the forkhead/wing-helix family of transcription factor repressors• Expression exclusively restricted to Treg• Master regulator of suppressive phenotype• CD4+CD25+foxp3 as well as CD4+CD25-foxp3 Treg.

Stimulate a CD8+ CTL response against foxp3

Foxp3 is a nuclear protein - cannot use antibodies or ONTAK®-like reagents for depletion of foxp3 expressing cells in vivo

No additional procedure: Co-vaccination against tumor antigen and foxp3

Foxp3 is expressed in the thymus

1. Thymocytes destined to become TregFontenot, J.D et al. 2003. Nat Immunol 4:330-336

2. Thymic stromaChang, X. et al., 2005, J Exp Med 202:1141-1151

Immunization (1x) against Foxp3 enhances antitumor immunity in B16 melanoma tumor-bearing mice

d3d0

Tumor

Treg

Vaccination

(TRP-2)

Impact on tumor growth

ActinFoxp3

TRP-2 + Foxp3TRP-2

Days to tumor onset

Tum

or f

ree

mic

e (%

)

0

10

20

30

40

50

60

70

80

90

100

10 15 20 25 30 35 40

Foxp3 vaccination

Tum

or f

ree

mic

e (%

)

Days to tumor onset

0

10

20

30

40

50

60

70

80

90

100

10 15 20 25 30 35 40

ActinCD25

TRP-2 + CD25TRP-2

CD25 depletion

Repeated depletion of Treg subsequent to tumor vaccinationFoxp3 immunotherapy versus CD25 Ab depletion

Days to tumor onset

0

10

20

30

40

50

60

70

80

90

100

12 16 20 24 28 32 36 40

Actin + CD25TRP-2 + CD25TRP-2 + CD25, CD25

Tu

mor

fre

e m

ice

(%)

0

10

20

30

40

50

60

70

80

90

100

12 16 20 24 28 32 36 40

Actin + Foxp3TRP-2 + Foxp3TRP-2 + Foxp3, Foxp3

Tu

mor

fre

e m

ice

(%)

Days to tumor onset

d10d3d0

Tumor

Treg (1X)

Vaccination

Treg (2X)

Impact on tumor growth

1week

1.32%0.40%

0.46%

0.62% 0.30%

0.12%

TRP-2

TRP-2 +

CD25 Ab

TRP-2 + Foxp3

Sid

e S

catt

er

Foxp3 CD4 CD8

Sid

e S

catt

erS

ide

Sca

tter 0.29%

0.05%

0.07%

TRP-2TRP-2 + CD25 Ab TRP-2 + Foxp3

Rat

io o

f %

pos

itiv

e ce

lls

0

2

4

6

8

10

CD4+Foxp3-/Foxp3+ CD8+/Foxp3+

Treg depletion enhances the ratio of conventionalTcells/Treg in the tumor

Fate of foxp3-expressing cells in mice vaccinated against foxp3 or treated with CD25 Ab

Tumor

CD

25

Side

Sca

tter 2.8% 1.1%

CD

25

Side

Sca

tter 0.2% 0.06%

2.6% 1.1%

0.9%

CD

25

Side

Sca

tter

2.7% 0.5%

1.3%

CD

25

Side

Sca

tter

Foxp3 CD4 Foxp3 CD4

TRP-2

TRP-2 + CD25 Ab

TRP-2

TRP-2 + Foxp3Si

de S

catt

erSi

de S

catt

erSi

de S

catt

erSi

de S

catt

er

CD

25C

D25

CD

25C

D25

Foxp3 CD4 Foxp3 CD4

4.1%

1.8%

3.2%

3.3%

2.5%

1.2%

2.4%

2.2%

A. CD25

B. Foxp3

Lymph node Spleen

Nair et al. Can. Res., 2007, 67:371

Fate of foxp3-expressing cells in mice vaccinated against foxp3 or treated with CD25 Ab

Periphery

Shift emphasis from inducing immunity to developing methods targeting tumor-induced immune suppression




Immune suppression


+




Regulatory T cellsIL-13 secreting NKT cellsMyeloid derived suppressor cells (MDSC)Tolergenic DC (“iDC”, pDC)“Alternatively activated” M (AAMs)…and other

Cox-2 generated prostanoidsB7H1TGFIL-10Decoy receptor 3 (DcR3)VEGFSTAT3cAMPAdenosineIndoleamine deoxygenase (IDO)…and more

???



+Immune suppression

Immune escape


TCR attenuation

Costimulation

4-1BB

• Upregulated on antigen-activated T cells

• Enhances survival and proliferation of activated CD8+ T cells

Costimulatory receptors on T cells

• CD28• CD27• OX40• 4-1BB• CTLA-4• PD-1• HVEM• CD30

Agonistic 4-1BB antibodies enhance proliferation of activated CD8+ T cells and potentiate tumor immunity in mice

1. Complexity & cost of development

2. Regulatory approval process

3. Cost of manufacturing

4. Limited & uncertain access (companies)

Limitations to use of antibodies (or protein-based ligands) as therapeutic reagents

Melero, I., W.W. Shuford, S.A. Newby, A. Aruffo, J.A. Ledbetter, K.E. Hellstrom, R.S. Mittler, and L. Chen. 1997, Nat Med 3:682-685.

Antibodies are cell based products

Antibody combinations - synergistic antitumor effectsMurine studies

Antibodies Reference

4-1BB + CTLA-4 Kocak, et al., 2006, Cancer Res 66:727644-1BB + OX40 Lee et al., 2004, J. Immunol., 173:30024-1BB + B7H1 Hirano et al., Can. Res., 2005, 65:10894-1BB + CD40 + DR5 Uno et al., Nat. Med., 2006, 12:693




QuickTime™ and aTIFF (Uncompressed) decompressor

are needed to see this picture.

Eradication of established 4T1 breast carcinoma tumors in mice by combination therapy with DR5+CD40+CD137

*Uno et al., Nat. Med., 2006, 12:693




In vitro selection of oligonucleotide aptamers

An Aptamer Library = A Vast Shape Library

Aptamer Library

AGGACGAUGCGGNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNCAGACGACUCGC

440 possible sequences

In vitro selection (SELEX)

40 nucleotide random region

Advantages of aptamers vs antibodies as therapeutics

• Specificity & avidity comparable or better than antibodies • Synthesized chemically; they are not cell-based products.

– Vastly simpler regulatory approval process– Development & manufacturing - cost effective

• Superior pharmacology - tumor penetration• Lack of immunogenicity• Amenable to chemical modification

Aptamers can be made to most any target

Target Protein Affinity(Kd) Function Ref.

PDGF 0.1nM Inhibitor Green et al., 1996P-Selectin 0.03nM Inhibitor Jenison et al., 1998Complement C5 0.03nM Inhibitor Biesecker et al., 1999MAb to AChR 60nM Inhibitor Lee and Sullenger, 1997Interferon-Gamma 2.7nM Inhibitor Kubik et al., 1997VEGF 0.15 Inhibitor Ruckman et al., 1998Factor VIIa 11nM Inhibitor Rusconi et al., 2000mCTLA-4 30nM Inhibitor Santulli-Marotto, et al. 2003

0.0 0.5 1.0 1.5 2.0 2.5 3.00.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7Round 12 PoolRNA Library

Fra

ctio

n R

NA

Bou

nd

Log([4-1BB-Fc](nM))

M12-2(722): 5'-CGACCGAACGUGCCCUUCAAAGCCGUUCACUAACCAGUGC-3'M12-3(722): 5'-CGACCGAACGUGCCCUUCAAAGCCGUUCACUAACCAGUGG-3'M12-5(722): 5'-CGACCGAACGUGCCCUUCAAAGCCGUUCACUAACCAGUGG-3'M12-8(722): 5'-CGACCGAACGUGCCCUUCAAAGCCGUUCACUAACCAGUGG-3'M12-11(819): 5'-CGACCGAACGUGCCCUUCAAAGCCGUUCACUAACCAGUGG-3'

*M12-23(819): 5'-CGACCGAACGUGCCCUUCAAAGCCGUUCACUAACCAGUGG-3'M12-2(923): 5'-CGACCGAACGUGCCCUUCAAAGCCGUUCACUAACCAGUGA-3'M12-12(923): 5'-CGACCGAACGUGCCCUUCAAAGCCGUUCACUAACCAGUGG-3'M12-18(923): 5'-CGACCGAACGUGCCCUUCAAAGCCGUUCACUAACCAGUGA-3'M12-33(923): 5'-CGACCGAACGUGCCCUUCAAAGCCGUUCACUAACCAGUGG-3'

M12-17(923): 5'-GAAGUGACAGCUCCCAGCGCUUCAAAGCUCAUCUAUAACU-3'M12-23(923): 5'-CAGAAACUAGACCUCCGAUCGGACACCCGGUCCCUUCGUC-3'M12-24(923): 5'-GAAGCACAAUAGGCCGCAACACUUCAAAACCCAUUCAAUC-3'

*M12-9(722): 5'-CAAGCACUCUUCAGGCUAAGGACUCUCUUGACACCCCGC-3'

*M12-12(722): 5'-GCACAGCAACACCACGACCCCCCCUAGGCUUCCGCCCGCC-3'M12-25(819): 5'-GCACAGCAACACCACGACCCCCCCUAGGCUUCCGCCCGCG-3'M12-5(923): 5'-GCACAGCAACACCACGACCCCCCCUAGGCUUCCGCCCGCA-3'M12-7(923): 5'-GCACAGCAACACCACGACCCCCCCUAGGCUUCCGCCCGCG-3'

*M12-22(819): 5'- GCACAGCAACACCACGACCCCCCCUAGGCUUCCGCCCGCG-3'

M12-1(722): 5'-UAACGGCCCAAUGACUUCGCCUUACUGCCCCCCUAAGCUUC-3'M12-7(722): 5'-AAAGCGACAAUUCUUACUACUCCCCAAGCUCCACGCCUUU-3'M12-15(819): 5'-AAGACGAUACCUAGCCUCAAAAUUCCUCCCCCGACUUCCU-3'

*M12-9.3(819): 5'- CGAGAACCCGCAUCUUCGGAUGCGCCCCCCUAGGACUUAC-3'

*M12-20.1(819): 5'-GACCAAGGGCAGCAUCACCGUUCCCCCCCUAGGAGCUUAC-3'

*M12-20.3(819): 5'-UAACGGCCCAAUGACUUCGCCUUCUGCCCCCCUAAGCUUC-3'

M12-1(923): 5'-CGCUCUCUCACAACCACGACCUCCGAUCUGAUAAUUCGUC-3'M12-16(923): 5'-CGCUCUCUCACAACCACGACCUCCGAUCUGAUAAUUCGUC-3'

*M12-3(819): 5'-GCACCAAACACCGGUUCAGAACCCAUCAUGUAACUCCUUG-3'

*M12-5(819): 5'-AACUACCUCCUCGAACCAUAGUUCAACACCAUCCAGCCAU-3'

Isolation of aptamers which bind to murine 4-1BB in solution

Isolate CD8+ T cells from BALB/C mice.

Incubate o/n with sub-optimal concentration of anti-CD3.

Add anti-4-1BB antibody or aptamers coupled to beads.

Proliferation assay 48 hrs later (CFSE dilution)and/or

IFN release

4-1BB in vitro costimulation assay

Enhancement of proliferation or IFN release from suboptimally activated CD8+ T cells

4-1BB signaling requires ligand-induced receptor dimerization

+

MAb

+

Sequence and computer-predicted secondary structure of a 4-1BB binding aptamer

M12-23

mutM12-23

mutM12-23-A + mutM12-23-B

M12-23-A + M12-23-B

100b

p L

adde

r

M12

-23-

A +

M12

-23-

B

M12

-23-

A

M12

-23-

B

mut

M12

-23-

A +

mut

M12

-23-

B

mut

M12

-23-

A

mut

M12

-23-

B

Dimer

Monomer

Generating aptamer dimers using complementary 3’ extensions

Stimulated (CD3)

Unstimulated

Competition

4-1BB Ab-AF488

100

80

60

40

0

20

Cou

nts

100 101 102 103 104

a

M12-23 dimer-FAM100 101 102 103 104

100

80

60

40

0

20

Cou

nts

b

mutM12-23 dimer-FAM100 101 102 103 104

100

80

60

40

0

20

Cou

nts

c

M12-23 dimer-FAM +Isotype Ab

100

80

60

40

0

20

Cou

nts

100 101 102 103 104

d

M12-23 dimer-FAM +4-1BB Ab

100

80

60

40

0

20

Cou

nts

100 101 102 103 104

e

4-1BB Ab-AF488100 101 102 103 104

100

80

60

40

0

20

Cou

nts

f

M12-23 dimer-FAM100 101 102 103 104

100

80

60

40

0

20

Cou

nts

g

4-1BB aptamer dimer binds specifically to activated CD8+ T cells

Binding of monomeric and dimeric forms of 4-1BB aptamers to 4-1BB expressed on the cell surface

100

101

102

103

104

4 nM

40

100

80

60

0

20

Cou

nts 2.5

Cou

nts

20 nM10

010

110

210

310

4

40

100

80

60

0

20

3.0

Cou

nts

100

101

102

103

104

100 nM

40

100

80

60

0

20

7.3

Cou

nts

100

101

102

103

104

500 nM

40

100

80

60

0

20

97.4

100

101

102

103

104

4 nM

40

100

80

60

0

20

Cou

nts 9.9

100

101

102

103

104

20 nM

40

100

80

60

0

20

Cou

nts 27.4

100

101

102

103

104

100 nM

40

100

80

60

0

20

Cou

nts 77.7

100

101

102

103

104

500 nM

40

100

80

60

0

20

Cou

nts

98.3

Monomer

Dimer

AptamersAntibodies

Untreateda

IgG + CD3b

4-1BB + CD3c

mutM12-23 dimer + CD3

d

M12-23 dimer + CD3e

M12-23 monomer + CD3f

M12-23 dimer + IgGg

0.02%

0

20

40

60

80

100

Cou

nts

100 101 102 103 104

CFSE

0

20

40

60

80

100

Cou

nts 13.5% 13.7%

0

20

40

60

80

100

Cou

nts

100 101 102 103 104

CFSE

40.2%

0

20

40

60

80

100

Cou

nts

100 101 102 103 104

CFSE

11.3%

100 101 102 103 104

CFSE

0

20

40

60

80

100

Cou

nts

32.3%

100 101 102 103 104

CFSE

0

20

40

60

80

100

Cou

nts

100 101 102 103 104

CFSE

0

20

40

60

80

100

Cou

nts

0.08%

4-1BB Aptamer Dimers Costimulate T Cells(CFSE proliferation assay)

0

2

4

6

8

10

12

14

16

IgG

4-

1BB

Ab

mut

M12

-23

dim

er

M12

-23

dim

er

Unt

reat

ed

IFN

re

leas

e (f

old

incr

ease

)

4-1BB Aptamer Dimers Costimulate T Cells(IFN production)

0

200

400

600

800

1000

2 3 4 52 3 4 5

Mea

n tu

mor

vol

ume

(mm3 )

Day 4

2 3 4 52 3 4 5

Day 6

2 3 4 52 3 4 5

Day 8

0 2 4 6 8 10 12

Mea

n t

um

or

vo

lum

e (m

m3 )

Days after injection

800

600

400

200

0

PBSIsotype Ab4-1BB AbMutM12-23 dimerM12-23 dimer

A

B C

0 2 4 6 8 10 12 14 160

2

4

6

8

10

PBSIsotype Ab4-1BB AbMutM12-23 dimerM12-23 dimer

Days after injection

Num

ber

of M

ice

Rem

aini

ng

D

0

100

200

300

400

500

Mea

n t

um

or

Vo

lum

e (m

m3 )

Rejection of P815 mastocytoma tumors injected with 4-1BB aptamer dimers

Summary

• High affinity 4-1BB binding aptamers can be isolated

• A subset of which - when multimerized - can function as 4-1BB agonists

• A low-tech clinically applicable approach

Next:1. Improve aptamer potency by post selection modifications2. Antitumor potential - stringent murine immunotherapy models3. Do monomers block 4-1BB signaling?4. Development of human 4-1BB agonists and clinical studies.

The potential of aptamer technology to manipulate immunity

• Ligands as well as targeting agents for drugs (siRNAs)

• Feasibility

• Replace antibodies and expand therapeutic applications?

Concluding thoughts

Vaccination: Inducing de novo, or expanding preexisting, immune responses against tumor-associated antigens

orPotentiating the ability of the disseminated tumor to stimulate immune responses on its own


Yesterday


Potentiating the ability of the disseminated tumor to stimulate immune responses on its own

Today

Mounting evidence that tumors in cancer patients are capable of stimulating, transiently, protective immunity

• Frequent induction of immune responses in cancer patients. (reviewed by Hodi & Dranoff, Adv. Immunol., 2006, 90:341)

• Correlation between lack of tumor progression in cancer patients and immune infiltrates.– Ovarian cancer: Zhang, L., et al. Intratumoral T cells, recurrence, and

survival in epithelial ovarian cancer. N Engl J Med, 2003, 348:203

– Colorectal cancer: Galon, J., et al.Type, density, and location of immune cells within human colorectaltumors predict clinical outcome. Science, 2006, 313:1960


Tomorrow


And then...


Overcoming tumor-induced immune suppression

Delivering co-stimulatory ligands to the tumor

Promoting “immunogenic” death of the tumor

Enhancing the antigenicity of the tumor

Concept development Translation 2-Arm clinical trials

• Murine studies• Human in vitro studies

Development andoptimization ofclinical reagents andprotocols

1o Immunological2o Clinical

End points:

4-1BB aptamers

James McNamaraDespina KoloniasFernando Pastor

CollaborationPaloma GiangrandeBruce Sullenger

Lieping ChenRobert Mittler

Jenz DannullZhen SuPhilip DahmDoris Coleman

Center for Translational Research, Duke University Medical Center

Foxp3 vaccination

Smita NairDavid BoczkowskiMartin Fassnacht

Sylvia SichiBenjamin YangMelinda MalreadyDonna Yancey

Eli Gilboa Johannes Vieweg

Duke Cancer Immunotherapy Program

Concept development Translation 2-Arm clinical trials

• Murine studies• Human in vitro studies

Development andoptimization ofclinical reagents andprotocols

1o Immunological2o Clinical

End points:

4-1BB aptamers

James McNamaraDespina KoloniasFernando Pastor

CollaborationPaloma GiangrandeBruce Sullenger

Lieping ChenRobert Mittler

Jenz DannullZhen SuPhilip DahmDoris Coleman

Center for Translational Research, Duke University Medical Center

Foxp3 vaccination

Smita NairDavid BoczkowskiMartin Fassnacht

Sylvia SichiBenjamin YangMelinda MalreadyDonna Yancey

Eli Gilboa Johannes Vieweg

Duke Cancer Immunotherapy Program

Business

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