# Molecular mechanisms of T cell responses to a clonal neoantigen resulting from a mutated driver oncogene.

> **NIH NIH R37** · SLOAN-KETTERING INST CAN RESEARCH · 2024 · $492,199

## Abstract

PROJECT SUMMARY/ABSTRACT
Immunotherapy induces durable remissions in a subset of patients with highly mutated cancers. However,
most cancers are modestly mutated and fail to respond to current immunotherapy treatments. This is
especially true for malignancies caused by activating mutations in phosphatidylinositol 3-kinase catalytic
subunit alpha (PIK3CA), the most commonly mutated driver oncogene in humans. Mutant PIK3CA cancers
exhibit resistance to conventional treatments, including chemotherapy, hormonal therapy, and antibodies.
Innovative new approaches that bring the curative potential of immunotherapy to PIK3CA mutated cancers are
therefore urgently needed. We and others previously performed detailed immune monitoring studies of
exceptional patient responders to resolve the mechanisms of successful immunotherapy. These analyses
revealed that T cells from responders often recognize neoantigens (NeoAgs) - peptides derived from the
protein products of somatic mutations presented by a patient’s unique complement of human leukocyte antigen
(HLA) molecules. In >99% of cases, NeoAgs are exclusive to an individual patient because they result from
passenger mutations that do not contribute to cancer cell fitness and therefore are subject to clonal
heterogeneity. NeoAg clonal heterogeneity has emerged as a major cause of immunotherapy resistance. We
hypothesize that clonally expressed NeoAgs derived from hotspot mutations in mutant PIK3CA can be
immunogenic and are amenable to therapeutic targeting using T cell receptors (TCRs). In support of our
hypothesis, we discovered through a mass spectrometry (MS) screen that a shared NeoAg derived from
mutant PIK3CA is naturally processed and presented in the context of a prevalent HLA allele. We have termed
this unique subset of antigens “public” NeoAgs because they are cancer-specific yet expressed by groups of
patients, enabling the use of off-the-shelf reagents. Using a novel TCR discovery platform, we successfully
generated multiple T cell clones specific for this PIK3CA public NeoAg, retrieved their unique TCR gene
sequences, and exogenously transferred public NeoAg reactivity to non-specific T cells. These results confirm
the immunogenicity of MS-identified public NeoAgs and enable the development of TCR-based gene
therapies. Building on these preliminary data, we propose in Aim 1 to develop a novel therapeutic approach for
cancers expressing a PIK3CA public NeoAg using TCR gene transfer and adoptive immunotherapy. In Aim 2,
we will establish in cancer patients the frequency, immune-compartmentalization, and potential pathways of
resistance to T cells specific for a PIK3CA public NeoAg. In Aim 3, we will resolve the physical basis for
PIK3CA public NeoAg immunogenicity by studying the physical and structural properties of public NeoAg/HLA
molecules, their wild type counterparts, and the complexes they form with TCRs. Together, this work will
elucidate the fundamental principles governing NeoAg immunoge...

## Key facts

- **NIH application ID:** 10812346
- **Project number:** 5R37CA259177-04
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** Christopher Austin Klebanoff
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $492,199
- **Award type:** 5
- **Project period:** 2021-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10812346

## Citation

> US National Institutes of Health, RePORTER application 10812346, Molecular mechanisms of T cell responses to a clonal neoantigen resulting from a mutated driver oncogene. (5R37CA259177-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10812346. Licensed CC0.

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