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IL21R signaling in CD4 T cells converts transient KRASi responses to long term remissions

Award Number: R01CA303051
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2026
PERIOD OF PERFORMANCE END DATE: 07/31/2031

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IL21R signaling in CD4 T cells converts transient KRASi responses to long term remissions - Project Summary Interleukin-21 is a plieotropic cytokine with potential to augment anti-tumor immunity. Using AI-assisted computational design, we have developed a de novo IL-21 mimic, 21h10, which displays augmented stability and high signaling potency in both humans and mice. Unlike native IL-21, which degrades rapidly upon systemic administration, 21h10 is functionally stable for >24 hours in vivo, allowing for mechanistic interrogation of the roles of IL21R signaling in anti-tumor immunity. Pancreatic ductal adenocarcinoma (PDAC) is refractory to most therapies. Direct inhibitors of KRAS, the dominant oncogene in 90% of PDAC, are clinically promising although patients on these drugs inevitably relapse. We have modeled KRASi response and relapse in mice with orthotopic PDAC and show that - unlike chemotherapy or checkpoint blockade combinations - combination of 21h10 with KRASi is curative. Mechanistically, we show efficacy of 21h10 in PDAC is not dependent on CD8 T cells or MHC class I expression by the tumor, but rather that IL21R signaling engages cDC2-primed CD4 T cells to induce an immune response that converts a transient KRASi effect to a durable response. We hypothesize that, in pancreatic cancer, IL21R signaling expands antigen-specific effector CD4 T cells which are responsible for tumor clearance. In Aim 1, we will define the role of IL21R signaling in anti-tumor immunity. We have shown that CD4 T cells, but not CD8 T cells, B cells, or NK cells, are required for clearance of orthotopic PDAC tumors treated with 21h10 and KRASi. We will use CD4 T cells from various cytokine and receptor gene deficient backgrounds as a source of donor lymphocytes to reconstitute TCRƒÑ-/- PDAC tumor-bearing mice and mechanistically define the role of CD4 T cells in response to IL21R agonism. We will determine which cells present relevant antigen on MHC class II and respond to IFNƒ× using mice with loss of cDC1s versus cDC2s or conditional deletion of MHC class II or IFNgR1 in macrophages, DCs, or B cells. In Aim 2, we will expand the therapeutic window of 21h10. Prolonged dosing of 21h10 damages the exocrine pancreas but spares other organs. Although toxicity can be mitigated by TNFƒÑ blockade, the designed nature of 21h10 makes it highly amenable to further engineering. We will optimize an antibody-drug conjugate approach for affinity and valency of the cytokine. We also have designed a masking domain that binds to 21h10 and can be cleaved by a proteasesensitive linker. 21h10 and variants will be further tested in combination with KRAS inhibition in the KPC GEMM model of spontaneous pancreatic tumors. In Aim 3, we will use human PDAC explant cultures to show that human PDAC can respond to 21h10 and provide critical foundational data to support clinical translation. We will determine whether IL21R expressing CD4 and/or CD8 T cells are activatable and define the transcriptional response elicited from human PDAC T cells. These experiments will offer insight into how this axis can be safely targeted for cancer therapy. Mice are necessary to evaluate the effects of IL-21 signaling in an immune competent whole animal model. Key data will be validated using ex vivo human cultures.


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 = $643,414 )
2026	2026	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Treatment Research	000	1	8/1/2026	NEW	$643,414
														Subtotal = $643,414

Grand Total All Awards = $643,414

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IL21R signaling in CD4 T cells converts transient KRASi responses to long term remissions

Award Number: R01CA303051

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2026

PERIOD OF PERFORMANCE END DATE: 07/31/2031

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