NW Symposium in MelanomaMay 22, 2010

Adoptive T Cell Therapy

Cassian Yee MD

Member

Program in Immunology

Fred Hutchinson Cancer Research Center

cyee@fhcrc.org

T Cell Melanoma Cell

T Cell

Melanoma Cell

T Cell Tumor Cell

TCR

Target Antigen

Tissue Expression Antigen Tumors Normal Tissues

Differentiation Antigens (overexpres sed) Tyrosinase Melanoma Melanocytes MART1/MelanA Melanoma Melanocytes gp100 Melanoma Melanocytes

Differentiation Antigens (normally expr.) Prostate specific an tigens Prostate Cancer Prostate CD20, Idiotype B cell malignancies B cells

Cancer-Testis Antigens MAGE-1, MAGE-3 Melanoma, Lung, Others Testis, Placenta NY-ESO-1 Breast, Ovarian, Lung,

Melanoma, Others Testis, Placenta

Oncofetal Antigens CEA Colon Cancer, Others Liver, Others AFP Liver Cancer

Viral Antigens EBV NPC, Hodkgin’s, LPD Mutated Antigens

CASP-8 Head and Neck Cancer - CDK4-kinase, MUM-3 Melanoma - Beta-catenin Melanoma, Lung, Others -

Minor Histocompatibility Antigens HA-1, HA-2 Leukemia, RCC, Breast *allogeneic

RBCsplatelets

WBCs

B cells T cells

WBCs

1 in 100,000

T Cell Tumor Cell

TCR

Target Antigen

CD8+

DCDC

DCDCCD8

CD4

Normal Tumor

Tumor Immune Surveillance

• Immune evasion

• T cell frequency : Tumor burden

Possible Reasons For Failure of Tumor Immune Surveillance

Highly functional T cells

More of them

Vaccine Therapy Adoptive Therapy

DCDC

DCDCCD8

CD4

Tumor

Adoptive T Cell Therapy

WBCs

LEUKAPHERESIS

Study in Patients with Advanced Melanoma

Treated with T Cell Therapy

Recruited patients with metastatic disease progressive failing 2nd and 3rd attempts to treat cancer

Patient 1017-6

Patient 1017-8

Before After T cell infusion

Study in Patients with Advanced Melanoma

Treated with T Cell Therapy

• 30% Failed

• 30% Partial Response

• 30% Stabilized Response

• 10% near Complete Response

3 to > 30 months

20

Lymphoid Homeostasis

Increase 'space' for transferred T cellsEliminate 'suppressor cells'

Supply Growth FactorsIncrease 'space' for transferred T cells

Eliminate 'suppressor cells'Supply Growth Factors

Lymphodepletionbuilding a better environment

PROTOCOL # 2140Adoptive T Cell Therapy following Cyclophosphamide Lymphodepletion

Objectives : Eligibility Criteria : - Evaluate Safety - Stage IV (Metastatic) - Evaluate T Cell Persistence - HLA-A2 - Evaluate anti-tumor efficacy

T Cell Infusion: - Antigen-specific CD8+ T cell clones - Targeting MART-1, gp100 - Dose: 1010 cells / m2

CY60 mg/kg x 2

Low-Dose IL-2 (250,000 U s.c q12 h)

T cell persistence in vivo

5.3%1.1%

D18

2140-1

2140-2

Clinical Response

Patient Target Toxicity Persistence Disease Sites Response

2140-1 Tyrosinase F,N,R >290 days Cervical,supraclavicular LN, Chest Wall, BreastPulmonary nodules

MR

2140-2 Tyrosinase F 16 days Mediastinal, Pulmonary nodules PD

2140-3 gp100 F,N,R >85 days Mesenteric LN, scapular subcutaneous dz

CR (> 12 mths)

2140-4 MART-1 F, N, R n.d. Pulmonary, inguinal, subcutaneous

SD

2140-5 MART-1 F, N,R n.d. Right and left kidneys, adrenal, liver

PR

2140-6 MART-1 F, N, R n.d. Mediastinal, supra clavicular, mammary chain, periportal, portacaval nodes.

PR

Future Directions

Future of Adoptive T Cell Therapy

• LATE-STAGE DISEASE

• EARLY-STAGE DISEASE

• COMBINATION THERAPY

• WHICH CANCER TYPES?

Tissue Expression Antigen Tumors Normal Tissues

Differentiation Antigens (overexpres sed) Tyrosinase Melanoma Melanocytes MART1/MelanA Melanoma Melanocytes gp100 Melanoma Melanocytes

Differentiation Antigens (normally expr.) Prostate specific an tigens Prostate Cancer Prostate CD20, Idiotype B cell malignancies B cells

Cancer-Testis Antigens MAGE-1, MAGE-3 Melanoma, Lung, Others Testis, Placenta NY-ESO-1 Breast, Ovarian, Lung,

Melanoma, Others Testis, Placenta

Oncofetal Antigens CEA Colon Cancer, Others Liver, Others AFP Liver Cancer

Viral Antigens EBV NPC, Hodkgin’s, LPD Mutated Antigens

CASP-8 Head and Neck Cancer - CDK4-kinase, MUM-3 Melanoma - Beta-catenin Melanoma, Lung, Others -

Minor Histocompatibility Antigens HA-1, HA-2 Leukemia, RCC, Breast *allogeneic

31

Tissue Expression Antigen Tumors Normal Tissues

Differentiation Antigens (overexpres sed) Tyrosinase Melanoma Melanocytes MART1/MelanA Melanoma Melanocytes gp100 Melanoma Melanocytes

Differentiation Antigens (normally expr.) Prostate specific an tigens Prostate Cancer Prostate CD20, Idiotype B cell malignancies B cells

Cancer-Testis Antigens MAGE-1, MAGE-3 Melanoma, Lung, Others Testis, Placenta NY-ESO-1 Breast, Ovarian, Lung,

Melanoma, Others Testis, Placenta

Oncofetal Antigens CEA Colon Cancer, Others Liver, Others AFP Liver Cancer

Viral Antigens EBV NPC, Hodkgin’s, LPD Mutated Antigens

CASP-8 Head and Neck Cancer - CDK4-kinase, MUM-3 Melanoma - Beta-catenin Melanoma, Lung, Others -

Minor Histocompatibility Antigens HA-1, HA-2 Leukemia, RCC, Breast *allogeneic

Adoptive Therapy following Lymphodepletion

FLU25 mg/m2 x

5

HD IL-2720K u/kg TID

CY60 mg/kg x 2

TBI High-Dose IL-2 (600,000 u./kg q8)Low-Dose IL-2 (250,000 U s.c q12 h)

Adoptive Therapy following Cytoxan Lymphodepletion Protocol 2140

HD IL-2720K u/kg TID

CY60 mg/kg x 2

High-Dose IL-2 (600,000 u./kg q8)Low-Dose IL-2 (250,000 U s.c q12 h)

Isolate/Enrich Clone/Select

Expand

Translational Strategies to Augment the CD8 Effector Response

CD8-FITC

Te

t-P

E

Genetically Modify

Pre-infusion Immunomodulation

Post-infusion Immunomodulation

Intrinsic

Extrinsic

Phenotype- CD8/CD4- Memory phenotype

Cytokine modulation

Lymphodepletion- Chemotherapy/TBI

Cytokine help- Low-dose IL-2- High-dose IL-2- Other γ-chain receptor cytokines

Vaccine + adoptive therapy

TCR Chimeric receptor Costimulatory/Inhbitory modification Suicide gene

Ê CD4

Fludarabine

Hematol Oncol Clin North Am. 2006 Jun;20(3):711-3

T Cell Expansion & Infusion

Adoptive Therapy Using Antigen-Specific T cellsTransferred Receptor

Tumor Cell

Chimeric TCR + zeta

Chimeric Ig + zeta

Receptor Transfer