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Overcoming Immunotherapy Resistance in Patients with Metastatic Gastric/Esophageal Adenocarcinoma

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: 08/31/2031

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Overcoming Immunotherapy Resistance in Patients with Metastatic Gastric/Esophageal Adenocarcinoma - Abstract Text Development of effective therapies is an urgent unmet medical need for patients with metastatic gastroesophageal adenocarcinoma (mGEA). The combination of immune checkpoint inhibitors (ICI) with chemotherapy has shown efficacy, but most GEAs are heterogeneous and develop resistance to ICI and chemo. This highlights the critical unmet need to unravel tumor heterogeneity and gain mechanistic insights into ICI resistance, so as to develop novel immunotherapy combinations. Our long-term goal is to develop novel immune combination therapies through improved mechanistic understanding of GEA resistance to ICI and chemo. Our preliminary data indicates that (1) ICI induces unexpected vascular endothelial growth factor (VEGF) pathway upregulation characterized by spatial reorganization of the tumor microenvironment (TME) and (2) chemo depletes valuable antitumor immune populations — with both processes contributing to treatment resistance. We hypothesize that these impairments of antitumor immunity are therapeutically actionable or modifiable. To test this hypotheses, we will perform a Phase 2 trial (SEQUEL) utilizing anti-PD-1, anti-angiogenesis therapy, and chemotherapy with the following specific aims: Specific Aim 1 will determine the therapeutic efficacy of a promising novel ICI combination therapy to overcome ICI resistance; Specific Aim 2 will analyze the spatial architecture of the TME to gain mechanistic insights underlying clinical response to this therapy; Specific Aim 3 will define systemic T cell immunity during ICI + anti-angiogenesis therapy with intermittent vs continuous chemo. Our expected outcomes are to show improved clinical efficacy of this ICI combination therapy and to gain critical knowledge on the impact of this combination therapy on tumor-related local and systemic immune responses in patients with mGEA. 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: 2026 ( Subtotal = $748,291 )
2026	2026	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Cancer Treatment Research	002	6	9/15/2026	COMPETING CONTINUATION	$748,291
2026	2025	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Cancer Treatment Research	001	5	9/15/2026	NON-COMPETING CONTINUATION	$0
2026	2025	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Cancer Treatment Research	000	5	10/7/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $748,291

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 = $3,867,424

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Overcoming Immunotherapy Resistance in Patients with Metastatic Gastric/Esophageal Adenocarcinoma

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: 08/31/2031

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