Wednesday, January 15, 2025
1/15/2025
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 comparisons with CD19 CAR ab T-cells in human trials involving exercise with b-blockers and b-agonist infusion models. We expect these aims to identify underpinning mechanisms and pave the way for a clinical trial whereby exercise/b-agonist mobilized gd T-cells can be collected from donors and cancer patients to increase the potency of CAR T-cell therapies to treat refractory disease and relapse after HSCT.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).