Therapeutic potential of activated donor-derived NK and g/d T cell infusion with haploidentical hematopoietic stem cell transplantation 3753

Abstract Description Haploidentical hematopoietic stem cell transplantation (hapHSCT) is a vital treatment for hematologic malignancies, but graft-versus-host disease (GvHD) remains a major complication. NK and γ/δ T cells have potent anti-leukemic effects without triggering GvHD. Activated γ/δ T cells upregulate NKG2D on NK cells, enhancing their ability to target resistant tumors. Although NK cell infusions with hapHSCT have been safe in clinical trials, relapse rates remain a concern. We hypothesize that infusing activated NK and γ/δ T cell-enriched donor cells with hapHSCT will enhance anti-leukemic activity through CD137L/CD137 signaling and increased NKG2D expression, improving outcomes. We demonstrate that magnetic depletion of α/β T and B cells enriches NK and γ/δ T cells, with monocytes as the primary remaining cell type. Functional, transcriptomic, and phenotyping analyses reveal the enriched cells not only kill leukemic cells but exhibit unique activation profiles compared to purified NK cells, with potential for improved efficacy in hapHSCT. To investigate the mechanisms, we developed a bi-directional mouse hapHSCT model using MHCb/k donors and MHCb/d recipients, offering a more clinically relevant model. Flow cytometry and histology confirm engraftment and GvHD development after co-transplantation of T cells. Our study provides insights into NK and γ/δ T cell anti-leukemic mechanisms, with potential to improve hapHSCT outcomes by enhancing anti-tumor responses and minimizing GvHD. Funding Sources UAB Division of Hematology/Oncology Topic Categories Transplantation Immunology (TRAN)