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Defining features of the neoantigen-specific T cell response against a common EGFR mutation in lung cancer

Award Number: F30CA294669
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 07/01/2024
PERIOD OF PERFORMANCE END DATE: 06/30/2028

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Defining features of the neoantigen-specific T cell response against a common EGFR mutation in lung cancer - PROJECT SUMMARY/ABSTRACT Driver mutations confer increased fitness to cancer cells but can also encode neoantigens that stimulate an anti- cancer immune response. This anti-tumor immunity is mediated primarily by T cell receptor (TCR) recognition of mutation-derived peptides presented on Human Leukocyte Antigen (HLA) complexes. L858R promotes unchecked growth and is the most common epidermal growth factor receptor (EGFR) mutation in lung cancer, accounting for 40% of all observed mutations in the protooncogene. How L858R may stimulate an anti-tumor immune response is not yet understood. The objective of the proposed work is to understand the mechanisms through which the EGFR L858R mutation affects tumor biology in provoking anti-tumor immunity. My preliminary data show that L858R-derived peptides are capable of binding to and stabilizing HLA-A*03:01 and HLA-A*11:01 complexes. In two orthogonal assays, L858R peptide-HLA (pHLA) complexes stimulate CD8+ T cells more strongly than wild-type EGFR pHLA complexes. Finally, using pHLA multimer flow cytometry, I have identified CD8+ T cells from healthy donor PBMCs that recognize the L858R pHLA complex through their TCRs. I hypothesize that the EGFR L858R mutation generates an immunogenic neoantigen that provokes T cell- mediated anti-tumor immunity due to the high clonality of the mutation. In Aim 1, I will fully define determinants of L858R immunogenicity by characterizing the EGFR L858R-derived neopeptide and its ability to activate T cells. I will employ HLA immunoprecipitation coupled to liquid chromatography mass spectrometry to identify the L858R peptides presented on HLA, determine the relative contributions of CD4+ and CD8+ T cells in the immune response, and examine exhaustion phenotypes in L858R-specific T cells from patients using single cell RNA and TCR sequencing. In Aim 2, I will determine the ability of EGFR L858R-specific T cells to suppress tumor growth. I will also determine how mutation clonality and pHLA expression affect the anti-tumor immune response. This study employs cutting edge genetic tools and computational approaches to generate a detailed understanding of adaptive immunity against somatic mutations in tumors. Furthermore, this proposal is tailored for a physician-scientist in training, as it investigates clinically relevant determinants of a T cell-mediated immune response against EGFR-mutant cancers, and will inform the development of an adoptive T cell therapy for a large subset of lung cancer patients.


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: 2025 ( Subtotal = $54,538 )
2025	2025	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Cancer Research Manpower	000	2	6/12/2025	NON-COMPETING CONTINUATION	$54,538
														Subtotal = $54,538

Issue Date FY: 2024 ( Subtotal = $53,974 )
2024	2024	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Cancer Research Manpower	000	1	6/14/2024	NEW	$53,974
2024	2024	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Cancer Research Manpower	001	1	6/14/2024	NEW	$0
														Subtotal = $53,974

Grand Total All Awards = $108,512

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Defining features of the neoantigen-specific T cell response against a common EGFR mutation in lung cancer

Award Number: F30CA294669

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 07/01/2024

PERIOD OF PERFORMANCE END DATE: 06/30/2028

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