Vaccines and Immune Prevention in Lynch Syndrome

Aimee Lee Lucas, MD MS

Professor

Chief of Gastroenterology and Hepatology

Mount Sinai Morningside and Mount Sinai West

Disclosures

Advisory Board/Consulting

• Immunovia, Clearnote Health, Exact Sciences

Lynch syndrome

• Lynch syndrome (LS) is an inherited, autosomal-dominant disorder

characterized by germline loss-of-function variants in one allele of the MMR genes

MLH1, MSH2 (EPCAM), MSH6, and PMS2

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• As many as 1 in every 280 people may carry LS-associated germline alterations

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• Cancer risk in LS varies by germline variant; up to 80% lifetime risk for developing CRC

or endometrial cancers.

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• Urgent need to identify novel strategies to prevent cancers in high-risk patients

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Consensus hypothesis: biallelic loss of MMR gene products gives rise to

MMRd epithelial cell populations prior to malignancy

Lynch Syndrome patients have a high risk of developing MMRd colon and endometrial cancer

Endometrium of LS patient with germline pathogenic MMR gene mutation in MSH2

MSH2

Lee et al. Nature Communications. 2022.

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Harrold et al. Nature Medicine. 2023

Microsatellite instability-high (MSI-H) phenotype arises from defective DNA repair mechanisms due to loss of mismatch repair (MMR) activity

Yamamoto et al. Sem in Onc. 2019

Adapted from Gruber et al. JNCCN2002 and Nat. Rev. 2011

Modified from Mestrallet and Brown et al. Front Immunol. 2023.

MMRd cancers encode shared frameshift (fs)-neoantigen encoding mutations

Sharing of fs-neoantigen-encoding mutations in TCGA MMRd cancer cohort

Gene

Patients

Roudko and Czimen-Bozkus et al. Cell. 2020.

Identification of shared fs-peptides in

MSI-H UCEC, COAD, STAD tumors

Roudko et al., Cell, 2020

Circle: fs-peptide

Circle size= # predicted pMHC interactions

Color reflects somatic score of mutation

N=5; SLC35F5, SEC31A, TTK, SETD1B, RNF43 shared among all MSI-H UCEC, COAD and STAD

D’Alise et al. Nature Medicine. 2026

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D’Alise et al. Nature Medicine. 2026

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D’Alise et al. Nature Medicine. 2026

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D’Alise et al. Nature Medicine. 2026

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D’Alise et al. Nature Medicine. 2026

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D’Alise et al. Nature Medicine. 2026

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Phylogenetic trees of LS-associated CRC show that

variants causing MMR loss are highly truncal indicating

that MMR deficiency and potential neoantigen production

may occur early in tumor development

Nat Comm 2022

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Density of T cells in normal mucosa of cancer-free

LS patients c/w increased time to cancer onset

Gastroenterology 2022

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Activation of innate/adaptive immune pathways in polyps

JAMA Oncol. 2018

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Vaccination with cancer fs-neoantigens

(Nacad, Maz, Xirp1, and Senp6) reduced intestinal

tumorigenicity, and prolonged overall survival in LS

preclinical models

Gastroenterology. 2021

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Lynch

Non-Lynch

Bohaumilitzky et al. Gastroenterology. 2022

Modified from Mestrallet and Brown et al. Front Immunol. 2023.

SPECIFIC AIMS

Study Aims:

• Identify quality, shared fs-neoantigens expressed in premalignant adenomas which may contribute to immune surveillance.

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• Evaluate immunogenicity in LS precancerous lesions

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• Identify fs-specific TCRs
• for each of 4 more widely expressed HLA-restrictions
• HLA-A*02:01, HLA-A*11:01, HLA-A*24:02, HLA-B*07:02

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Advantage of shared fs-neoantigens:

• Practical study of neoantigen-specific T cell dynamics at different stages of tumor development

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• Development of immunotherapeutic interventions that do not need to be personalized to each patient

SUMMARY:

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• The identification of neoantigens and neoantigen-specific memory T cells within patients

and the significant expansion of a subset of cytotoxic neoantigen-specific T cells in the

tissues expressing these neoantigen targets suggests antigen-reactivity in situ.

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• These responses may enable precancerous immune surveillance and potential rejection

of epithelial cells expressing fs-neoantigens.

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• Neoantigen targets may be useful for multi-cancer T cell directed and vaccine efforts

in Lynch syndrome.

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Acknowledgements

Project Research Team:

Nina Bhardwaj, MD Phd

Cansu Cimen Bozkus, PhD

Marta Luksza, PhD

Leandra Velazquez

Ana Acuna-villaorduna, MD

Stephanie Blank, MD

Sharonne Holtzman, MD

Vera Mazeeva

Guillaume Mestrallet, PhD

Alexandros Polydorides, MD, PhD

Joyce Serebrenik

Storey Harbison

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Benjamin Greenbaum, PhD (MSKCC)

Claire Friedman, MD (MSKCC)

Jayon Lihm, PhD (MSKCC)

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Samstein Lab:

Miriam Saffern

Natalie Vaninov

Prerna Suri

Ezekiel Olumuyide

Juhana Habib

Carol Alencar Ribeiro

Maame Ackon

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Matthew Brown, PhD

CIP-Net

Thank you.

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