Project Summary/Abstract Overall Acute Myeloid Leukemia (AML) and multiple myeloma (MM) are diseases of the elderly, with median incidence of disease beyond 60 years of age. The mainstay of curative therapy for adult acute leukemia over the last two decades in younger patients has been allogeneic stem cell or bone marrow transplantation (hereafter referred to as HCT) but relapse remains the major limitation. MM has no traditional curative therapeutic options and induction therapy is typically consolidated with autologous stem cell transplantation to prolong progression free survival. However, relapse is largely inevitable. BCMA-targeted chimeric antigen receptor (CAR) T cells induce very high initial responses in relapsed/refractory MM but again, relapse dominates the clinical course of most patients. T cell receptor transgenic (TCR Tg) T cells have recently shown promise in the prevention and treatment of AML relapse after HCT. Unfortunately these Adoptive Cell Therapies (ACT) are also limited by opportunistic infection and immune toxicity, namely graft-versus-host disease (GVHD) after HCT, and Cytokine Release Syndrome (CRS) after CAR T cell therapy. Project 1 of this Adult Leukemia Research Center (ALC) grant seeks to understand the immunological underpinnings of immune toxicity and pathogen / leukemia and myeloma specific immunity after ACT in preclinical systems, modelling the clinical studies within projects 2 and 3 in order to define innovative new approaches to prevent relapse and infection. In Project 2, we will design and test new synthetic receptors that target MM antigens (Ag) with greater sensitivity and evaluate a novel approach for incorporating co-stimulation to augment and sustain T cell function. Relapse is frequently associated with loss of CAR T persistence and we will test a strategy that enriches memory stem cell phenotypes in engineered T cells to improve persistence and potency. Finally, we will interrogate a rich resource of samples from BCMA CAR T treated patients using high dimensional analysis to identify additional tumor intrinsic and extrinsic mechanisms associated with relapse that would inform further innovations to improve outcomes. Project 3 will study the ability and mechanisms by which a new generation of TCR Tg T cell targeting the Wilms tumor-1 (WT1) protein may prevent relapse in patients with high risk AML in patients who are not candidates for HCT. All clinical studies will be accompanied by high dimensional analysis of immune factors governing treatment success and failure. These highly interactive projects will be supported by Administration, Biostatistics and Data Management, High Dimensional Cellular and Spatial Analysis and Long Term Follow Up cores. This P01 renewal will bring together innovative preclinical and clinical mechanistic studies underpinning novel transplant and T cell engineering platforms aimed at overcoming current cell therapy limitations, namely toxicity and relapse. The program will...