Tuesday, September 16, 2025 9/16/2025

Enhancing engineered T cell therapeutic efficacy for the treatment of pancreatic ductal adenocarcinoma

Award Number: R01CA255039
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/16/2021
PERIOD OF PERFORMANCE END DATE: 07/31/2026

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Enhancing engineered T cell therapeutic efficacy for the treatment of pancreatic ductal adenocarcinoma - PROJECT SUMMARY Pancreatic ductal adenocarcinoma (PDA) is a highly lethal malignancy with a 5-year overall survival of <10%. Lethality is due to late diagnosis, early metastasis and therapeutic resistance. A hallmark characteristic of PDA is the robust fibroinflammatory and suppressive tumor microenvironment that compresses blood vessels and restricts drug access. This tumor microenvironment is also believed to interfere with immunotherapies, which are transforming the standard of care for many other cancer indications. Tumor-antigen specific T cells are responsible for mediating the therapeutic effects of immunotherapy. While much has been learned about suppressive cells within the pancreatic tumor microenvironment, factors that impact the differentiation program of antigen-specific T cells and their antitumor activity is markedly understudied in this disease. We created a novel engineered T cell therapy that shows marked anti-tumor and anti-stromal activity in an aggressive and difficult to treat genetically engineered PDA animal model that recapitulates many aspects of the human disease, including response to immunotherapy. T cells engineered to express a tumor-reactive T cell receptor specific to mesothelin, which is highly expressed by tumor cells yet poorly expressed by normal cells, is safe, destroys the stroma, alters myeloid cell composition, induces objective responses, and significantly prolongs animal survival. Notably, engineered T cells preferentially accumulate in primary tumors and metastasis, challenging the dogma that PDA is immune privileged. Based on this efficacy, candidate T cell receptors specific to mesothelin for use in patients have been identified leading to a Phase 1 clinical trial. However, despite engineered T cell persistence and significant antitumor activity in vivo, a principle obstacle to cure is the progressive loss of engineered T cell function within the suppressive pancreatic tumor microenvironment. While T cell functionality and differentiation are well-studied in other cancer indications, little is understood regarding how the pancreatic tumor microenvironment impacts tumor antigen-specific T cells. Here, we incorporate innovative tools we have developed to identify mechanistically how engineered T cells mediate stromal remodeling, how the tumor adapts and evades anti-tumor T cells, and then use this knowledge to develop a cutting edge engineered T cell therapy for patient treatment with strategic advancements as compared to most cell engineering approaches. Our Specific Aims are to: (1) Identify how engineered T cells mediate stromal remodeling, (2) Identify the contribution of TCR affinity and the tumor microenvironment on T cell differentiation and functionality, and (3) Test the safety and efficacy of a novel cell engineering approach for targeting solid tumors. Our studies will identify characteristics of T cells and the tumor microenvironment that produce durable antitumor responses during immunotherapy to create safe and durable clinical opportunities for pancreatic cancer patient treatment.


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 = $445,845 )
2025	2025	REGENTS OF THE UNIVERSITY OF MINNESOTA	2221 UNIVERSITY AVE SE STE 100	MINNEAPOLIS	MN	55414	HENNEPIN	USA	Cancer Biology Research	000	5	8/12/2025	NON-COMPETING CONTINUATION	$354,563
2025	2025	REGENTS OF THE UNIVERSITY OF MINNESOTA	2221 UNIVERSITY AVE SE STE 100	MINNEAPOLIS	MN	55414	HENNEPIN	USA	Cancer Biology Research	001	5	9/8/2025	SUPPLEMENT FOR EXPANSION	$91,282
														Subtotal = $445,845

Issue Date FY: 2024 ( Subtotal = $423,553 )
2024	2024	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Cancer Biology Research	000	4	7/24/2024	NON-COMPETING CONTINUATION	$336,835
2024	2024	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Cancer Biology Research	001	4	7/25/2024	SUPPLEMENT FOR EXPANSION	$86,718
														Subtotal = $423,553

Issue Date FY: 2023 ( Subtotal = $438,753 )
2023	2023	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Cancer Biology Research	000	3	8/8/2023	NON-COMPETING CONTINUATION	$347,471
2023	2023	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Cancer Biology Research	001	3	9/18/2023	SUPPLEMENT FOR EXPANSION	$91,282
														Subtotal = $438,753

Issue Date FY: 2022 ( Subtotal = $347,471 )
2022	2022	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Cancer Biology Research	000	2	7/31/2022	NON-COMPETING CONTINUATION	$347,471
														Subtotal = $347,471

Issue Date FY: 2021 ( Subtotal = $354,563 )
2021	2021	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Cancer Biology Research	000	1	9/16/2021	NEW	$354,563
														Subtotal = $354,563

Grand Total All Awards = $2,010,185

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Enhancing engineered T cell therapeutic efficacy for the treatment of pancreatic ductal adenocarcinoma

Award Number: R01CA255039

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/16/2021

PERIOD OF PERFORMANCE END DATE: 07/31/2026

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