# Identifying and targeting neoantigens in aggressive salivary carcinomas

> **NIH NIH R01** · SLOAN-KETTERING INST CAN RESEARCH · 2020 · $545,430

## Abstract

PROJECT SUMMARY/ABSTRACT
We propose to develop a mechanism for effective targeting of neoantigens in salivary gland cancers (SGCs),
which are understudied, treatment-resistant malignancies. This is the first step toward our long-term goal of
employing immunotherapy as a curative treatment for patients with SGC. Currently, most recurrent and
metastatic SGCs are incurable, and effective therapy is lacking. The efficacy of immune checkpoint inhibitors
(ICIs) in SGCs has been largely unexplored, though preliminary data suggest modest response rates. Drawing
upon our understanding of other cancer types, we reason that neoantigens and other genetic and immunologic
features of SGCs may reflect their likelihood of response to ICI, and that such knowledge will reveal tumor
vulnerabilities and nominate the most promising immunotherapeutic strategies for clinical investigation. In our
preliminary data, we show that SGC histologies differ greatly in mutational/neoantigen load and immune
infiltration. Therefore, it is unlikely that one clinical approach will be effective across histologies. We seek to
identify and test neoantigen and immunologic vulnerabilities in four aggressive types of SGC: high-grade
adenocarcinoma and adenoid cystic, salivary duct, and myoepthielial carcinomas. We will first define the
mechanisms of immunogenicity and immune escape in these salivary cancers (Aim #1) through integrated
analyses of exome and RNA sequencing and multiplex immunohistochemistry of clinical tumor samples, and
through mass cytometry of tumor-infiltrating lymphocytes. Of particular interest is the identification of fusion-
associated neoantigens that are shared across multiple SGC patients. We will then identify genetic and
immunologic determinants of SGC response to ICI (Aim #2), taking advantage of biopsies and blood samples
collected as part of our ongoing Phase II clinical trial of combined T cell checkpoint inhibitor therapy (nivolumab
plus ipilimumab). We will have access to serial tissue and blood samples from 64 SGC patients treated with
this combination, enabling exome and RNA sequencing and multiplex immunohistochemistry in tumor samples
and T cell receptor (TCR) sequencing in blood. We will test whether neoantigen load and immune infiltration
correlate with response to treatment; we will also test other genetic and immune factors for correlation with
outcome in exploratory analyses. In Aim #3, we will focus on adenoid cystic carcinoma (ACC), the most
common metastatic SGC histology. Most ACCs are driven by a MYB-NFIB gene fusion, which we have found
can generate immunogenic neoantigens. In patient samples, we will identify fusion-associated immunogenic
neoantigens, then generate TCR-engineered T cells targeting shared neoantigens, and test their efficacy in
humanized mouse models of ACC. Our well-established multi-disciplinary team of SGC investigators will carry
out this research, which will help identify targets for immunotherapy, identify new biomar...

## Key facts

- **NIH application ID:** 9895432
- **Project number:** 5R01DE027738-03
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** Timothy An-thy Chan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $545,430
- **Award type:** 5
- **Project period:** 2018-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9895432

## Citation

> US National Institutes of Health, RePORTER application 9895432, Identifying and targeting neoantigens in aggressive salivary carcinomas (5R01DE027738-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9895432. Licensed CC0.

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