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Defining the features of T cell response to tumor and self-antigens as predictors of response to checkpoint therapy

Award Number: R01CA231226
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2019
PERIOD OF PERFORMANCE END DATE: 12/31/2025

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Defining the features of T cell response to tumor and self-antigens as predictors of response to checkpoint therapy - PROJECT SUMMARY/ABSTRACT Immune checkpoint inhibitor therapies have revolutionized the field of solid tumor oncology - in particular, they have played a substantial role in improving the survival of patients with advanced lung or bladder cancer. However, despite clinical successes, immune checkpoint inhibitors are not effective in all cases, and may be associated with serious immune-related adverse events. This application is in response to the National Cancer Institute’s Provocative Question #8: “What are the predictive biomarkers for the onset of immune-related adverse events (irAE) associated with checkpoint inhibition, and are they related to markers for efficacy?” The goal of the proposed studies is to identify T cell biomarkers that predict autoimmune-related irAE associated with ICI therapy. The central hypothesis for the proposed studies is that the frequency and phenotype of T cells specific for self-antigens predicts autoimmune irAE, which in turn predicts therapeutic efficacy in some patients. The following four Specific Aims will address this hypothesis. Aim 1 studies will determine how immune checkpoint inhibitor therapy alters the frequency and phenotype(s) of tumor- and autoantigen-specific T cells using an innovative approach to isolate antigen-specific T cells, and a longitudinal cohort of subjects before and after immune checkpoint inhibitor therapy. Aim 2 studies will use an innovative single cell RNA-sequencing approach to determine if expanded T cell clones arise with immune checkpoint inhibitor therapy, and whether these T cells have phenotypic or functional properties predictive of anti-tumor and autoimmune responses. Aim 3 studies will determine whether immune checkpoint inhibitor therapy alters the CD4 and CD8 T cell landscape in cancer making it similar to that seen in individuals with natural autoimmunity. Aim 4 studies will test the hypothesis that immune checkpoint inhibitor therapy releases quiescent autoreactive T cells from regulation, leading to increased frequency and activation distinct from the global T cell response. Together, these studies will systematically elucidate the relationship between tumor- and auto- immunity following immune checkpoint inhibitor therapy, and will provide insight into the potential of T cell biomarkers to predict clinical outcome.


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 = $0 )
2026	2024	BENAROYA RESEARCH INSTITUTE AT VIRGINIA MASON	1201 9TH AVE	SEATTLE	WA	98101	KING	USA	Cancer Treatment Research	000	6	5/1/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2024	BENAROYA RESEARCH INSTITUTE AT VIRGINIA MASON	1201 9TH AVE	SEATTLE	WA	98101	KING	USA	Cancer Treatment Research	000	6	8/18/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $465,623 )
2024	2024	BENAROYA RESEARCH INSTITUTE AT VIRGINIA MASON	1201 9TH AVE	SEATTLE	WA	98101	KING	USA	Cancer Treatment Research	000	6	8/31/2024	NON-COMPETING CONTINUATION	$465,623
														Subtotal = $465,623

Issue Date FY: 2023 ( Subtotal = $1,494,377 )
2023	2023	BENAROYA RESEARCH INSTITUTE AT VIRGINIA MASON	1201 9TH AVE	SEATTLE	WA	98101	KING	USA	Trans-NIH Research Support	002	5	9/18/2023	SUPPLEMENT FOR EXPANSION	$648,776
2023	2023	BENAROYA RESEARCH INSTITUTE AT VIRGINIA MASON	1201 9TH AVE	SEATTLE	WA	98101	KING	USA	Cancer Treatment Research	001	5	8/18/2023	NON-COMPETING CONTINUATION	$845,601
2023	2022	BENAROYA RESEARCH INSTITUTE AT VIRGINIA MASON	1201 9TH AVE	SEATTLE	WA	98101	KING	USA	Cancer Treatment Research	000	4	5/25/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $1,494,377

Issue Date FY: 2022 ( Subtotal = $901,309 )
2022	2022	BENAROYA RESEARCH INSTITUTE AT VIRGINIA MASON	1201 9TH AVE	SEATTLE	WA	98101	KING	USA	Cancer Treatment Research	000	4	8/11/2022	NON-COMPETING CONTINUATION	$901,309
														Subtotal = $901,309

Issue Date FY: 2021 ( Subtotal = $423,377 )
2021	2021	BENAROYA RESEARCH INSTITUTE AT VIRGINIA MASON	1201 9TH AVE	SEATTLE	WA	98101	KING	USA	Cancer Treatment Research	000	3	9/1/2021	NON-COMPETING CONTINUATION	$423,377
														Subtotal = $423,377

Issue Date FY: 2020 ( Subtotal = $946,097 )
2020	2020	BENAROYA RESEARCH INSTITUTE AT VIRGINIA MASON	1201 9TH AVE	SEATTLE	WA	98101	KING	USA	Cancer Treatment Research	000	2	8/27/2020	NON-COMPETING CONTINUATION	$946,097
														Subtotal = $946,097

Issue Date FY: 2019 ( Subtotal = $874,780 )
2019	2019	BENAROYA RESEARCH INSTITUTE AT VIRGINIA MASON	1201 9TH AVE	SEATTLE	WA	98101	KING	USA	Cancer Treatment Research	000	1	8/20/2019	NEW	$874,780
														Subtotal = $874,780

Grand Total All Awards = $5,105,563

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Defining the features of T cell response to tumor and self-antigens as predictors of response to checkpoint therapy

Award Number: R01CA231226

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2019

PERIOD OF PERFORMANCE END DATE: 12/31/2025

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