Official websites use .gov

A .gov website belongs to an official government organization in the United States.

Secure .gov websites use HTTPS

A lock ( 🔒 ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites.

Need Help

Mechanisms underlying combination therapy mobilizing NK cells

Award Number: R01CA270790
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/17/2022
PERIOD OF PERFORMANCE END DATE: 03/31/2027

Group Awards By:

View Award Description

Mechanisms underlying combination therapy mobilizing NK cells - Checkpoint therapy is remarkably effective against many malignancies that were previously devoid of effective treatment options. Nevertheless, even for the types of cancer where it is effective, many patients do not respond, or their cancers recur. The therapy is ineffective in many other types of cancer. Evidence has accumulated that ineffective checkpoint therapy is often due to either the dearth of neoantigens in a given type or example of cancer, or acquired resistance to therapy, which is frequently due to loss of MHC I antigen presentation or neoantigen expression. Therapeutics that mobilize NK cells may dramatically complement T cell mediated anti- tumor mechanisms, because NK cells do not depend on neoantigens, and are especially effective against MHC- deficient tumors, which arise during checkpoint therapy. Preliminary data show that innate agonists, such as a STING agonist, dramatically synergize with an IL-2 superkine called H9-MSA, leading to NK-dependent indefinite long term tumor free survival in mice with established MHC I-deficient tumors, including the cold B16-B2m-/- model and the MC-38-B2m-/- model, which were otherwise refractory to each therapy alone. Strikingly, this therapy combination was also effective in “curing” mice of MHC I+ B16 tumors, mediated by CD8 T cells, and primary methylcholanthrene (MCA)-induced sarcomas, a highly stringent autochthonous model of cancer that was also refractory to checkpoint therapy, where both T cells and NK cells mediated antitumor effects. In the latter model, the addition of checkpoint therapy led to long term remissions in ~half the animals. In clinical trials, STING agonists alone have been disappointing in cancer patients, but our new evidence of great synergy of STING agonists and IL-2 superkine suggests that the combination may have great potential for applications in human cancer therapy. We will interrogate the mechanisms of synergistic efficacy of this combination, including whether STING agonist, via IFN, protects NK cells from fratricide induced by the superkine, or cooperatively prevents NK desensitization. We will further address the impact of checkpoint therapy on top of or preceding this therapy combination, including understanding how T cells and NK cells cooperate. We will model the acquired resistance of tumors to checkpoint therapy via selection of MHC-loss variants expression in a tumor transfer model. Finally, we will employ the MCA sarcoma model undergoing therapy to test the roles of T cells in selecting MHC I deficient or other NK sensitive variants, and of NK cells in potentially selecting T cell sensitive variants. The culmination of these studies will provide a strong basis for understanding and applying this form of combination therapy in human patients with cancer.


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 = $474,939 )
2026	2026	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	119 CALIFORNIA HALL	BERKELEY	CA	94720	ALAMEDA	USA	Cancer Treatment Research	000	5	3/24/2026	NON-COMPETING CONTINUATION	$474,939
														Subtotal = $474,939

Issue Date FY: 2025 ( Subtotal = $474,939 )
2025	2025	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 201	BERKELEY	CA	94710	ALAMEDA	USA	Cancer Treatment Research	000	4	4/3/2025	NON-COMPETING CONTINUATION	$427,445
2025	2025	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 201	BERKELEY	CA	94710	ALAMEDA	USA	Cancer Treatment Research	001	4	5/30/2025	NON-COMPETING CONTINUATION	$47,494
														Subtotal = $474,939

Issue Date FY: 2024 ( Subtotal = $451,192 )
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 201	BERKELEY	CA	94710	ALAMEDA	USA	Cancer Treatment Research	000	3	3/19/2024	NON-COMPETING CONTINUATION	$427,445
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 201	BERKELEY	CA	94710	ALAMEDA	USA	Cancer Treatment Research	001	3	4/16/2024	NON-COMPETING CONTINUATION	$23,747
														Subtotal = $451,192

Issue Date FY: 2023 ( Subtotal = $465,439 )
2023	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 201	BERKELEY	CA	94710	ALAMEDA	USA	Cancer Treatment Research	000	2	4/25/2023	NON-COMPETING CONTINUATION	$465,439
														Subtotal = $465,439

Issue Date FY: 2022 ( Subtotal = $474,939 )
2022	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 201	BERKELEY	CA	94710	ALAMEDA	USA	Cancer Treatment Research	000	1	5/17/2022	NEW	$474,939
														Subtotal = $474,939

Grand Total All Awards = $2,341,448

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Mechanisms underlying combination therapy mobilizing NK cells

Award Number: R01CA270790

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/17/2022

PERIOD OF PERFORMANCE END DATE: 03/31/2027

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer