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Structural modeling of neoantigen presentation for rational design of heteroclitic neoepitope vaccines

Award Number: F32CA271470
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 12/01/2022
PERIOD OF PERFORMANCE END DATE: 12/02/2024
AWARD TERMINATION DATE: 04/09/2025

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Structural modeling of neoantigen presentation for rational design of heteroclitic neoepitope vaccines - Project Summary Pancreatic ductal adenocarcinoma cancer (PDAC) is highly resistant to frontline surgical resection and chemotherapy treatments. Many treatment-resistant cancer types have benefited from immunotherapies that activate cytotoxic anti-tumor T cells against the somatic mutations, or neoantigens, expressed in cancer cells. One major challenge to the development of neoantigen-targeted immunotherapy for PDAC has been the low number and weakly immunogenic profile of identified neoantigens. Efficient activation of neoantigen-specific T cells is dependent on the recognition of 8- to 11-mer neoepitopes displayed on human leukocyte antigen (HLA) class I molecules. This recognition is the culmination of the biophysical and stereochemical contacts between the peptide, HLA, and T cell receptor (TCR) molecules. One mechanism to improve neoepitope immunogenicity is by modifying the peptide amino acid residues to enhance HLA binding or TCR recognition, thereby enhancing cognate T cell activation, while conserving reactivity to the parental epitope. These modified epitopes are termed heteroclitic epitopes. However, the stereochemical features of heteroclitic epitopes that enhance HLA binding or TCR recognition are understudied. Additionally, heteroclitic epitopes have been explored in the context of a limited number of HLA subtypes, restricting their development and application across patients. We hypothesize that rational design of heteroclitic neoepitope vaccines through structural modelling will improve T cell responses against PDAC neoantigens. To address this hypothesis, we will define the structural binding and spatial display dynamics of both shared and private PDAC heteroclitic neoepitopes in diverse HLAs. Among shared neoantigens expressed in PDAC, activating mutations in KRAS at codon 12 are present in up to 80% of PDAC tumors. In Specific Aim 1, we will interrogate the structural mechanics and immunogenic profile of heteroclitic KRAS G12D/V/C epitopes in a panel of 18, globally representative HLA subtypes. In Specific Aim 2, we will develop a computational pipeline to identify, prioritize and optimize patient- specific heteroclitic neoantigen vaccine candidates based on structural epitope features. We will use HLA binding measurements and T cell reactivity assays to validate immunogenic features of our computationally modelled heteroclitic epitopes. Together, these aims will define the structural features of immunogenic neoantigens in diverse HLAs, generate heteroclitic epitope vaccine candidates for shared and private PDAC antigens, and improve the therapeutic potential of cancer vaccines for hard-to-treat cancers such as PDAC.


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: 2026 ( Subtotal = -$10,727 )
2026	2025	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Dietary Supplement Research Program	001	3	1/27/2026	TERMINATION	-$10,701
2026	2024	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Dietary Supplement Research Program	000	2	1/27/2026	NON-COMPETING CONTINUATION	-$26
														Subtotal = -$10,727

Issue Date FY: 2025 ( Subtotal = $5,570 )
2025	2025	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Dietary Supplement Research Program	001	3	4/7/2025	NON-COMPETING CONTINUATION	-$70,555
2025	2025	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Dietary Supplement Research Program	000	3	12/11/2024	NON-COMPETING CONTINUATION	$81,256
2025	2024	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Dietary Supplement Research Program	002	2	5/20/2025	NON-COMPETING CONTINUATION	-$5,131
														Subtotal = $5,570

Issue Date FY: 2024 ( Subtotal = $78,784 )
2024	2024	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Dietary Supplement Research Program	001	2	5/7/2024	NON-COMPETING CONTINUATION	$4,784
2024	2024	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Dietary Supplement Research Program	000	2	12/11/2023	NON-COMPETING CONTINUATION	$74,000
														Subtotal = $78,784

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2022	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Dietary Supplement Research Program	000	1	7/20/2023	NEW	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $71,674 )
2022	2022	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Dietary Supplement Research Program	001	1	8/17/2022	NEW	-$3
2022	2022	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Dietary Supplement Research Program	000	1	5/10/2022	NEW	$71,677
2022	2022	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Dietary Supplement Research Program	002	1	8/17/2022	NEW	$0
														Subtotal = $71,674

Grand Total All Awards = $145,301

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Structural modeling of neoantigen presentation for rational design of heteroclitic neoepitope vaccines

Award Number: F32CA271470

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 12/01/2022

PERIOD OF PERFORMANCE END DATE: 12/02/2024

AWARD TERMINATION DATE: 04/09/2025

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