# Lynch Vaccine

> **NIH NIH U54** · WEILL MEDICAL COLL OF CORNELL UNIV · 2022 · $441,081

## Abstract

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.

## Key facts

- **NIH application ID:** 10505678
- **Project number:** 1U54CA272688-01
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Steven M Lipkin
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $441,081
- **Award type:** 1
- **Project period:** 2022-09-01 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10505678

## Citation

> US National Institutes of Health, RePORTER application 10505678, Lynch Vaccine (1U54CA272688-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10505678. Licensed CC0.

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