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Ketogenic metabolic therapy as therapeutic adjunct in patients undergoing immune checkpoint inhibition therapy for non-small cell lung cancer

Award Number: R21CA312387
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2026
PERIOD OF PERFORMANCE END DATE: 06/30/2028

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Ketogenic metabolic therapy as therapeutic adjunct in patients undergoing immune checkpoint inhibition therapy for non-small cell lung cancer - ABSTRACT Immune checkpoint inhibition (ICI) therapy has revolutionized treatment of several cancers including non-small cell lung cancer (NSCLC) but few patients achieve lasting remission. Therefore, much effort is directed at finding approaches to optimize immune response and overcome treatment resistance. We propose study of ‘ketogenic metabolic therapy’ (KMT) as an adjunct to ICI therapy in patients with NSCLC. The state of ketosis has been proposed to enhance therapeutic efficacy in cancer patients via the “Warburg Effect,” since lung and other highly glycolytic tumors are dependent on glucose for growth and are impaired by a ketotic environment. In a recent Nature Medicine report the short-term administration of a ketogenic diet (KD) intervention was shown to boost adaptive immunity in healthy human subjects thereby offering a promising potential adjunct to ICI. In this two- year project, 20 patients with NSCLC will undergo a KMT intervention comprised of three nutritional supplements: beta hydroxybutyrate (BHB), medium chain triglycerides and alpha-ketoglutarate, all contained in a premixed powder form, together with metformin in tablet form which in combination will exogenously induce a state of physiologic ketosis without the requirement for carbohydrate restriction. As compared to a standard KD, the pharmacologic KMT (pKMT) supplement formulation is designed to rapidly and durably induce a state of ketosis while maximizing patient compliance and minimizing burden. The dose of BHB will be the minimum required to achieve the primary endpoint: BHB values above >0.5 mM a minimum of 50% of the time based on home monitoring by study participants. The starting dose of 5g BHB will be adjusted upward in 5g increments as needed to a maximum of 15g to achieve targeted therapeutic levels of ketones. The safety profile of the pKMT intervention is excellent with no dose-limiting toxicity expected. Participants will initiate pKMT three weeks prior to ICI and will continue pKMT for three additional weeks after ICI commences. Based on prior research and investigator experience, the majority should achieve ketosis within one to several days of commencing pKMT regardless of caloric intake and composition of the diet. During the 6-week pKMT intervention, participants will self-monitor glucose and ketone bodies via regular capillary ‘prick’ testing. They will also be measured for body weight and composition, provide blood and fecal samples, and complete surveys on symptoms, side-effects, and quality of life, and dietary recall questionnaires. Primary study endpoints include adherence to the protocol and efficacy of pKMT intervention to induce ketosis. An exploratory aim is to study changes in peripheral immune cell profiles following induction of ketosis. Secondary objectives are to monitor patient quality of life and tumor response to ICI therapy. The two-year study will provide data essential for planning phase 3 trials determining efficacy of pKMT intervention as an adjuvant to immune-boosting cancer therapy.


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 = $432,473 )
2026	2026	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 USF MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Treatment Research	000	1	6/23/2026	NEW	$432,473
														Subtotal = $432,473

Grand Total All Awards = $432,473

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Ketogenic metabolic therapy as therapeutic adjunct in patients undergoing immune checkpoint inhibition therapy for non-small cell lung cancer

Award Number: R21CA312387

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2026

PERIOD OF PERFORMANCE END DATE: 06/30/2028

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