Project 2: Mechanisms of Resistance to Neoantigen Vaccines in PDAC

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ABSTRACT We have made important contributions to the immunobiology of cancer neoantigens, and have developed a robust, publically available, and frequently downloaded suite of software tools for neoantigen prediction. With support from our previous SPORE in Pancreatic Cancer and SU2C, we have now completed enrollment to two phase 1 clinical trials in PDAC testing neoantigen DNA vaccines (NCT03122106) and synthetic long peptide (SLP) vaccines (NCT03956056). Preliminary analyses confirm that both neoantigen vaccine platforms can induce robust immune responses, and suggest that PDAC patients treated with neoantigen vaccines have better than predicted clinical outcomes. We recently developed algorithms for the prioritization of class II neoantigens and demonstrated that optimized vaccines incorporating both class I and II neoantigens improve the success of neoantigen vaccines. With funding from Leidos Biomedical Research, we are currently testing optimized neoantigen SLP vaccines in PDAC patients using a window trial design (NCT05111353). Aim 1: Test the hypothesis that optimized neoantigen vaccines can increase the number and improve the function of neoantigen-specific T cells in PDAC. We are currently testing optimized neoantigen vaccines in PDAC patients following neoadjuvant chemotherapy in the window prior to surgery (NCT05111353). The window clinical trial design provides the opportunity to study neoantigen-specific T cell responses in the tumor microenvironment (TME) after vaccination. In Aim 1, we will use biospecimens from the trial to rigorously assess the functional biology of neoantigen-specific T cells present in the TME using coupled single-cell RNA sequencing (scRNA-seq) and TCR sequencing. Aim 2: Test innovative strategies to address the paucity of cDC1 in PDAC. We have made important contributions to understanding the development and biology of cDC1. We recently demonstrated that cDC1 orchestrate CD4 and CD8 immune responses in cancer, and that PDAC impairs development of cDC1, restraining antitumor immunity. We are currently testing an innovative strategy to expand and license cDC1 in PDAC (NCT04536077). We will test innovative strategies to enhance neoantigen vaccine therapy in PDAC by expanding and licensing cDC1 in vivo. We will also test biospecimens from NCT05111353 and NCT04536077 to evaluate the impact of cDC1 paucity on the response to neoantigen vaccines. Aim 3: Test the hypothesis that the TIGIT pathway restrains the response to optimized neoantigen vaccines in PDAC. We and others have generated data using human specimens and preclinical models suggesting that the TIGIT pathway restrains antitumor immune responses in PDAC. We propose correlative studies to determine if TIGIT signaling also restrains neoantigen-specific T cell responses in human PDAC. These studies have immediate translational relevance given that anti-TIGIT and anti-PD-1 antibodies are currently being tested in early phase clinical trials