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CD4+ T cells and neoantigens in melanoma immunotherapy.

Award Number: R01CA246547
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/01/2020
PERIOD OF PERFORMANCE END DATE: 11/30/2025

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CD4+ T cells and neoantigens in melanoma immunotherapy. - PROJECT ABSTRACT Recent clinical trials, using checkpoint blockade, antigen-specific T cell receptor (TCR) or CD19-chimeric antigen receptor (CAR), have shown promising clinical results for patients with metastatic cancer. However, despite the impressive and durable clinical response in cancer patients treated with anti-PD-1 antibody, more than 50% of cancer patients fail to respond to this checkpoint blockade treatment. Immunotherapy based on vaccines and TCR in many solid tumors is still lacking due to lack of tumor-specific targets. Therefore, new targets and strategies are urgently needed for the development of immunotherapeutic approaches for solid tumors including melanoma. Whole exome sequencing approach in combination with computer-assisted prediction algorithms has provided an exceptional opportunity to identify new patient-specific antigen targets for cancer immunotherapy. By taking advantage of next-generation sequencing and tumor-reactive T cells, we recently identified many neoantigens recognized by tumor-reactive CD4+ T cells as well as CD8+ T cells. Importantly, we found that some of CD4+ T clones with a single TCR could recognize multiple neoantigens, but not the corresponding wild-type antigens. Recent clinical studies show that mutation-specific CD4+ T cells can mediate tumor growth inhibition in melanoma and epithelial cancers, suggesting that CD4+ T cells play a critical role in inhibiting tumor growth and orchestrating overall antitumor immunity. However, clinical responses of cancer patients are correlated with the trafficking, persistence and cytotoxic ability of T cells. We show that CD4+ T cells can be reprogrammed to increase their cytotoxicity activity against cancer cells. Based on these premises, we hypothesize that neoantigen-specific T cells, in particular CD4+ T cells, play an important role in recognizing neoantigens that drive tumor-specific antitumor immunity, leading to tumor regression. These neoantigens can be identified from melanoma and exploited as therapeutic targets for immunotherapy. We further hypothesize that neoantigen-specific CD4+ T cells can be engineered for improving their T cell persistence and cytolytic activity in combination with anti-PD-1 blockade. Based on these premises, we propose to identify novel neoantigens with emphasis on MHC class II neoantigens using genome-wide sequencing analysis and a genetic targeting expression system (Aim 1). We further plan to investigate whether potent therapeutic antitumor immunity can be generated by immunodominant neoantigen and a novel SAPNANO vaccine technology (Aim 2). Finally, we pursue our studies to determine whether SAPNANO vaccine-induced or T cell transfer immunity can be further enhanced by immune checkpoint blockade or reprogramming T cells to improve their cytotoxicity, (Aim 3). In all, the successful completion of our proposed studies will potentially shift the paradigm by the development of novel immunotherapies for many types of cancer including melanoma.


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 = $640,273 )
2025	2025	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90033	LOS ANGELES	USA	Cancer Treatment Research	000	5	11/21/2024	NON-COMPETING CONTINUATION	$576,246
2025	2025	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90033	LOS ANGELES	USA	Cancer Treatment Research	001	5	2/14/2025	NON-COMPETING CONTINUATION	$0
2025	2025	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90033	LOS ANGELES	USA	Cancer Treatment Research	002	5	6/5/2025	NON-COMPETING CONTINUATION	$64,027
														Subtotal = $640,273

Issue Date FY: 2024 ( Subtotal = $608,260 )
2024	2024	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90089	LOS ANGELES	USA	Cancer Treatment Research	001	4	4/17/2024	NON-COMPETING CONTINUATION	$32,014
2024	2024	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST	LOS ANGELES	CA	90089	LOS ANGELES	USA	Cancer Treatment Research	000	4	11/30/2023	NON-COMPETING CONTINUATION	$576,246
														Subtotal = $608,260

Issue Date FY: 2023 ( Subtotal = $627,467 )
2023	2023	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST	LOS ANGELES	CA	90089	LOS ANGELES	USA	Cancer Treatment Research	001	3	3/16/2023	NON-COMPETING CONTINUATION	$51,221
2023	2023	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST	LOS ANGELES	CA	90089	LOS ANGELES	USA	Cancer Treatment Research	000	3	12/1/2022	NON-COMPETING CONTINUATION	$576,246
														Subtotal = $627,467

Issue Date FY: 2022 ( Subtotal = $627,467 )
2022	2022	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Cancer Treatment Research	001	2	6/13/2022	NON-COMPETING CONTINUATION	$51,222
2022	2022	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Cancer Treatment Research	000	2	11/30/2021	NON-COMPETING CONTINUATION	$576,245
														Subtotal = $627,467

Issue Date FY: 2021 ( Subtotal = $640,273 )
2021	2021	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Cancer Treatment Research	000	1	12/1/2020	NEW	$640,273
														Subtotal = $640,273

Grand Total All Awards = $3,143,740

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CD4+ T cells and neoantigens in melanoma immunotherapy.

Award Number: R01CA246547

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 12/01/2020

PERIOD OF PERFORMANCE END DATE: 11/30/2025

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