# Cancer Immune-Interception for Lynch Syndrome

> **NIH NIH R01** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2021 · $692,579

## Abstract

ABSTRACT
Lynch Syndrome (LS) is the most common cause of hereditary colorectal cancer (CRC), affecting >1 million
Americans. LS is caused by germline mutations in the DNA mismatch repair (MMR) genes. Normal colorectal
epithelial cells in LS patients become MMR deficient upon acquisition of a ‘second’ somatic hit in the alternative
allele of the same MMR gene that harbors the germline mutation, thus triggering the accumulation of hundreds
to thousands of base-to-base mismatches and insertion-deletion mutations (indels) in microsatellite sequences.
These mutations generate frameshift peptides (FSP) that become neoantigens (neoAg) and stimulate the
adaptive immune system. We have reported that LS pre-cancers are immune activated and present strikingly
high levels of expression of adaptive immune genes. Therefore, LS patients constitute a well-defined and
prevalent population that has the potential to benefit from immune-interception strategies to prevent CRC. We
have acquired a substantial amount of genomic data from LS colorectal pre-cancers and tumors to catalog and
to identify the most frequent recurrent neoAg present in these lesions. In addition, we have been studying
chemopreventive strategies that could augment the immune response and observed increased activation of the
resident immune cells in the colorectal mucosa upon exposure to naproxen, a non-steroidal anti-inflammatory
drug (NSAID), from our biomarker analysis of our NCI-sponsored Phase Ib clinical in LS patients. Furthermore,
we have performed a co-clinical trial in a humanized LS mouse model that has observed that peptide vaccination
with neoAg is highly effective in preventing LS CRC with the activity that is further enhanced by its combination
with naproxen, thus laying the foundations for this grant proposal. The central hypothesis of this proposal is
that naproxen is an immune-modulator that activates resident immune cells in the colorectal mucosa, and these
will increase the recognition of NeoAg and activation of resident T-cells eliciting tumor cell killing. To explore this
hypothesis, we propose three specific aims: 1. To characterize the immune cell types that are regulated after
the administration of chemopreventive naproxen and aspirin in LS patients using single-cell genomics and
imaging mass cytometry within a randomized phase II clinical trial; 2. To assess the immunogenicity of candidate
shared neoAg identified LS patients pre-cancers and tumors for personalized immunoprevention using tetramer
bound to magnetic beads in ELISpots, Tetramer stain, and cytotoxicity assays of co-cultured patient-derived
organoids and autologous CD8+ T cells; 3. To profile the T cell Receptor (TCR) of neoantigen-specific CD8+ T
cell clones for tracking tumor immunogenicity in LS patients. The proposed research will significantly impact the
field by developing a combination of a peptide vaccination and an NSAID for immune-interception in hereditary
cancers for the first time. The proposal is...

## Key facts

- **NIH application ID:** 10143786
- **Project number:** 1R01CA257375-01
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Steven M Lipkin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $692,579
- **Award type:** 1
- **Project period:** 2021-09-21 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10143786

## Citation

> US National Institutes of Health, RePORTER application 10143786, Cancer Immune-Interception for Lynch Syndrome (1R01CA257375-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10143786. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*