Survey
* Your assessment is very important for improving the work of artificial intelligence, which forms the content of this project
Download Yee_Power_Point_Presentation
Document related concepts
no text concepts found
Transcript
NW Symposium in Melanoma May 22, 2010 Adoptive T Cell Therapy Cassian Yee MD Member Program in Immunology Fred Hutchinson Cancer Research Center [email protected] T Cell Melanoma Cell Melanoma Cell T Cell Tumor Cell T Cell TCR Target Antigen Antigen Differentiation Antigens (overexpressed) Tyrosinase MART1/MelanA gp100 Differentiation Antigens (normally expr.) Prostate specific an tigens CD20, Idiotype Cancer-Testis Antigens MAGE-1, MAGE-3 NY-ESO-1 Oncofetal Antigens CEA AFP Viral Antigens EBV Mutated Antigens CASP-8 CDK4-kinase, MUM -3 Beta-catenin Minor Histocompatibility An tigens HA-1, HA-2 Tissue Expression Tumors Normal Tissues Melanoma Melanoma Melanoma Melanocytes Melanocytes Melanocytes Prostate Cancer B cell malignancies Prostate B cells Melanoma, Lung , Others Breast, Ovarian, Lung , Melanoma, Others Testis, Placenta Testis, Placenta Colon Cancer, Others Liver Cancer Liver , Others NPC, Hodkgin’s , LPD Head and Neck Cancer Melanoma Melanoma, Lung , Others Leukemia, RCC, Breast *allogeneic WBCs B cells RBCs platelets WBCs T cells Tumor Cell T Cell CD8+ TCR 1 in 100,000 Target Antigen Tumor Immune Surveillance Tumor Normal CD4 CD8 DC DC DC DC Possible Reasons For Failure of Tumor Immune Surveillance Highly functional • Immune evasion T cells • T cell More offrequency them : Tumor burden Vaccine Therapy Adoptive Therapy Adoptive T Cell Therapy Tumor CD4 CD8 DC DC DC DC LEUKAPHERESIS WBCs 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 Before Patient 1017-6 Patient 1017-8 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 Lymphoid Homeostasis 20 Lymphodepletion building a better environment Increase 'space' for transferred T cells Eliminate 'suppressor cells' Supply Growth Factors PROTOCOL # 2140 Adoptive T Cell Therapy following Cyclophosphamide Lymphodepletion Objectives : - Evaluate Safety - Evaluate T Cell Persistence - Evaluate anti-tumor efficacy Eligibility Criteria : - Stage IV (Metastatic) - HLA-A2 T Cell Infusion: - Antigen-specific CD8+ T cell clones - Targeting MART-1, gp100 - Dose: 1010 cells / m2 CY 60 mg/kg x 2 Low-Dose IL-2 (250,000 U s.c q12 h) T cell persistence in vivo 250000 2140-1 200000 150000 9.4% 100000 5.3% 50000 1.1% 0 0 D18 50 100 150 200 250 200 250 300 Days post Infusion 5000 2140-2 CTL frequency/10^6 4000 3000 2000 1000 0 0 50 100 150 Days post Infusion 300 Clinical Response Patient Target Toxicity Persistence Disease Sites Response 2140-1 Tyrosinase F,N,R >290 days Cervical,supraclavicular LN, Chest Wall, Breast Pulmonary 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? Antigen Differentiation Antigens (overexpressed) Tyrosinase MART1/MelanA gp100 Differentiation Antigens (normally expr.) Prostate specific an tigens CD20, Idiotype Cancer-Testis Antigens MAGE-1, MAGE-3 NY-ESO-1 Oncofetal Antigens CEA AFP Viral Antigens EBV Mutated Antigens CASP-8 CDK4-kinase, MUM -3 Beta-catenin Minor Histocompatibility An tigens HA-1, HA-2 Tissue Expression Tumors Normal Tissues Melanoma Melanoma Melanoma Melanocytes Melanocytes Melanocytes Prostate Cancer B cell malignancies Prostate B cells Melanoma, Lung , Others Breast, Ovarian, Lung , Melanoma, Others Testis, Placenta Testis, Placenta Colon Cancer, Others Liver Cancer Liver , Others NPC, Hodkgin’s , LPD Head and Neck Cancer Melanoma Melanoma, Lung , Others Leukemia, RCC, Breast *allogeneic Antigen Differentiation Antigens (overexpressed) Tyrosinase MART1/MelanA gp100 Differentiation Antigens (normally expr.) Prostate specific an tigens CD20, Idiotype Cancer-Testis Antigens MAGE-1, MAGE-3 NY-ESO-1 Oncofetal Antigens CEA AFP Viral Antigens EBV Mutated Antigens CASP-8 CDK4-kinase, MUM -3 Beta-catenin Minor Histocompatibility An tigens HA-1, HA-2 31 Tissue Expression Tumors Normal Tissues Melanoma Melanoma Melanoma Melanocytes Melanocytes Melanocytes Prostate Cancer B cell malignancies Prostate B cells Melanoma, Lung , Others Breast, Ovarian, Lung , Melanoma, Others Testis, Placenta Testis, Placenta Colon Cancer, Others Liver Cancer Liver , Others NPC, Hodkgin’s , LPD Head and Neck Cancer Melanoma Melanoma, Lung , Others Leukemia, RCC, Breast *allogeneic Adoptive Therapy following Lymphodepletion TBI FLU CY 60 mg/kg x 2 25 mg/m2 x 5 HD IL-2 720K u/kg TID Low-Dose s.c q12 High-DoseIL-2 IL-2(250,000 (600,000Uu./kg q8)h) Adoptive Therapy following Cytoxan Lymphodepletion Protocol 2140 CY 60 mg/kg x 2 HD IL-2 720K u/kg TID Low-Dose s.c q12 High-DoseIL-2 IL-2(250,000 (600,000Uu./kg q8)h) Translational Strategies to Augment the CD8 Effector Response Ê Isolate/Enrich Cytokine modulation CD4 Genetically Modify TCR Chimeric receptor Costimulatory/Inhbitory modification Suicide gene Tet-PE Intrinsic Clone/Select Phenotype - CD8/CD4 - Memory phenotype CD8-FITC Expand Extrinsic Pre-infusion Immunomodulation Lymphodepletion - Chemotherapy/TBI Fludarabine Post-infusion Immunomodulation Cytokine help - Low-dose IL-2 - High-dose IL-2 - Other -chain receptor cytokines Vaccine + adoptive therapy Hematol Oncol Clin North Am. 2006 Jun;20(3):711-3 Adoptive Therapy Using Antigen-Specific T cells Transferred Receptor Tumor Cell Chimeric TCR + zeta Chimeric Ig + zeta Receptor Transfer T Cell Expansion & Infusion
Related documents