Abstract LB066: Acute systemic beta-adrenergic receptor activation to improve graft composition and outcomes in hematopoietic stem cell transplantation

Abstract Background: Graft-versus-host disease (GvHD) and relapse persist as significant hurdles in achieving successful outcomes following allogeneic hematopoietic cell transplantation (alloHCT). The composition of the graft plays a substantial role in influencing transplant outcomes. Higher numbers of naïve CD4 and naïve CD8 T cells correlate with increased GvHD risk, conversely, elevated numbers of NK cells are associated with enhanced graft-versus-leukemia (GvL) effects. Acute systemic β-adrenergic receptor activation triggers the mobilization of favorable effector lymphocytes into the bloodstream, leading to a significant alteration in the composition of circulating immune cells. Aim: This study investigated whether infusion with the non-selective beta-agonist isoproterenol (ISO), following granulocyte colony-stimulating factor (G-CSF) mobilization, would enhance human peripheral blood hematopoietic cell (PBHC) grafts and improve transplant outcomes in NSG mice. Methods: Ten healthy volunteers received ISO infusion (50 ng/kg/min) for 20 minutes after 5 days of G-CSF. Blood samples were collected before and during the last 5 minutes of ISO infusion. Results: ISO infusion increased the total number of G-CSF-mobilized CD34 cells (28±13 cell/µl to 32±13 cells/µl) and significantly improved G-CSF-mobilized PBHC composition, increasing favorable graft cell subsets—NK cells (9.5% to 27.9%) and γδ T cells (5.0% to 7.5%)—and reducing unfavorable graft components—B cells (12.6% to 7.7%), naïve CD4 (18.1% to 11.2%), and naïve CD8 (8.9% to 5.8%) T cells (all p<0.05). NSG mice receiving G-CSF+ISO mobilized grafts exhibited lower GvHD (P=0.012) and extended survival (median survival: G-CSF alone = 45 days, G-CSF+ISO = 78 days) compared to mice receiving grafts mobilized by G-CSF alone. No difference in human CD45 engraftment was observed between the groups, with ~50% engraftment in both groups of mice. Upon challenge with the K562 chronic myeloid leukemia cell line, 42% of NSG-Tg(Hu-IL15) mice receiving G-CSF+ISO mobilized grafts were alive with low tumor burden at day 40, compared to 15% of mice receiving G-CSF mobilized grafts. In vitro, PBHC mobilized by G-CSF+ISO demonstrated an 8-fold increase in cytolysis against K562 compared to PBHC mobilized by G-CSF only (P=0.0002). Conclusion: ISO infusion post-G-CSF treatment favorably enhances graft composition, mitigates GvHD, prolongs survival, and augments GvL effects. Our findings suggest that acute systemic beta-adrenergic receptor activation could be a valuable strategy to enhance outcomes in alloHCT. Citation Format: Helena Batatinha, Grace M. Niemiro, Nicole Pena, Giovannah Hoskin, Preteesh Mylabathula, Forrest Baker, Tiffany Zuniga, Kyle Smith, Douglass Diak, Michael Seckeler, Emmanuel Katsanis, Richard Simpson. Acute systemic beta-adrenergic receptor activation to improve graft composition and outcomes in hematopoietic stem cell transplantation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB066.