Donor Derived CD19/CD22 CAR T Cells as Concurrent Therapy Against Relapse in Adults with B-ALL

Stanford University, Stanford CA

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Abstract

Abstract Allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative therapy for patients with hematologic malignancies. Yet, relapse and graft versus host disease (GVHD) are the leading causes of morbidity and mortality. Administering regulatory T cells (Tregs) with the allograft mitigates GVHD but relapse remains a significant issue. Likewise, chimeric antigen receptor (CAR) T cell therapy has contributed to substantial progress in the treatment of patients with hematologic malignancies, but 60% of patients treated with CD19-targeting experience progressive disease. A clinical study of an autologous bispecific CAR targeting CD19 and CD22 (CD19-22.BB.z-CAR = CAR19/22) induced remission in patients with B-cell acute lymphoblastic leukemia (B-ALL) (n=17), but a high rate of relapse was also noted in these patients (NCT03233854). Preclinical and clinical data suggest that donor CAR T cells administered following allo-HCT induce less GVHD compared to unmodified donor T cells. Hence, in a phase I, single center study we are investigating whether relapse may be diminished in patients with B-ALL by combining Treg allo-HCT and donor CD19/CD22 CAR-T cells (NCT05507827). Patients with B-ALL will receive an allo-HCT consisting of purified Tregs, CD34+ hematopoietic progenitor cells, and conventional T cells (Tcons) followed by a consolidative dose of donor CAR19/22. Hence, we will utilize correlative studies from the phase 1 clinical study and a preclinical model assess the following Specific Aims: (1) compare efficacy, toxicity, and pharmacokinetics of human donor CAR19/22 with Treg allo-HCT in a phase 1 clinical trial relative to autologous CAR19/22 and allo-HCT alone, (2) assess the impact of donor CAR19/22 on graft immune reconstitution, and (3) determine the effects of clonal hematopoiesis (CH) mutations and lentiviral integrations among CD19/CD22 CAR T cells. We anticipate that combining donor CAR19/22 with Treg allo-HCT will increase anti-tumor activity and decrease relapse without causing GVHD. The clinical and correlative insights gained from the research proposed in Aims 1 and 2 will guide the use of combined cell therapies in diseases other than B-ALL. Moreover, the studies in Aim 3 regarding CH in CD19/CD22 CAR T cells may identify unanticipated benefits for using donor cells in CAR manufacturing.