CD45RA-DEPLETED CD19-CAR T CELL CONSOLIDATION AFTER TCR alphabeta+ T CELL-DEPLETED HAPLOIDENTICAL HEMATOPOIETIC CELL TRANSPLANTATION FOR RELAPSED/REFRACTORY CD19+ ALL AND LYMPHOMA

About This Grant

ABSTRACT Allogeneic hematopoietic cell transplantation (allo-HCT) is a curative cellular therapy strategy for pediatric patients with high-risk B-cell ALL but is associated with significant complications, the most consequential of which are relapse, GVHD and the devasting consequences of use of total body irradiation (TBI) as conditioning therapy. CAR T cell therapy has emerged as a novel, powerful cellular therapy for the treatment of relapsed/refractory B- ALL. We now propose to combine these two powerful cellular therapies, namely allo-HCT and transplant donor- derived allogeneic CAR T cell therapy to minimize the risk of relapse and eliminate TBI. In addition, we will use graft engineering approaches to minimize GVHD by select use of immune effectors. We will use for : i) The transplant platform : TCRαβ T cell depletion approach as TCRαβ T cells are key mediators of GVHD and ii) the CART platform : a naïve T-cell depleted product as naïve T cells are key mediators of GVHD leaving behind memory T cells which do not cause GVHD, to manufacture our CAR T cell product, (CD19-CAR(Mem) T cells). We hypothesize that combining allogeneic transplant donor-derived CD19-CAR(Mem) T cells infusion prophylactically after TCRαβ+ T cell depleted alloHCT will provide complimentary and augmented immune-mediated graft-versus-leukemia effects which will decrease risk of relapse and allow for the use of a TBI- free conditioning regimen while maintaining low rates of GVHD. A secondary hypothesis is that that carefully orchestrated correlative studies are needed to decipher the mechanisms of response and resistance of our approach to enable future innovation. We will test these hypotheses in two aims: Aim 1: To assess feasibility, safety, and clinical outcomes of prophylactic CD19-CAR(Mem) T cell infusion after TCRαβ+ depleted transplant and reduced-toxicity TBI-free conditioning. Aim 2: To characterize the fate and function of infused CAR T cells, their impact on immune reconstitution, and mechanisms of response and resistance using advanced state-of-the art correlative testing including TCR analysis and 10x scRNAseq analysis of immune cells and malignant blasts. If successful, this strategy could enable powerful, TBI-free transplant strategies that will lead to long-term remissions with minimal morbidity and mortality for pediatric B-ALL. Extensive correlative data generated will provide critical information for the field of transplantation and cell therapy. While this application is focused on pediatric B-ALL, these findings could be readily applied to broader pediatric and adult populations enabling novel, innovative, combinatorial cell-therapy based approaches across the spectrum of high-risk hematological malignancies.