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Rational in situ programming of cancer vaccine-responding T-cell clones

Award Number: R01CA261858
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2021
PERIOD OF PERFORMANCE END DATE: 06/30/2026

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Rational in situ programming of cancer vaccine-responding T-cell clones - Project Summary Currently no method exists that would allow physicians to rapidly and reliably establish T-cell immunity against tumor antigens. Bioinformatics tools can predict antigens on cancer cells that are recognized by T cells, but the vaccines based on them often fail because the immunized individuals have too few T cells with the appropriate receptors or lack them altogether. The overall goal of our research proposal is to resolve this problem by developing injectable nanoreagents that introduce into the peripheral T-cell repertoire engineered T-cell receptors (TCRs) that optimally bind the most prevalent vaccine epitope. Specifically, we hypothesize that a customized specificity can be programmed into T cell populations by combining anti-cancer vaccines with techniques that genetically enable endogenous CD8 T cells to express TCRs specific for the vaccines. We further hypothesize that we can use this platform to program CD4 T helper cells with defined MHC class-II- restricted TCRs, and thereby improve tumor-specific CD8 lymphocyte and B cell responses to tumor antigens compared to conventional immunization methods. Our multidisciplinary team of immunologists, bioengineers and geneticists has already established that intramuscularly injected nanoparticles can deliver engineered TCR genes into host T cells so they recognize cancer vaccine antigen. Following rapid vaccine-induced expansion, nanoparticle-programmed T cells ultimately differentiate into long-lived memory T cells. Our long-term goal is to develop a full suite of nanoparticles drugs that would allow physicians to rapidly establish anti-cancer immunity by introducing exogenous antigen-specific TCRs into the patient's T-cell pool. As essential steps toward achieving this goal, we propose the following Specific Aims: (1) To test the wider applicability and long- term safety of programming vaccine specificity into CD8+ T cells, (2) to quantify the degree to which host CD4+ T cells programmed with TCRs to cancer-vaccine antigens boost the immune response, and (3) to determine if providing optimized CD4 T-cell help and reversing tumor immune evasion mechanisms enables in situ programmed vaccine-specific T cells to eradicate disease. We believe that data, reagents, and technology systems generated by our research will provide a conceptual framework for the design of a broad repertoire of gene modification systems designed to generate selective immunity against any type of cancer. Using these in the clinic could make cancer vaccines not only more effective, but also reduce the likelihood of vaccine failure.


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 = $473,651 )
2025	2025	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Cancer Treatment Research	000	6	6/10/2025	NON-COMPETING CONTINUATION	$473,651
														Subtotal = $473,651

Issue Date FY: 2024 ( Subtotal = $449,968 )
2024	2024	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Cancer Treatment Research	000	5	5/3/2024	NON-COMPETING CONTINUATION	$449,968
														Subtotal = $449,968

Issue Date FY: 2023 ( Subtotal = $446,342 )
2023	2023	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Cancer Treatment Research	000	4	6/21/2023	NON-COMPETING CONTINUATION	$446,342
														Subtotal = $446,342

Issue Date FY: 2022 ( Subtotal = $464,178 )
2022	2022	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Cancer Treatment Research	002	3	7/12/2022	NON-COMPETING CONTINUATION	$464,178
2022	2021	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Cancer Treatment Research	003	1	8/16/2022	NEW	$0
2022	2021	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Cancer Treatment Research	000	1	5/26/2022	NEW	-$384,876
2022	2021	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Cancer Treatment Research	001	2	5/27/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$384,876
														Subtotal = $464,178

Issue Date FY: 2021 ( Subtotal = $511,520 )
2021	2021	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Cancer Treatment Research	000	1	5/26/2021	NEW	$511,520
														Subtotal = $511,520

Grand Total All Awards = $2,345,659

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Rational in situ programming of cancer vaccine-responding T-cell clones

Award Number: R01CA261858

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2021

PERIOD OF PERFORMANCE END DATE: 06/30/2026

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