# T Cell Responses to Neoantigens in Fibrolamellar Carcinoma

> **NIH NIH F31** · ST. JUDE CHILDREN'S RESEARCH HOSPITAL GRADUATE SCHOOL OF BIOMEDICAL SCIENCES, LLC · 2022 · $42,752

## Abstract

PROJECT SUMMARY
 Fibrolamellar carcinoma (FLC) is a rare liver tumor with poor outcomes: 5-year overall survival is
reported at only 35-45%, and relapse rates are reported at 57-100%. Surgical resection is currently the
mainstay of treatment, so novel therapies are desperately needed for FLC. A potential therapeutic vulnerability
in this cancer is a characteristic gene fusion between DNAJB1 and PRKACA that is highly specific for FLC,
expressed in all FLC tumors, and necessary to drive FLC tumorigenesis in a mouse model. Genetic mutations
that alter amino acid sequence, including such gene fusions, can be presented as neoantigens on the surface
of cancer cells by human leukocyte antigen (HLA) class I molecules and thereby elicit anti-tumor immune
responses mediated by cytotoxic T cells. T cell receptor (TCR) recognition of neoantigens is the basis of
several types of immunotherapy, which could serve as novel treatments for FLC. The goal of this study is to
test the hypothesis that FLC neoantigens, including the conserved DNAJB1-PRKACA fusion, can elicit T cell
responses in FLC patients and serve as targets for novel T cell-based immunotherapies for FLC.
 Understanding which FLC neoantigens elicit immune responses and which TCRs best recognize those
neoantigens is crucial for both identifying and prioritizing potential targets and therapeutic agents for
immunotherapy. This study will therefore first seek to define the neoantigen landscape in human FLC patients
and identify TCRs specific for putative neoantigens in each patient. The presence of both a conserved
mutation (the DNAJB1-PRKACA fusion) and patient-specific mutations in FLC offers the opportunity to
compare anti-tumor immune responses against conserved and patient-specific neoantigens. This study will
additionally determine which neoantigens are preferentially targeted by the immune response and which TCRs
dominate the anti-neoantigen response to facilitate prioritization of neoantigen targets and neoantigen-specific
TCRs for future study and therapeutic development. Further, these experiments may uncover previously
unknown principles of neoantigen recognition that may be applied to other cancer types.
 Preliminary experiments have already identified both a functional T cell response directed against the
DNAJB1-PRKACA fusion and DNAJB1-PRKACA-specific TCRs in one FLC patient. This study will therefore
also evaluate this conserved fusion protein as a potential target for TCR-engineered immunotherapy
approaches in FLC. TCRs specific for DNAJB1-PRKACA neoantigens will be identified and tested for their
ability to mediate responses against fusion-expressing cells in both in vitro functional assays and proof-of-
principle in vivo experiments using xenograft mouse models. Together, these studies will provide key
foundational data for clinical pursuit of neoantigen-targeted immunotherapies in FLC.

## Key facts

- **NIH application ID:** 10440262
- **Project number:** 5F31CA254423-02
- **Recipient organization:** ST. JUDE CHILDREN'S RESEARCH HOSPITAL GRADUATE SCHOOL OF BIOMEDICAL SCIENCES, LLC
- **Principal Investigator:** Allison Mackenzie Kirk
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $42,752
- **Award type:** 5
- **Project period:** 2021-04-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10440262

## Citation

> US National Institutes of Health, RePORTER application 10440262, T Cell Responses to Neoantigens in Fibrolamellar Carcinoma (5F31CA254423-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10440262. Licensed CC0.

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