# Exercise as an Immune Adjuvant for Gamma Delta T-cell Therapies in Hematologic Malignancies

> **NIH NIH R01** · UNIVERSITY OF ARIZONA · 2024 · $599,469

## Abstract

SUMMARY: Exercise as an Immune Adjuvant for gd T-cell Therapies in Hematologic Malignancies
gd T-cells are being considered as an alternative to standard CAR ab T-cells for treating leukemic relapse after
hematopoietic stem cell transplantation (HSCT), largely due to their ability to function across MHC barriers
without causing graft-versus-host disease (GvHD)1. gd T-cells can be readily expanded in vitro and in vivo using
zoledronate (ZOL) and have demonstrated anti-tumor activity in preclinical and early phase clinical trials, but
their efficacy against CD19-expressing tumors including acute lymphoblastic leukemia (ALL) and non-Hodgkin’s
lymphoma (NHL) has been modest3. Recently, CD19 CAR gd T-cells were found to have profound effects against
CD19+ tumors in vitro and in xenogeneic mice, albeit inferior to CD19 CAR ab T-cells, although CD19 CAR gd
T-cells were more effective at eliminating CD19 negative escape variants5, 6. As such, if the natural cytotoxicity
of gd T-cells could be enhanced they would become a highly attractive “off the shelf” therapeutic option for ALL
and NHL. Our goal is to improve gd T-cell therapeutics by collecting “superior” gd T-cells that have been mobilized
to peripheral blood by exercise or a synthetic b2-adrenergic receptor (AR) agonist and arming them with a CAR.
We will build on several novel and important observations we have made: (i) a single exercise bout
instantaneously mobilizes gd T-cells bearing a cytotoxic, co-stimulatory and tissue migration phenotype, allowing
their ex vivo manufacture with ZOL+IL-2 to increase by 100-300%4; (ii) exercise expanded gd T-cells have higher
in vitro cytotoxicity against several hematologic tumors4 and are more capable of inhibiting K562 leukemic growth
in xenogeneic mice, particularly when combined with ZOL sensitization; (iii) exercise skews expanded gd T-cells
toward an activated phenotype with heightened NKG2D, TRAIL, DNAM-1 and lowered NKG2A expression, and
blocking these activating receptors, or their ligands on K562 cells, abrogates the exercise effects on gd T-cell
cytotoxicity; and (iv) the mobilization of these superior gd T-cells with exercise is driven by b2-AR activation4. We
hypothesize that exercise will also enhance the quality of CAR gd T-cells by mobilizing gd T-cells with sustained
activation of cytotoxicity, co-stimulation, oxidative phosphorylation, homing and proliferation related genes, and
that this mobilization will be precipitated by increased cAMP signaling. Our aims are: 1) Determine if a single
exercise bout can improve the quality of CAR gd T-cells expanded from healthy donors. 2) Explore the
transcriptomic basis for the enhanced expansion and cytotoxicity of exercise mobilized gd T-cells and expanded
products. 3) Identify the b2-AR signaling pathways responsible for mobilizing gd T-cells with enhanced expansion
and cytotoxicity potential. Our approach involves the use flow cytometry, xenogeneic mouse models, single cell
RNA sequencing, and com...

## Key facts

- **NIH application ID:** 10814921
- **Project number:** 5R01CA277493-02
- **Recipient organization:** UNIVERSITY OF ARIZONA
- **Principal Investigator:** EMMANUEL KATSANIS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $599,469
- **Award type:** 5
- **Project period:** 2023-04-01 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10814921

## Citation

> US National Institutes of Health, RePORTER application 10814921, Exercise as an Immune Adjuvant for Gamma Delta T-cell Therapies in Hematologic Malignancies (5R01CA277493-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10814921. Licensed CC0.

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