Abstract IA01: Turning the heat up on pancreatic cancer: Lessons on overcoming a “cold” immunologic microenvironment

Abstract

Abstract 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.