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Serial immunotherapy combination to modulate the tumor environment in patients with metastatic gastroesophageal cancer

Award Number: R01CA248147
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2021
PERIOD OF PERFORMANCE END DATE: 12/31/2026

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Serial immunotherapy combination to modulate the tumor environment in patients with metastatic gastroesophageal cancer - PROJECT SUMMARY/ABSTRACT Development of effective therapies is an urgent unmet medical need for patients with metastatic gastroesophageal adenocarcinoma (mGEA). The advent of immune checkpoint inhibitors such as anti- programmed death (PD)-1 antibodies has revolutionized treatment of some cancers but benefits only a minority of patients with GEA. Combination approaches are required to extend this benefit to more patients. Most studies of immunotherapy combinations in GEA initiate PD-1 blockade at the same time as cytotoxic therapy despite the possibility that cytotoxic agents may kill some of the very T cells invigorated by PD-1 blockade, as our group and others have shown. Our long-term goal is to develop immunotherapy combinations that avoid this problem through rational sequencing of immunotherapy with other anti-cancer agents to enhance tumor destruction and improve patient survival. Based on our preliminary data, we hypothesize that serial combination immunotherapy utilizing anti-PD-1 and anti-angiogenesis therapy with immunomodulatory chemotherapy in a predefined sequence leads to meaningful improvements in clinical outcomes in association with disruption of the immunosuppressive tumor microenvironment and promotion of antitumor systemic immune responses. To test this hypothesis, we will perform a phase II trial to determine the therapeutic efficacy of serial combination immunotherapy and examine its impact on local and systemic immune responses in patients with mGEA through the following specific aims: Aim 1 will determine the therapeutic efficacy of serial combination immunotherapy in patients with metastatic GEA. Aim 2 will interrogate patient samples collected longitudinally from the parent trial to identify the impact of serial immunotherapy on immunosuppressive, antitumor, and angiogenic components within the tumor environment, including tumor- related local and systemic immune responses. Our expected outcomes are to show improved clinical efficacy using an innovative immunotherapy combination in which PD-1 blockade is delivered in a predefined sequence and to gain critical knowledge on the impact of this serial immunotherapy approach on tumor-related local and systemic immune responses in patients with mGEA patients. Together, these new proof-of-concept data are expected to inform the design of future definitive clinical trials that can improve the survival of patients with immunotherapy-resistant metastatic GEA.


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 = $627,404 )
2025	2025	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Cancer Treatment Research	002	5	6/4/2025	NON-COMPETING CONTINUATION	$62,740
2025	2025	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Cancer Treatment Research	001	5	2/14/2025	NON-COMPETING CONTINUATION	$0
2025	2025	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Cancer Treatment Research	000	5	1/3/2025	NON-COMPETING CONTINUATION	$564,664
														Subtotal = $627,404

Issue Date FY: 2024 ( Subtotal = $591,765 )
2024	2024	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Cancer Treatment Research	001	4	4/18/2024	NON-COMPETING CONTINUATION	$31,143
2024	2024	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Cancer Treatment Research	000	4	12/13/2023	NON-COMPETING CONTINUATION	$560,622
														Subtotal = $591,765

Issue Date FY: 2023 ( Subtotal = $620,514 )
2023	2023	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Cancer Treatment Research	001	3	3/16/2023	NON-COMPETING CONTINUATION	$50,651
2023	2023	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Cancer Treatment Research	000	3	1/4/2023	NON-COMPETING CONTINUATION	$569,863
														Subtotal = $620,514

Issue Date FY: 2022 ( Subtotal = $639,268 )
2022	2022	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Cancer Treatment Research	000	2	1/6/2022	NON-COMPETING CONTINUATION	$575,342
2022	2022	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Cancer Treatment Research	002	2	8/23/2022	NON-COMPETING CONTINUATION	$12,787
2022	2022	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Cancer Treatment Research	001	2	4/25/2022	NON-COMPETING CONTINUATION	$51,139
														Subtotal = $639,268

Issue Date FY: 2021 ( Subtotal = $640,182 )
2021	2021	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Cancer Treatment Research	000	1	12/21/2020	NEW	$640,182
														Subtotal = $640,182

Grand Total All Awards = $3,119,133

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Serial immunotherapy combination to modulate the tumor environment in patients with metastatic gastroesophageal cancer

Award Number: R01CA248147

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/01/2021

PERIOD OF PERFORMANCE END DATE: 12/31/2026

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