Endogenous and Exogenous Vaccination in the Context of Immunologic Checkpoint Blockade Jedd Wolchok Ludwig Center for Cancer Immunotherapy Memorial Sloan-Kettering Cancer Center MEMORIAL SLOAN- KETTERING
Disclosure Consultant: Bristol-Myers Squibb
CTLA-4 Blockade Enhances Tumor-Specific Immune Responses Attenuated or Terminated Proliferation Unrestrained Proliferation IL-2 Tumor APC APC Necrotic Death Vaccines Chemotherapy Irradiation Hormone therapy Anti-angiogenesis Antibodies Targeted Therapies TCR Peptide/MHC CD28 B7-1,2 CTLA-4
Anti-CTLA-4 Induces Regression of Transplantable Colon Carcinoma Average Tumor Size (mm 2) Rx Anti-CD28 No Rx Anti-CTLA-4 Days After Tumor Injection Leach
Anti-CTLA-4 and GM-CSF Tumor Cell Vaccine Synergize to Eradicate Established B16 Melanoma Average Tumor Size (mm 2 ) 400 200 No Rx GM-Vaccine Anti-CTLA-4 0 Both 12 16 20 24 28 32 36 0 Days After Tumor Injection van Elsas, Hurwitz
Ipilimumab Pattern of Response: Responses After the Appearance and Subsequent Disappearance of New Lesions Pre-treatment July 2006 Week 12: Progression 3 mg/kg ipilimumab Q3W X 4 New lesions Week 20: Regression Week 36: Still Regressing Source: 2008 ASCO Abstract #3020 Wolchok.
Hypopigmentation
MDX010-20: Study Design Pre-treated Metastatic Melanoma (N=676) R A N D O M I Z E Ipilimumab + gp100 Ipilimumab + placebo gp100 + placebo (N=403) (N=137) (N=136) ASCO 2010 8
Kaplan-Meier Analysis of Survival Ipi + gp100 (A) Ipi alone (B) gp100 alone (C) Survival Rate Ipi + gp100 N=403 ASCO 2010 9 1 2 3 4 Years Ipi + pbo N=137 gp100 + pbo N=136 1 year 44% 46% 25% 2 year 22% 24% 14%
PFS: Impact of Both Ipilimumab Regimens vs gp100 Ipi + gp100 (A) Ipi alone (B) gp100 alone (C) Comparison Hazard Ratio (C.I.) p-value Arms A vs C 0.81 (0.66 1.00) 0.0464 Arms B vs C 0.64 (0.50 0.83) 0.83) 0.0007 Arms A vs B 1.25 (1.01 1.53) 1.53) 0.0371 1 2 Years 3 4 = 1 st tumor assessment as per protocol ASCO 2010 10
Ipilimumab Improves Best Objective Response Rate (BORR) Arm A Ipi + gp100 N=403 Arm B Ipi + pbo N=137 Arm C gp100 + pbo N=136 BORR, % 5.7 10.9 1.5 P-value: A vs C 0.0433 P-value: B vs C 0.0012 DCR, % 20.1 28.5 11.0 P-value: A vs C 0.0179 P-value: B vs C 0.0002 Disease control rate: percentage of patients with CR, PR, or SD ASCO 2010 11
Vaccines and CTLA-4 Blockade Pre-clinical models in melanoma support synergy Clinical trial shows equivalent overall survival but inferior response and disease control rates Correct vaccine? Antigen escape? Polarization of response? Antigen sink?
CTLA-4 Blockade: A Case Study for Immunotherapy in Need of Biomarkers Knowns Unknowns Clinical benefit for a subset of patients with refractory melanoma Reversible mechanism-based side effects Tumor responses tend to be durable Kinetics of response unlike cytotoxics Biomarkers for response Biomarkers for toxicities Effect on effector vs regulatory T cells in humans Antigens recognized after infusion Importance of vaccination before treatment Relevance of PBMC vs tumor site findings
11/28/06 2/12/07
Tumorous nodule with melanin pigment (macrophages and lymphocytes; no melanocytes) Macrophages and lymphocytes are present, but no tumor cells Klaus Busam
CD8-positive T-cells CD4-positive T-cells (macrophages are also weakly pos for CD4) Klaus Busam
NY-ESO-1 antibody and CD4 T-cell response were detected after full-length NY-ESO-1 protein vaccination Reciprocal Titer % IFN + CD4 T cells NY-ESO-1 recombinant protein NY-ESO-1 peptide pool Modified from Adams S et al. J Immunology 2008, 181:776 Modified from Adams S et al. J Immunology 2008, 181:776
NY-ESO-1 CD4 and CD8 T-cell specific response after CTLA-4 blockade (Patient IMF-11) Reciprocal titer Percent of IFN- + MIP-1 + or IFN- + TNF- + T cells CD8 T cells CD4 T cells IMF-11 experiencing complete response
Grand Serology in CTLA-4 treated patients (peak response): Correlation with clinical benefit 10,000,000 1,000,000 100,000 10,000 1,000 100 CR 11 17 32 56 58 2 3 18 23 37 43 62 8 13 16 24 28 29 33 41 48 52 55 60 PR Clinical Benefit SD 22 26 30 31 35 36 38 44 46 49 53 59 4 6 7 9 10 15 19 20 27 39 40 42 45 50 51 54 57 63 64 65 67 70 71 72 75 61 47 66 68 73 74 76 78 79 80 POD DOD Awaiting No Clinical Benefit NY-ESO-1 LAGE-1 MAGE-1 MAGE-3 MAGE-4 MAGE-10 Melan-A CT7 CT10 CT45 CT46 CT47 SSX1 SSX2 SSX4 PLAC1 SOX2 p53 XAGE-1 ZH1347 ZH_P24 DHFR GAGE7 CXorf48 PASD1 CXorf61 CSAG2 ERG NXF2 SAGE1 ACTL8 NY-ESO-1 LAGE-1 MAGE-1 MAGE-3 MAGE-4 MAGE-10 Melan-A CT7 CT10 CT45 CT46 CT47 SSX1 SSX2 SSX4 PLAC1 SOX2 p53 XAGE-1 ZH1347 ZH_P24 DHFR GAGE7 CXorf48 PASD1 CXorf61 CSAG2 ERG NXF2 SAGE1 ACTL8
Correlation of NY-ESO-1 antibody with clinical course following anti-ctla-4 treatment Patients with NY-ESO-1 antibodies at any time point during study Response # patients Status at wk24 (%) # NY-ESO-1 SERONEGATIVE Status wk24 (%) # NY-ESO-1 SEROPOSITIVE Status wk24 (%) CR 6 (5.1%) 4 2 PR 14 (12.0%) 9 5 SD 25 (21.4%) 19 6 Clinical Benefit 45 (38.5%) 32 (33.7%) 13 (59.1%) No Clinical Benefit 72 (61.5%) 63 (66.3%) 9 (40.9%) Total 117 (100%) 95 22 According to Immune-related response criteria: Fisher's exact test: P value 0.0498 CR: Complete Response PR: Partial Response SD: Stable Disease POD: Progression of Disease (includes MR: mixed response) DOD: Dead of Disease Gnjatic & Wolchok, Ludwig Center/MSKCC Halaban and Sznol, Yale
Polyfunctional NY-ESO-1 Specific T cells in Blood Of Melanoma Patients Treated with actla-4 % IFN- + MIP-1 + T-cell * * * * * * % IFN- + TNF- + T-cell * * * * CD8 CD4 CD8 CD4 % of total CD4+ T cell response 4 Pre-therapy WK7/12 1 WK20 0.5 0.4 0.3 0.2 0.1 0 IFN- MIP-1 TNF- Function s 3 2 1 Patients without clinical benefit Patients with clinical benefit Pre-therapy wk7/12 wk20 Yuan, Gnjatic, Wolchok
NY-ESO-1 antigen-specific CD4 T cell response No Clinical Benefit (5/9)Clinical Benefit (10/11) P=0.127 by Fisher s Exact Test
NY-ESO-1 antigen-specific CD8 T cell response No Clinical Benefit (3/9) Clinical Benefit (10/11) P=0.016 by Fisher s Exact Test
Kaplan-Meier Overall Survival Curve Percent survival 100 80 60 40 20 Ab+ & CD8 T-cell Response Ab+ & CD4 T-cell Response NY-ESO-1 Ab+ All CTLA-4 Pts NY-ESO-1 Ab- Ab+ & no CD8 T-cell Response Ab+ & no CD4 T-cell Response 0 0 10 20 30 40 50 Months NY-ESO-1 seropositivity with a CD8+ T-cell response correlates with survival (median survival not reached vs. 8 months, p=0.0158).
Tumor 1 Tumor 2 Primary Site
PHENOTYPE OF PBMCS (PT. IMF-91E) & TUMORS (00-144-413) 10 3 10 2 10 3 10 2 10 3 10 2 10 3 10 2 Tumor 1 10 1 12.7 10 1 56.6 10 1 33.1 10 1 49.5 0 0 0 0 0 10 1 10 2 10 3 0 10 1 10 2 10 3 0 10 1 10 2 10 3 0 10 1 10 2 10 3 CD4 10 3 10 2 10 1 11.5 10 3 10 2 10 1 26.4 10 3 10 2 10 1 19.6 10 3 10 2 10 1 17.1 Tumor 2 0 0 0 0 0 10 1 10 2 10 3 0 10 1 10 2 10 3 0 10 1 10 2 10 3 0 10 1 10 2 10 3 10 3 10 3 10 3 10 3 10 2 10 2 10 2 10 2 PBMC 10 1 1.3 10 1 2.99 10 1 7.32 10 1 7.79 0 0 0 0 0 10 1 10 2 10 3 0 10 1 10 2 10 3 0 10 1 10 2 10 3 0 10 1 10 2 10 3 PD 1 ICOS FOXP3 CD25
PHENOTYPE OF PBMCS (PT. IMF-91E) & TUMORS (00-144-413)
Tyrosinase and gp100 specific immunity in patient IMF-32 Oct 2005 DNA vaccination trial 00-142 GM-CSF DNA + gp100 and tyrosinase peptides Jan 2008 Anti-CTLA-4 antibody trial (CA184-008) Ipilimumab 10 mg/kg Every 3 weeks x four doses ++
Tyrosinase and gp100 antigen-specific response during GM-CSF DNA and CTLA-4 blockade HLA/A*0201 Tyrosinase tetramer GM-CSF DNA CTLA-4 blockade Pre-vaccine Post-vaccine Pre-therapy Wk12 Wk36 0.004 0.001 0.001 0.09 0.1 HLA/A*0201 gp100 tetramer 0.05 1.31 0.001 0.61 14.1 27 months prior to CTLA-4 CD8 CD8
Gp100 specific CD8 T-cell response during GM-CSF DNA and CTLA-4 blockade GM-CSF DNA CTLA-4 blockade Pre-vac Post-vac Pre-therapy Wk12 Wk36 IFN- 0.12 0.28 0.14 0.37 4.93 CD8
CD8 gp100 209 specific T-cell response during gp100 DNA vaccine and CTLA-4 blockade (patient IMF-24) Pre-vac Post-vac Post-therapy(wk60) Post-therapy (wk120) HLA/A*0201 gp100 tetramer 0.04 0.03 15.6 14.1 IFN- 0.1 0.04 7.9 10.6 CD8
Summary CTLA-4 blockade with ipilimumab results in prolonged survival of patients with refractory melanoma. Clinical response has been associated with: changes in ALC, NY-ESO-1 immunity and induction of ICOS expression on CD4+ T cells. These require prospective evaluation in ongoing clinical trials. De novo immune responses to self antigens has been manifest by autoimmune hypopigmentation. Tumor microenvironment is fertile ground to study the mechanism underlying immunologic checkpoint blockade.
Ludwig Center for Cancer Immunotherapy Jim Allison Lloyd Old Alan Houghton Sacha Gnjatic Charlotte Ariyan Jianda Yuan & the IMF Crew Supported by: NIH RC2 CA148868, Melanoma Research Alliance, Ludwig Trust, Swim Across America, Cancer Research Institute, Goodwin Commonwealth Cancer Research Fund