Lynch Vaccine

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Project 1: Project Summary/Abstract Lynch syndrome (LS) affects ~1.2 million Americans and predisposes them to colorectal cancer (CRC) and other malignancies. LS normal cells acquire somatic second mutations and become DNA mismatch repair deficient (MMRD). MMRD tumors have exceptionally high numbers of frameshift proteins. MMRD mutation rates are so elevated that precisely the same recurrent mutations are “shared” among tumors from different patients. For example, TGFBR2 has a 10bp adenine repeat that, when mutated, causes the identical frameshift protein (FSP) in ~80% of MMRD CRCs. Previously, we showed that (a) 100% of MMRD CRC patients have CD8+ T cells reactive against MMRD rFSPs, (b) performed first-in-human trials showing that peptide vaccination robustly upregulates T-cell immunity against rFSP in advanced MMRD cancer patients, and (c) demonstrated functionally in LS mouse models that vaccination with only four mouse recurrent neoantigens increases CD8+ killer and CD4+ helper T-cell immune response, reduces CRC burden and prolongs cancer-free survival. As new preliminary data, we and CAP-IT CRI Computational Tumor Immunology Core (CTIC) Co-PI Getz, a primary architect of NCI tumor genome atlases, have (a) sequenced the largest number of LS colorectal adenomas and adenocarcinomas worldwide and identified many promising MMRD recurrent neoantigen vaccine candidates, (b) used MMRD CRC cell lines, LS patient colon adenoma derived tumoroids and the NCI CPTAC tumor atlas to confirm that recurrent neoantigens are bona fide expressed as neo-peptides in tumors and (c) showed that in mice, lipo-nanoparticle RNA (LNP-RNA) rFSP vaccination is significantly more immunogenic than peptide vaccination. Here we propose to test the hypothesis that LNP-RNA rFSP vaccination elicits LS mouse CD8+/CD4+ immune response, reduces tumor burden, increases survival (AIM 1), and delineates the most immunogenic cytotoxic Lynch syndrome patient recurrent neoantigens (AIM 2). This project will identify the most immunogenic recurrent neoantigens for NCI PREVENT pre-IND vaccine development and NCI CP-NET LS immunoprevention clinical trials. Importantly, our studies will provide vital mechanistic insights into future generations of effective patient LNP RNA immunoprevention vaccines.