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T Cell Responses to Neoantigens in Fibrolamellar Carcinoma

Award Number: F31CA254423
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 04/01/2021
PERIOD OF PERFORMANCE END DATE: 06/19/2023

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T Cell Responses to Neoantigens in Fibrolamellar Carcinoma - 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = -$46,262 )
2024	2023	ST. JUDE CHILDREN'S RESEARCH HOSPITAL GRADUATE SCHOOL OF BIOMEDICAL SCIENCES, LLC	262 DANNY THOMAS PL # 1500	MEMPHIS	TN	38105	SHELBY	USA	Cancer Research Manpower	000	3	1/4/2024	NON-COMPETING CONTINUATION	-$23,493
2024	2023	ST. JUDE CHILDREN'S RESEARCH HOSPITAL GRADUATE SCHOOL OF BIOMEDICAL SCIENCES, LLC	262 DANNY THOMAS PL # 1500	MEMPHIS	TN	38105	SHELBY	USA	Cancer Research Manpower	002	3	4/24/2024	NON-COMPETING CONTINUATION	-$20,201
2024	2022	ST. JUDE CHILDREN'S RESEARCH HOSPITAL GRADUATE SCHOOL OF BIOMEDICAL SCIENCES, LLC	262 DANNY THOMAS PL # 1500	MEMPHIS	TN	38105	SHELBY	USA	Cancer Research Manpower	001	2	4/24/2024	NON-COMPETING CONTINUATION	-$2,568
														Subtotal = -$46,262

Issue Date FY: 2023 ( Subtotal = $43,694 )
2023	2023	ST. JUDE CHILDREN'S RESEARCH HOSPITAL GRADUATE SCHOOL OF BIOMEDICAL SCIENCES, LLC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Cancer Research Manpower	000	3	3/22/2023	NON-COMPETING CONTINUATION	$43,694
														Subtotal = $43,694

Issue Date FY: 2022 ( Subtotal = $42,752 )
2022	2022	ST. JUDE CHILDREN'S RESEARCH HOSPITAL GRADUATE SCHOOL OF BIOMEDICAL SCIENCES, LLC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Cancer Research Manpower	001	2	6/1/2022	NON-COMPETING CONTINUATION	$716
2022	2022	ST. JUDE CHILDREN'S RESEARCH HOSPITAL GRADUATE SCHOOL OF BIOMEDICAL SCIENCES, LLC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Cancer Research Manpower	000	2	3/24/2022	NON-COMPETING CONTINUATION	$42,036
														Subtotal = $42,752

Issue Date FY: 2021 ( Subtotal = $42,036 )
2021	2021	ST. JUDE CHILDREN'S RESEARCH HOSPITAL GRADUATE SCHOOL OF BIOMEDICAL SCIENCES, LLC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Cancer Research Manpower	000	1	2/19/2021	NEW	$42,036
2021	2021	ST. JUDE CHILDREN'S RESEARCH HOSPITAL GRADUATE SCHOOL OF BIOMEDICAL SCIENCES, LLC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Cancer Research Manpower	001	1	2/19/2021	NEW	$0
														Subtotal = $42,036

Grand Total All Awards = $82,220

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T Cell Responses to Neoantigens in Fibrolamellar Carcinoma

Award Number: F31CA254423

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 04/01/2021

PERIOD OF PERFORMANCE END DATE: 06/19/2023

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