Topics neo-antigens vs shared antigens as targets for vaccines - PDF document

3/5/2018 The Evolving Role of Cancer Vaccines COL (ret) George E Peoples, MD, FACS Topics • neo-antigens vs shared antigens as targets for vaccines • new clinical settings (hence endpoints) for vaccine trials • vaccines to improve CPIs range of clinical activity • new combinations (to include but not limited to CPIs) to improve the outcomes in vaccine trials • address recent failed vaccine trials Conclusions • Adjuvant setting is an appropriate place to test vaccines • Combination therapies may be even more effective • CPI + vaccines for the metastatic setting 1

3/5/2018 Vaccines for Solid Tumors • Hypothesis: Cancer vaccines will be more effective in a minimal disease (adjuvant) setting Adjuvant Setting – Why? • Vaccinate during disease-free interval – Healthier immune system – Build up anti-tumor immunity • Single tumor cells/micromets • Theoretically – Less tumor-related immune suppression – Fewer immune escape mechanisms – Less tumor microenvironment • Using vaccines as preventive agents Adjuvant Setting – Challenges • Disease-free survival endpoint – 2-3 yrs to endpoint • Based on recurrence rates – May require large reductions in RRR – Or large treatment groups • Large studies that take a long time = expensive • Difficult first step to prove efficacy of vaccine technology 2

3/5/2018 Proof of Concept in Phase III • Colon cancer – OncoVax = autologous tumor + BCG – Stage II/III resected (four trials with >700 pts) – DFS/OS advantage in stage II • Lung cancer – Stimuvax = MUC1 polypeptide – Stage III NSCLC treated with concurrent chemorads (n=1239, 806 pt subset) – Improved PFS/OS • Melanoma – Melacine = allogeneic tumor cell lysates – Stage III resected (n=689 pts) – OS advantage in HLA-A2+ and HLA-Cw3+ pts Proof of Efficacy (n=>1500 pts) • Breast cancer – AE37 (ph2 = 301 pts) – GP2 (ph2 = 180 pts) – NeuVax (ph2 = 195 pts, ph3 = 760 pts) • Ovarian cancer – FBP (ph1/2a = 51 pts) • Melanoma – TLPLDC (ph2b = 120 pts) – TLPO (ph2b = 60 pts) (ongoing) HER2 Extracellular Domain Trans Membrane Domain Intracellular Domain (aa 1-652) (aa 653-675) (aa 676-1255) ECD TMD ICD I I S A VV G I L GP2-peptide vaccine (aa 654-662) MHC Class I : HLA-A2 Stimulate CD8 T cells K I F G S L A F L G V G S P Y V S R L L G I C L E75-peptide vaccine (aa 369-377) AE37-peptide vaccine (aa 776-790) MHC Class I : HLA-A2 & HLA-A3 MHC Class II : multi-allele Stimulate CD8 T cells Stimulate CD4 T cells 3

3/5/2018 AE37/GP2 Phase II Trial R AE37+GM S A T N R D A O Specific Aims T M • NP or high- A2- I I 1. Recurrence risk NN F Z 2. Time to • HER2 IHC Y E GM only Recurrence 1+, 2+ or 3+ R 3. Immunologic • NED after GM only S A response SOC A2+ T N correlation therapy R D A O T M I I F Z Y GP2+GM E AE37/GP2 Phase II Trial Primary Analysis: GP2 37% RRR Mittendorf EA et al, Oncotarget 2016;7(40):66192-66201 4

3/5/2018 Primary Analysis: AE37 HER2 1+/2+ TNBC 40% RRR 60% RRR Mittendorf EA, et al . Ann Oncol 2016;27(7):1241-8. HER2 Extracellular Domain Trans Membrane Domain Intracellular Domain (aa 1-652) (aa 653-675) (aa 676-1255) ECD TMD ICD I I S A VV G I L GP2-peptide vaccine (aa 654-662) MHC Class I : HLA-A2 Stimulate CD8 + T cells K I F G S L A F L G V G S P Y V S R L L G I C L E75-peptide vaccine (aa 369-377) AE37-peptide vaccine (aa 776-790) MHC Class I : HLA-A2 & HLA-A3 MHC Class II : multi-allele Stimulate CD8 + T cells Stimulate CD4 + T cells E75 Phase II – 5 yr DFS 89.7% Fraction Surviving Disease Free 80.2% P =.08 Vaccinated (n=108) Control (n=79) Time (months) •Mittendorf EA et al. Ann Oncol 2014;25(9):1735-42. 5

3/5/2018 DFS – Optimal Dosing 94.6% Fraction Surviving Disease Free 87.1% 80.2% P =.05* Optimally dosed (n=37) Suboptimally dosed (n=71) Control (n=79) Time (months) Mittendorf EA et al. Ann Oncol 2014;25(9):1735-42 Phase III Study Schema: PRESENT (Prevention of Recurrence in Early Stage Node-Positive Breast Cancer with Low to Intermediate HER2 Expression with NeuVax Treatment Interim Study Population analysis by Endpoint DFS DSMB at at n=139 Adjuvant Breast cancer n=70 events events/36 mos. (BC) patients, n=700, randomized 1:1 E75 • Node positive (NP), HLA A2/A3+, low and + GM-CSF intermediate HER2 expression • Achieve CR with standard of care (SOC) Placebo • Stratified by Stage (IIA- IIIA), Type of Surgery, + GM-CSF Hormone Receptor and Menopausal status + Dosing to + 1 booster • Single dose level of Dosing 4 5 6 1 2 3 disease dose every GM-CSF +/- E75 by Month progression or 6 months 36 months thereafter PI: E.A. Mittendorf PRESENT Trial Results • N=758 – 376 VG vs 382 CG – well matched • 71 events triggered interim – recurrences, deaths, second cancers • mandatory annual scans • new radiographic findings (no bx, serial images, f/u) – Recurrences - VG > CG • same number of deaths, second ca, clinical recurrences • 3x the # of new radiographic findings in VG c/w CG 6

3/5/2018 Proof of Efficacy (n=>1500 pts) • Breast cancer – AE37 (ph2 = 301 pts) – GP2 (ph2 = 180 pts) – NeuVax (ph2 = 195 pts, ph3 = 760 pts) • Ovarian cancer – FBP (ph1/2a = 51 pts) • Melanoma – TLPLDC (ph2b = 120 pts) – TLPO (ph2b = 60 pts) (ongoing) Interim Analysis: E39 Interim Analysis: E39 7

3/5/2018 Conclusions • Adjuvant setting is an appropriate place to test vaccines – Hale DF, Vreeland TJ, Peoples GE. Arming the Immune System Through Vaccination to Prevent Cancer Recurrence. Am Soc Clin Oncol Educ Book. 2016;35:e159-67. • Combination therapies may be even more effective • CPI + vaccines for the metastatic setting Conclusions • Adjuvant setting is an appropriate place to test vaccines – Hale DF, Vreeland TJ, Peoples GE. Arming the Immune System Through Vaccination to Prevent Cancer Recurrence. Am Soc Clin Oncol Educ Book. 2016;35:e159-67. • Combination therapies may be even more effective • CPI + vaccines for the metastatic setting Combination Immunotherapy • E75 and GP2 trials –N = 89 patients with HER2 3+ breast cancer that received trastuzumab • 55 vaccinated • 34 unvaccinated controls 8

3/5/2018 Combination Immunotherapy 100% 84% Median f/u = 36 months Phase II: NeuVax (E75) + Herceptin v. Herceptin alone in HER2 IHC 1+/2+, early-stage breast cancer Primary Secondary Study Population Endpoint Endpoint DFS at DFS at Adjuvant Breast cancer 24 mos. 36 mos. (BC) patients, n=300, Herceptin randomized 1:1 • HLA A2/A3+, low and intermediate HER2 6 doses of NeuVax given (IHC 1+/2+) every 3 weeks starting with third dose of Herceptin expression; node positive (HR+/-) or NeuVax (E75) node negative (HR-) • Stratified by nodal + Herceptin status and HER2 status • Single dose level of Standard Herceptin dosing + 1 booster + Dosing to Herceptin + NeuVax every 3 weeks for 1 year dose every 6 disease vs Herceptin + GM- months progression or 36 months thereafter CSF alone E75 + trastuzumab Trials • In HER2 1-2+ trial – PI: Jarrod Holmes – 32 sites – Enrolled 284/300 pts (randomized 253) • Interim safety analysis – No SAEs, min related AEs – No increase in cardiotoxicity assoc with trastuzumab • Efficacy at 2 and 3 yrs 9

3/5/2018 E75 + trastuzumab Trials • In HER2 3+ trial – PI: Beth Mittendorf – 21 sites – Enrolled 77/100 pts (randomized 68) • Interim safety analysis – No SAEs, min related AEs – No increase in cardiotoxicity assoc with trastuzumab • Efficacy at 3 yrs Conclusions • Adjuvant setting is an appropriate place to test vaccines • Combination therapies may be even more effective • CPI + vaccines for the metastatic setting Vaccines + CPI • Rationale – CPI highly effective in a minority of pts – Less effective in tumors lacking infiltrating T cells – Vaccines induce tumor-reactive CTL • Metastatic setting – Tumor microenvironment known to be suppressive to tumor- reactive T cells – Vaccines largely ineffective in the metastatic setting • Therefore, – Vaccines can increase the number of tumor-reactive T cells for CPI – CPI can protect tumor-reactive T cells in the tumor microenvironment 10

3/5/2018 Vaccines + CPI Phase II Trials • Vreeland TJ, Clifton GT, Herbert GS, Hale DF, Jackson DO, Berry JS, Peoples GE. Gaining ground on a cure through synergy: combining checkpoint inhibitors with cancer vaccines. Expert Rev Clin Immunol 2016 Dec;12(12):1347-1357. • 19 trials, 14 vaccines, 7 disease types • 5 checkpoint modulators – ipilimumab – nivolumab – pembrolizumab – atezolizumab – Indoximod VADIS (Vaccine in DCIS) • Led by the NCI and MDACC • PI: Beth Mittendorf • N=40 pts, randomized 2:1 • Neoadjuvant vaccination with E75 + GM- CSF vs GM alone • Endpoints – TIL by HE/IHC – E75-specific CTL – Pathologic changes in the tumor Vaccination in DCIS • Vaccines may be most effective in DCIS: • Before tumor cells are genetically unstable and rapidly dividing • When patients are not immunosuppressed 11