Therapeutic Vaccines in Cancer

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1 Therapeutic Vaccines in Cancer Kunle Odunsi, M.D., Ph.D. 1,2 Department of Gynecologic Oncology 1 Center for Immunotherapy 2 Roswell Park Cancer Institute Buffalo, NY

2 Model of immune recognition of human cancers Lymph node CD8 + T cell Tumor Tumor cell APC Antigen CD8 + T cell Circulation Traffic Tumor Blood vessel Memory T cell

3 Objectives Summarize results from on-going vaccine studies utilizing NY-ESO-1 as target antigen in human ovarian cancer. What are the dominant mechanisms of immune escape in human cancers? - Programmed Death-1 (PD-1) and Lymphocyte Activation Gene-3 (LAG-3), that result in T cell unresponsiveness in human ovarian cancer.

4 Cumulative Survival Sato et al, PNAS. 2005, 102: Intraepithelial CD8+ TIL lowest tertile all others Log Rank test P= Overall Survival (Months) Median survival: 55 Vs 26 months Hazard ratio: 0.33 (p = )

5 What are the targets of immune recognition in human cancers? Categories of TA: Differentiation antigens: tyrosinase, MART1/melan-A, NY-BR-1. Mutational antigens : ras, p53. Over-amplified antigens: HER-2/neu, p53, WT- 1, CD20. Viral antigens such as HPV-16, 18-derived E6 and E7. Cancer/Testis (CT) antigens:ny-eso-1, MAGE, SSX, OY-TES-1, AKAP3, XAGE.

6 Cumulative Survival Potential Contribution of Antigen Specific CD8 + T cells: NY-ESO-1 Discovered by serological screening of a recombinant cdna. expression library obtained from an esophageal tumor (SEREX) Expression limited to germ cells and tumor cells Immunogenic NY-ESO-1 CD8 TIL NY-ESO-1 (-) CD8+TIL(-) NY-ESO-1(-) CD8+TIL(+) NY-ESO-1(+) CD8+TIL(-) NY-ESO-1(+) CD8+TIL(+) Focal, 1+ to 4+ immunostaining Expression frequency 43% (n = 190) Humoral response: 30% Odunsi et al. Cancer Res. 2003, 63:6076) Sato et al, PNAS. 2005, 102: Overall Survival (Months)

7 RPCI Ovarian Cancer Vaccine Program Vaccination with an NY-ESO-1 peptide of HLA class I/II specificities induces integrated humoral and T cell responses in ovarian cancer. Odunsi et al, PNAS. 2007, 104:12837 Efficacy of vaccination with recombinant vaccinia and fowlpox vectors expressing NY-ESO-1 antigen in ovarian cancer and melanoma patients. Odunsi et al, PNAS. 2012, 109:5797 I125207: Phase I Study of ALVAC(2)-NY-ESO-1(M)/TRICOM (vcp2292) in Patients with Epithelial Ovarian, Fallopian Tube or Primary Peritoneal Carcinoma Whose Tumors Express NY-ESO-1 or LAGE-1 Antigen (n=12) (Unpublished).

8 I13303: A Phase II study of rv-ny-eso-1 and rf- NY-ESO-1 in patients with ovarian cancer whose tumors express NY-ESO-1 or LAGE-1 antigen (n=22) Day rvny-eso-1 3.1x10 7 PFU id rfny-eso-1 7.4x10 7 PFU sc Hypothesis: A diversified prime and boost vaccine regimen using two different pox-viral vaccines would lead to enhanced CD4 and CD8 T cell activation and sustained response against ovarian tumor. Objective(s): To establish that the time to failure (ttf) for the proposed therapy is greater than the ttf for standard therapy.

9 Summary of Protocol I13303: Diversified prime boost rv- NY-ESO-1 and rf-ny-eso1 in ovarian cancer patients (n=22) Antibody responses: 3/22 (14%) baseline seropositives 8/19 (42%) seroconverted. Total ab responses: 11/22 (50%) CD8 T cell responses: 3/22 (18%) with pre-existing CD8+ T cells 7/19 (42%) developed de novo CD8+ T cell responses. CD4 T cell responses : 9/22(40%) with pre-existing CD4+ T cells 7 additional patients developed de novo CD4+ T cell responses.

10 Distribution Function Overall Survival by Immune Response Category Median 53 mths 0.50 Median 48 months LogRank Pval= <.001 Median 14 months Time at Risk (Months) Immune Category GOG 182: OS 40mths 1:No AB, CD4 or CD8 2:No AB. >=1 CD4 or CD8 Post 3:No Pre AB. Post AB. 4:Pre and Post AB

11 ALVAC(2)-NY-ESO-1(M)/TRICOM H6 NYESO-1 ALVAC(2)-NYESO-1-TRICOM (vcp2292) NYESO-1 H6 C3 C6 C3 C5 C5 30K hlfa- hica hb7. hb7. hica hlfa- I3 se/l H6 K3 E3 E3L se/l I3 30K The expression of each of the structural genes is driven by a vaccinia virus promoter Amino acid at position 165 of NY-ESO-1 changed from cysteine to valine. GM-CSF days 1-4 of vaccination.

12 Protocol I125207: Phase I study of ALVAC(2)-NY-ESO-1(M)/TRICOM in patients with ovarian cancer whose tumors express NY-ESO-1 or LAGE-1 antigen Month 1 Month 2 Month 3 Month 4 Month 5 Month 6 Legend: ALVAC(2)-NY-ESO-1(M)TRICOM Vaccine SC once monthly GM-CSF 100mcg/day Day 0-4 SC

13 Titer Antibody responses for NY-ESO #001 #002 #003 #004 #005 #006 #007 #008 #009 #010 #011 #012 1 pre d29 d57 d85 d113 d141 d169 Days

14 p1-20 p11-30 p21-40 p31-50 p41-60 p51-70 p61-80 p71-90 p p p p p p p p p Pat. No. CD8 pool N/A N/A N/A CD4 p1-20 p11-30 p21-40 p31-50 p41-60 p51-70 p61-80 p71-90 p p p p p p p p p pool N/A N/A N/A Pre-vaccination Post-vaccination CD8 and CD4 epitopes

15 IFN-g Enhanced multifunctional effector cells, and TCR avidity TNF-a EC50 (pep conc. for 50% IFN-g+) Multicytokine pre d IFN-g % 3.48% DP % 25.07% % 38.12% 48.27% 7.75% GM-CSF % 4.35% DN 4.16% 0.31% 93.97% 1.56% % 6.82% GM-CSF % 10.32% % 19.35% #001 #003 #004 #005 #006 #007 #010 #011 #012 Avg IL Pre Mid End

16 Summary: I NY-ESO peptide; rv/rf induced integrated humoral, CD4 + and CD8 + T cell responses in a significant proportion of EOC patients. Improved survival in a phase II trial. ALVAC-NY-ESO-1/TRICOM vaccination elicits NY-ESO-1-specific immune responses in all patients multicytokine producing CD4 and CD8 T cells Skews towards Th1polarization. Generates T cells with higher TCR avidity compared with pre-existing T cells. Long lived functional CD4 + T and CD8 + T cells at 6 months in all patients, and at 12 months in some patients. OS months

17 Overview of vaccination strategies in clinical trials Vaccine Phase Tumor PTS * Note Vaccines with viral vectors PSA-TRICOM II Prostate mos OS improvement PANVAC-VF III Pancreatic 255 Failed >OS. Vaccines with peptides Sipuleucel-T (Provenge) III Prostate mo OS improvement Vitespen (Oncophage) III Melanoma 322 Prolonged OS in M1a or M1b subpopulation Vaccines with tumor cells or tumor cell lysates III Renal 818 No difference in DFS and OS OncoVAX III Colon 254 Significant improvement in DFS and OS in stage II Reniale III Renal 558 Significant improvement in DFS and OS GVAX III Prostate 626 Failed to improve OS versus docetaxel

18 Camouflage and sabotage: ovarian cancer escapes from immune attack Role of regulatory T cells. Loss of antigen expression Role of molecules that mediate immune tolerance and T cell exhaustion: Indoleamine 2,3 dioxygenase (IDO) Program Death-1 (PD1) Lymphocyte Activation Gene-3 (LAG-3) CTLA-4 Odunsi K, et al. PNAS. 2007; Nishikawa H et al., JI, 2006; Qian et al, Cancer Res. 2009; Matsuzaki J. et al PNAS 2010.

19 KIEELE KIEELE PD-1 and LAG-3 co-inhibitory molecules ITSM ITIM Dephosphorylation P P SHP- 2 P P Proximal signaling kinases Less T cell activation Cytoplasmic domain of PD-1 contains two motifs ITIM: Immunoreceptor tyrosine-based inhibitory motif ITSM: Immunoreceptor tyrosine-based switch motif PD-1 PD-1 ligand CD-3 TCR MHC Class II LAG-3 APC

20 Expression of PD-1, LAG-3 and CTLA-4 on NY-ESO-1 specific CD8+ cells at the tumor site 5.2% IFN-γ +ve 33.9% IFN-γ +ve The capacity for IFN-γ production is diminished in LAG-3+ and PD1+ subsets of tumor-antigen-specific T cells.

21 Dual LAG-3 and PD-1 pathway blockade during priming efficiently restores frequency and effector function of NY-ESO-1 specific CD8+ T cells Clone RPOV10: HLACw3

22 Safety and Activity of PD1-PDL-1 pathway blockade in humans Safety, activity, and immune correlates of anti-pd-1 antibody in cancer. Topalian SL et al, N Engl J Med; 366:2443, Cumulative response rates were 18% NSCLC, 28% melanoma and 27% RCC; PD-L1-positive tumors (36%). Safety and activity of anti-pd-l1 antibody in patients with advanced cancer. Brahmer JR, et al, N Engl J Med; 366:2455, of 52 patients with melanoma, 2 of 17 with renal-cell cancer, 5 of 49 with non-small-cell lung cancer, and 1 of 17 with ovarian cancer.

23 On-going and Future Work NK cell IFN-γ TUMOR CELLS IDO-DC Proinflammatory cytokines (e.g. IL-6) CTL B cell CD-4 + T cell Treg MDSC TAM Tumor immunity Critical questions: Which antigen(s)? Vaccine / Immunotherapy strategies? -DCs Vs other platforms, ACT Tumor growth What are the most significant mechanisms of immune evasion in human cancer? Desirable immune response? - Memory Vs Effector

24 Perspectives for 2012 Consolidation with immune therapy to minimize relapse is feasible, yields robust immunological results. Combination of vaccination with strategies to overcome immune suppression. Integration of cellular therapies (dendritic cells, engineered T cells) into treatment paradigms.

25 Acknowledgements Roswell Park Cancer Institute Buffalo, NY Junko Matsuzaki Raya Huang Feng Qian Amy Beck Tony Miliotto Cheryl Eppolito Ludwig Institute, NY Sacha Gnjatic Erika Ritter Gerd Ritter Linda Pan Ralph Venhaus Lloyd J. Old** Shashikant Lele Nefertiti DuPont Ovarian Cancer Research Fund NCI R01CA A1 P30 CA