Abstract
Immune checkpoint inhibitors have been most successful for the treatment of patients with cancers, such as melanoma and smoking associated non-small cell lung cancer - cancers that are inherently rich in infiltrating T cells and harbor a high number of somatic mutations. A subset of these somatic mutations express neoantigens, which are tumor-specific proteins produced during cancer progression and are recognized as foreign to the immune system. However, the majority of aggressive cancers (>70%) which include pancreatic adenocarcinoma, do not respond to immune checkpoint therapy. These tumors typically have a low burden of mutations, express much fewer neoantigens, and therefore fail to attract infiltrating T cells into their immunosuppressive or “cold” tumor microenvironment. An ongoing challenge has thus been to harness an immune response in such insensitive tumors. We show that a neoantigen-targeted vaccine in combination with checkpoint modulators can effectively induce de novo neoantigen-specific T cells into the tumor and result in tumor clearance in a murine pancreatic cancer model, Panc02 (Kinkead et al., JCI Insight 2018). Using Panc02 cell line, 12 immunogenic neoantigens have been identified by combining whole exome sequencing and RNAseq with neoantigen prediction algorithms; the latter provide estimates of MHC binding affinity (NetMHC). 20mer long synthetic long peptides (SLPs) were generated with the mutated residue in the center of the peptide. When the pool of peptides were admixed with a STING-targeted adjuvant, transient tumor regression was evoked. However, when combined with an agonist OX40 antibody and an anti-PD-1 antibody, most mice receiving both vaccine and OX40 antibody cleared established tumors. Flow cytometry of these triple-treatment tumors also revealed a less exhausted population of CD8+ T cells within the tumor (evident as a decreased population of PD1+Lag-3+ CD8+ T-cells). We thus provide proof-of-concept for using a neoantigen-targeted vaccine to activate and expand the limited repertoire of T cells specific for the expressed neoantigens with one or more checkpoint modifiers to induce clinically relevant anti-tumor responses in low mutation load tumors. Further work is focused on identifying ways to better identify which neoantigens to include in vaccine. Notably, current algorithms oftentimes “miss” immunogenic epitopes that have a lower binding affinity. We have thus utilized in silico structural modeling to identify structural correlates of immunogenicity with our pool of Panc02 neoepitopes. Importantly, we implicate the importance of solvent-exposed area of the mutated residue with immunogenicity. We note that non-immunogenic epitopes are often buried within the MHC-I molecule and not “seen” the T cell receptor. Finally, we are currently enriching our neoepitope-targeted vaccine with SLPs that would evoke a preferential CD4+ T cell response, which we suspect will further enhance CD8+ T cell cytotoxicity. We hypothesize that these strategies will further enhance the immunogenicity of neoantigen-targeting vaccines and provide new insights into neoantigen prediction for vaccine immunotherapy. * 1. Kinkead, HL, H... Armstrong TD, Jaffee EM, Zaidi N (2018). Combining STING-based neoantigen-targeted vaccine with checkpoint modulators enhances antitumor immunity in murine pancreatic cancer. JCI Insight 18:20.
Citation Format: Neeha Zaidi, Mariya Soban, Shozeb Haider, Fangluo Chen, Todd D. Armstrong, Elizabeth M. Jaffee. Neoantigen targeted vaccine converts pancreatic tumors into immune sensitive tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-020.
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