# Identification and assessment of unconventional tumor-associated antigens as potential targets for cytotoxic T-cell based immunotherapy of cancer

> **NIH NIH R01** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2022 · $596,742

## Abstract

PROJECT SUMMARY / ABSTRACT:
Cytotoxic T lymphocyte (CTL)-based immunotherapies have shown great success in the treatment of
patients with several different cancer types. CTLs recognize peptide antigens presented at the tumor cell
surface by HLA class I molecules, triggering specific tumor cell lysis. Defining the nature of such tumor-
associated antigens (TAAs) can directly facilitate therapeutic tumor targeting through a number of
interventions, including personalized vaccines, endogenous T cell infusion, or TCR-engineered
immunotherapies. However, only a minority of human TAAs can be confidently identified using conventional
proteomic methodologies. Recent evidence suggests this may be due to the fact that most of the
immunopeptidome is comprised of peptides derived from ‘non-canonical’ sources such as those derived
from translated introns, RNA editing, proteasome splicing, or containing post-translational modifications.
Although these represent potentially high value tumor targets, few of these have yet been validated as bona
fide TAAs. However, overcoming the challenges inherent in non-canonical TAA identification holds the
promise of significantly expanding the landscape of targetable antigens for cancer patients.
 The specific objective of this project is to identify and assess non-canonical TAAs as potential
therapeutic targets for melanoma, as a necessary prerequisite and foundation for generating effective CTL-
based immunotherapies for treating patients with this disease. It is our central hypothesis that unique, non-
canonical TAAs can constitute shared immunotherapeutic CTL targets, and that those TAAs induced
downstream of oncogenic driver mutations such as BRAF(V600E) will show greater tumor specificity and
refractoriness to antigen loss. We have formulated this hypothesis based on preliminary data showing that
potentially targetable non-canonical TAA peptides can be identified using an integration of highly sensitive
mass spectrometry (MS) combined with genetic sequencing analysis and a novel, in-house bioinformatics
pipeline. We have also shown that constitutive oncogenic MAPK pathway activation leads to dramatic global
tumor immunopeptidome shifts that appear to potentially involve thousands of non-canonical TAAs. There is
a strong clinical rationale for this antigen discovery work since it will directly facilitate the development of
novel, CTL-based therapies with the potential to benefit large numbers of cancer patients.
 The proposed work is innovative, because it will explore different categories of non-canonical TAAs
in cancer and assess their immunogenicity and potential therapeutic value as shared cancer targets. It will
also shed light on the transcriptomic and proteomic changes that occur upon oncogenic-mediated MAPK
pathway activation, and how this influences the tumor immunopeptidome. Lastly, fulfilling the outlined
objectives will have an important positive clinical impact, because they will facilitate development of ...

## Key facts

- **NIH application ID:** 10365225
- **Project number:** 1R01CA258526-01A1
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** PATRICK HWU
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $596,742
- **Award type:** 1
- **Project period:** 2022-07-01 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10365225

## Citation

> US National Institutes of Health, RePORTER application 10365225, Identification and assessment of unconventional tumor-associated antigens as potential targets for cytotoxic T-cell based immunotherapy of cancer (1R01CA258526-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10365225. Licensed CC0.

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