Immune checkpoint inhibitors (ICIs) are providing durable clinical responses in about 20% of cancer patients, but these agents have minimal effect in cancers without intratumoral T cells. Approaches that turn currently unresponsive cancers into ones that are more “antigenic” are needed to sensitize tumors to ICIs. Tumor genome mutations can express mutant proteins that are tumor-specific and not expressed on normal cells (neoantigens), and cancers with the highest mutational burdens are more likely to respond to single-agent ICIs. However, most cancers have lower mutational loads resulting in lower antigenicity, weaker endogenous T-cell repertoires, and T cells in the tumor. The best example of a high mutation load cancer is mismatch repair deficient (MMRd) cancers; these cancers often have >1,000 mutations/exome and have a >50% response to anti-PD-1 ICIs. However, cancers including pancreatic ductal adenocarcinoma (PDA) and microsatellite stable colorectal carcinoma (MSS CRC) have on average only 50-70 expressed mutations per exome and do not respond to single-agent ICIs. Emerging data suggest that it should be possible to develop precision immunology approaches that combine a neoantigen targeting vaccine to activate and expand the limited repertoire of T cells specific for the expressed neoantigens found in low-mutation cancers, with ICIs to induce clinically relevant antitumor responses. Challenges to successful immunization include knowledge about the repertoire and functional state of pre-existing antitumor T cells, identification of the best adjuvants, and approaches that more precisely predict which expressed neoantigens are the best T-cell targets for immunization. In addition, we now appreciate that there are many different immune-regulatory signals on T cells, monocytes and other tumor microenvironment cell populations that are likely regulated by the genetic alterations specific to a given patient’s tumor. This talk will discuss current knowledge of precision immune oncology and novel clinical trial approaches under development.
1. Kinkead HL, Hopkins A, Lutz E, Wu AA, Yarchoan M, Cruz K, Woolman S, Vithayathil T, Glickman L, Ndubaku CO, McWhirter SM, Dubensky Jr, TW, Armstroing TD, Jaffee EM, Zaidi N. Combining STING-based neoantigen-targeted vaccine with checkpoint modulators enhances anti-tumor Immunity in murine pancreatic cancer. JCI Insights 2018.
2. Hopkins AC, Yarchoan M, Durham JN, Yusko EC, Rytlewski JA, Robins HS, Laheru DA, Le DT, Lutz ER, Jaffee EM. T cell receptor repertoire features associated with survival in immunotherapy-treated pancreatic ductal adenocarcinoma. JCI Insight 2018;3(13).
3. Yarchoan M, Johnson BA, 3rd, Lutz ER, Laheru DA, Jaffee EM. Targeting neoantigens to augment antitumour immunity. Nat Rev Cancer 2017;17(4):209-22; PMCID: PMC5575801.
4. Yarchoan M, Hopkins A, Jaffee EM. Tumor mutational burden and response rate to PD-1 inhibition. N Engl J Med 2017;377(25):2500-1.
5. Tsujikawa T, Kumar S, Borkar RN, Azimi V, Thibault G, Chang YH, Balter A, Kawashima R, Choe G, Sauer D, El Rassi E, Clayburgh DR, Kulesz-Martin MF, Lutz ER, Zheng L, Jaffee EM, Leyshock P, Margolin AA, Mori M, Gray JW, Flint PW, Coussens LM. Quantitative multiplex immunohistochemistry reveals myeloid-inflamed tumor-immune complexity associated with poor prognosis. Cell Reports 2017;19(1):203-17; PMCID: PMC5564306.
Citation Format: Elizabeth M. Jaffee. Turning the heat up on pancreatic cancer: Lessons on overcoming a “cold” immunologic microenvironment [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr IA01.