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Exercise-Enhanced Off-the-Shelf Allogeneic Cell Therapies for Relapsed Leukemia

Award Number: R01CA311242
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: 06/30/2031

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Exercise-Enhanced Off-the-Shelf Allogeneic Cell Therapies for Relapsed Leukemia - SUMMARY Relapse after allogeneic hematopoietic cell transplantation (alloHCT) remains a primary cause of treatment failure in patients with leukemia. Donor lymphocyte infusion (DLI), while widely accessible, often provides only modest and inconsistent graft-versus-leukemia (GvL) effects. In contrast, allogeneic “off-the-shelf” cell therapies—such as cytokine-induced killer (CIK) cells, ãä T cells, and cytokine-induced memory-like (CIML) NK cells—offer immediate availability, potent antitumor activity, and reduced risk of graft-versus-host disease (GvHD). Yet, there remains a critical need to enhance their therapeutic efficacy and better understand mechanisms that potentiate their function. Exercise has emerged as a powerful immune modulator capable of mobilizing tissue-resident, memory-like, and cytotoxic lymphocyte subsets into the peripheral blood. Our group has demonstrated that acute exercise reprograms the transcriptional landscape and function of CD8. T cells and enhances NK- and T cell–mediated antitumor responses in vitro and in vivo. Preliminary data show that lymphocytes collected during exercise—used to generate CIK, ãä T, and CIML NK cells—exhibit significantly enhanced killing of leukemic targets compared to resting-derived products. Moreover, combinations of these exercise-expanded cell products synergistically amplify anti-leukemic efficacy beyond additive effects. This project will evaluate whether exercise can serve as an upstream biological amplifier to improve the potency and clinical potential of off-the-shelf adoptive cell therapies. Aim 1 will characterize the cytotoxic capacity of exercisederived immune products against leukemic cell lines and primary patient-derived AML and ALL samples, with and without combination therapies such as rituximab and blinatumomab. Blood will be collected pre- and duringexercise from healthy donors enrolled in our ongoing clinical trial (NCT06643221) that examines â-adrenergic regulation of exercise-induced immune mobilization. Aim 2 will test the in vivo efficacy of each product individually and in sequential combination using patient-derived xenograft (PDX) mouse models, assessing tumor burden, survival, and therapeutic synergy. These studies require immunodeficient mouse models engrafted with human leukemia tissues and human immune cell products because no currently available in vitro system can adequately recapitulate the complex in vivo interactions governing human immune cell trafficking, persistence, and anti-leukemic activity. Aim 3 will use CITE-seq and IsoPlexis single-cell proteomics to define transcriptional, surface marker, and cytokine changes that occur in response to exercise, revealing mechanisms underlying reprogramming and synergy. Together, this work will provide novel insights into how acute physical activity enhances adoptive cell therapies, potentially transforming how we generate and deploy immunotherapies for patients with relapsed leukemia. The proposed studies align with the goals of NOSI NOT-CA-24-074 by investigating exercise as a mechanistically defined, behaviorally driven modulator of immune-based cancer interception strategies.


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 = $632,905 )
2026	2026	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Cancer Treatment Research	000	1	6/30/2026	NEW	$632,905
														Subtotal = $632,905

Grand Total All Awards = $632,905

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Exercise-Enhanced Off-the-Shelf Allogeneic Cell Therapies for Relapsed Leukemia

Award Number: R01CA311242

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: 06/30/2031

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