# Neoantigen Vaccination for Lynch Syndrome Immunoprevention

> **NIH NIH U01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2021 · $638,061

## Abstract

Lynch syndrome (LS) is a genetic disease predisposing to colorectal cancer (CRC) that affects more than one
million Americans. Germline mutations in DNA mismatch repair (MMR) genes, primarily MLH1 and MSH2,
cause deficient DNA mismatch repair (dMMR) and LS. LS CRCs have exceptionally high numbers of small
insertion/deletion frameshift and missense mutations. Elevated dMMR mutation rates cause some mutations to
recurrently arise in tumors from different patients. For example, the human TGFβR2 gene has a poly(A) coding
repeat, and the same “shared” frameshift mutation is recurrently identified in >60% of LS dMMR CRCs. Here,
we will use state of the art tools to systematically delineate recurrent LS mouse and human pre-malignant
neoantigens, test whether vaccination with frequently mutated “shared” immunogenic neoantigens reduces LS
mouse CRC penetrance, and elucidate adaptive immune mechanisms for CRC immunoprevention. In Aim 1
we will comprehensively delineate frequently mutated recurrent neoantigens in Lynch syndrome mouse
colorectal mucosa and adenomas. This will provide insights into pre-malignant colon dMMR immunoediting
mechanisms, the timing and sequence of dMMR neoantigen appearance, and systematically delineate the
most immunogenic recurrent shared dMMR neoantigen vaccine targets for LS mouse CRC immunoprevention.
In Aim 2 we will test the hypothesis that recurrent neoantigen vaccination reduces mouse Lynch syndrome
mismatch repair deficient epithelial cells in colon mucosa. This will give insights into the mechanism of dMMR
colon mucosal immunoediting, and test the efficacy and safety of a dMMR recurrent neoantigen vaccine
strategy using the earliest neoantigen mutations for LS immunoprevention. In Aim 3, we will test the hypothesis
that recurrent neoantigen vaccination reduces mouse Lynch syndrome colorectal tumor burden. This will
evaluate the efficacy and safety of a dMMR recurrent adenoma neoantigen vaccine strategy for Lynch
syndrome immunoprevention and provide insights into the mechanisms of dMMR immunoediting. Finally, in
Aim 4 we will systematically delineate Lynch syndrome patient adenoma recurrent neoantigens. This will
delineate the most promising candidate recurrent neoantigens that can be used for LS patient tumor vaccine
clinical trials and give insights into dMMR immunoediting mechanisms. Our overall goal is to develop effective,
safe mechanism based neoantigen vaccination strategies for Lynch syndrome CRC immunoprevention.

## Key facts

- **NIH application ID:** 10240627
- **Project number:** 5U01CA233056-04
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Steven M Lipkin
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $638,061
- **Award type:** 5
- **Project period:** 2018-09-30 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10240627

## Citation

> US National Institutes of Health, RePORTER application 10240627, Neoantigen Vaccination for Lynch Syndrome Immunoprevention (5U01CA233056-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10240627. Licensed CC0.

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