Cancer Vaccines and Immune Checkpoint Blockade Roisin O’Cearbhaill MD Research Director Gynecologic Medical Oncology Service Clinical Director Solid Tumor Malignancies, Cellular Therapy Memorial Sloan Kettering Cancer Center Immune System and Cancer Tumors regressed in areas of infection Busch (1868) , William B. Coley (1890) Tumors are not just composed of cancer cells Kerkar SP , Restifo NP Cancer Res 2012;72:3125-3130 Presence of TILs and immune gene expression signatures are prognostic in ovarian cancer (so immunotherapy makes sense!) TIL counts per HPF N Engl J Med 2003; 348:203-213 Negative (17%) Low: 1-2 (17%) Moderate: 3-19 (44%) High: >20 (22%) JAMA Oncology 2017 Verhaak et al., JCI 2013 Current immunotherapy approvals in gynecologic cancers Cancer type Subtype/ Drug/ drug Line ORR FDA NCCN Reference biomarker combination approval approval MSS pembrolizumab+ 2+ 36.2 Yes Yes KEYNOTE-146 lenvatinib1 % Endometrial MSI-H 2+ 63.6 No No KEYNOTE-146 % PD-L1 CPS1 2+ 14.3 Yes Yes KEYNOTE-158 Cervical pembrolizumab2 % PD-L1 CPS<1 2+ 0% No No KEYNOTE-158 Undiff pembrolizumab3,4 2+ 23% No Yes SARC-028 Uterine pleomorphic sarcoma* sarcoma only Vulvar PD-L1 CPS1 pembrolizumab 2+ No Yes MSI-H pembrolizumab5 2+ 39.6 Yes Yes KEYNOTE-012 % KEYNOTE-016 Cancer- KEYNOTE-028 agnostic KEYNOTE-158 KEYNOTE-164 TMB 10 pembrolizumab6 2+ 29% Yes Yes KEYNOTE-158 *Pembrolizumab is NCCN-approved for undifferentiated pleomorphic sarcoma (UPS) only. This is rare. Cancer Vaccines Recognition of cancer by the immune system is dependent on Tumor-Associated (TAAs) and Tumor-Specific Antigens (TSAs) • Tissue-specific antigens: non-mutated self-proteins more prevalent on cancer cells (e.g. gp100, CD20, HER2/neu, CEA, PSA, mesothelin). • Oncofetal (differentiation) antigens: proteins expressed during development but not in adult life (e.g. AFP) Tumor Associated • Cancer-Testis Antigens (e.g. NY-ESO1, MAGE A3): expressed in immune- privileged sites and during development • Glycoproteins with altered side chain carbohydrates (e.g. MUC1). Tumor • Viral antigens in virus-induced tumors (HPV, EBV) Specific • Proteins resulting from mutations, translocations, alternative processing (most are not oncoproteins): specific to each patient, also known as neoantigens • Cross-reactivity with normal tissues may lead to autoimmunity (e.g. paraneoplastic autoimmune syndromes, dermatomyositis) Cancer vaccines aim to enhance recognition of tumor antigens by the immune system by boosting preexisting response or inducing new responses In situ vaccines - Surgery Adjuvants (e.g. TLR - Radiation T cell agonists, cytokines, - Chemotherapy Montanide ISA-51) - Ablative therapies - Targeted therapies CD28 TCR - Tumor-targeting antibodies - Oncolytic viruses Tumors B7-1/B7-2 MHC-peptide TAA/TSA cytokines APC Dendritic cell (DC) loaded with TAA/TSA protein or peptides Whole modified tumor cells (GVAX) TAA/TSA encoded by Whole TAA bacterial vector Protein (CRS-207, ADX S11- (MAGE A3) 011) TAA encoded DNA TAA/TSA by virus expressing Peptide vector TAA/TSA (ISA101) (PROSTVAC) Courtesy of Dr Zamarin (VGX3100) Peptide vaccines Advantages: • Easy to synthesize • Require minimal to no processing by APCs Disadvantages: • Each peptide is optimized only for a specific HLA type (e.g. HLA-A2) • Marginal therapeutics efficacy Considerations: • Short (HLA-restricted) vs. long (non-HLA-restricted) peptides • Targeting single vs. multiple antigens • Targeting CD4 vs. CD8 T cell immunity • Choice of antigen(s) • Choice of adjuvant • Early vs. advanced disease setting Early disease setting: HPV16 peptide vaccination for VIN 2/3 Kenter et al., NEJM 2009 Late disease setting: HPV16 vaccination for advanced cervical cancer ORR: 0% Van Poelgeest et al., J. Transl Med. 2013 Why don’t vaccines work for established cancers? • 1. The target is wrong – Antigen is not expressed/presented to sufficient level in tumor tissue – Antigen is not immunogenic enough – Single target might not be sufficient • 2. Vaccine preparation/delivery method is wrong – Adjuvant does not sufficiently activate antigen-presenting cells – Vaccine does not persist long enough or persists too long • 3. The host is not receptive to vaccination – Genetic factors (e.g. polymorphisms in immune genes) – Environmental factors (e.g. gut microbiota) – Acquired immune suppression (e.g. secondary to anti-cancer therapy or systemic immune suppression from tumor) • 4. Tumor microenvironment is not receptive to vaccine-specific T cells The major challenge of tumor vaccines is to break immune tolerance to tumor-antigens 1. Optimize the target: Neoantigen vaccines Carreno et. al, Science 2015 Blass E and Ott P. Nat. Rev. Clin. Oncol. 2021 Neoantigen vaccines Public (APVAC1) and private (APVAC2) vaccination in patients with newly diagnosed glioblastoma Hilf N et al., Nature. (2018) 2. Optimize the preparation/delivery DNA-encoded vaccines Strategy • TAA/TSA encoded by a DNA plasmid vector Advantages: • DNA acts as an adjuvant • Endogenous antigen processing, no HLA restriction Disadvantages: • Delivery may be cumbersome (e.g. typically requires electroporation) Example: • VGX3100: DNA vaccine against HPV16, 18 E6/E8 proteins in CIN2/3 patients Trimble et. al, Lancet 2015 Sahin U et al., Nature. 585:107 (2020) RNA-encoded vaccines Strategy: » TAA encoded by mRNA Advantages: » RNA acts as an adjuvant » Endogenous antigen processing, no MHC restriction Example: » Fixvac: RNA vaccine against TAA in melanoma Sahin U et al., Nature. 585:107 (2020) Bacteria-vectored vaccines Strategy • TAA encoded by recombinant bacteria Advantages: • Bacteria act as an adjuvant • Sustained TAA production Disadvantages • Potential safety concerns, challenges with administration Example • ADX-S11-001 – engineered Listeria monocytogenes expressing HPV16 E7 Huh W et. al ASCO 2016 Virus-vectored vaccines Strategy: • TAA encoded by a replicating or non-replicating virus vector Advantages: • Virus-induced activation of immune response acts as an adjuvant Disadvantages • Potential safety concerns, challenges with administration • Infection concerns Example: • PROSTVAC (vaccine composed of two poxvirus vectors, vaccinia and fowlpox, encoding PSA, B7.1, ICAM-1, and LFA-3) Kantoff et al., JCO 29:1099 (2010) Oncolytic viruses don’t just lyse cancer cells, they also make them more immunogenic Activation and recruitment of innate HSPs Ecto-CRT and adaptive immune effectors B7-1,2 1. DC maturation 2. ↑MHC 1.↑MHC, 3. ↑Costimulatory ligands 2.↑Costimulatory ligands 4. ↑Cytokines, chemokines 3.↑Surface HSPs and ecto-CRT MHC 4.↑Type I IFN Tumor antigens Danger signals PAMPS PAMPS virus Zamarin D. and Wolchok J.D., Molecular Therapy- Oncolytics 1 (2014) Cellular vaccines GVAX + CRS-207 prime-boost in pancreatic cancer GVAX: Two irradiated allogeneic pancreatic cancer cell lines secreting GM-CSF Strategy: CRS-207: Recombinant attenuated Listeria monocytogenes expressing mesothelin (a TAA » Autologous or allogeneic cancer cells modified to be more commonly expressed in pancreatic cancer) immunogenic » Cells are inactivated (e.g. irradiated) prior to injection back into patients » Allogeneic strategy relies on antigens shared among patients Advantages: » Potential for recognition of multiple tumor antigens » Endogenous antigen processing, no MHC restriction Disadvantages: » Complex (for autologous); require fresh tumor resections Example: » GVAX – allogeneic tumor cell lines expressing GM-CSF. Le D., JCO 2015 Vaccine adjuvants Adjuvants stimulate the immune system’s response to the target antigen, but do not in themselves confer immunity Types: » Inorganic compounds (aluminum hydroxide, aluminum phosphate, beryllium) » Mineral oil (paraffin oil) » Bacterial products (killed bacteria, Mycobacterium bovis, toxoids) » Nonbacterial organics (squalene, thimerosal) » Detergents (Quil A) » Cytokines (IL-1, IL-2, IL-12) » Combinations (complete Freund’s adjuvant, incomplete Freund’s adjuvant), e.g. Montanide ISA-51 Mechanisms: » Depots that trap antigens at the injection site providing slow release » Stabilization of antigen formulation » Immune stimulation In situ vaccination Goal: Generate localized antigen release and activation of antigen presenting cells leading to systemic T cell response Exploit broad TAA repertoire available at the tumor site » Local ablative therapies (radiation, cryotherapy, microwave ablation, etc.) » Intratumoral cytokine injection (e.g. IL-12) » Intratumoral co-stimulatory ligand injection (e.g. CD40 agonist) » Intratumoral TLR agonist injection (e.g. TLR3,7,8,9) » Intratumoral STING agonist injection » Intratumoral injection of bacteria (e.g. Clostridium novyi) » Intratumoral injection of viruses (e.g. Talimogene laherparepvec) 3. Optimizing the host and the tumor microenvironment Intra and Inter-tumor Heterogeneity Can Often Be Seen in Gyn Cancers Different Tumor Microenvironments within the Same Patient Jimenez-Sanchez et al., Cell 2017 PD-1 blockade in cervical cancer: KEYNOTE 158 Study Total (N=98) PD-L1+ (N=82) PD-L1- (N=15) ORR 12 (14.6%) 0 (0%) Pembrolizumab is FDA- approved for previously treated PD-L1+ cervical cancer Chung et al., JCO 2019 Response to single agent anti-PD-1 or anti-PD-L1 in endometrial cancer Pembrolizumab Avelumab MSI-H MSS MSI-H Endometrial ORR: 53% Approved by FDA MSS Endometrial ORR: 13% Responders: 1- POLE 1- MSS 1- MS-unknown Le D. et al., Science 2017; Ott et al., JCO 2017, Konstantinopoulos et al., JCO 2019 PD-1 blockade as a single agent has modest activity in ovarian cancer ORR 9.6% ORR 8% Matulonis et al., Annals of Oncology, 2019