Defining the Mechanisms of Immune Escape After Adoptive T cell Therapies

Abstract Disease relapse, graft-versus-host disease (GVHD)/cytokine release syndrome (CRS) and opportunistic infection are major limitations of adoptive cell therapy (ACT) that includes hematopoietic cell transplantation (HCT), chimeric antigen receptor (CAR) and T cell receptor (TCR) transgenic T cell therapies. Cytomegalovirus (CMV) infection is a frequent and life-threatening infectious complication in these immune suppressed patients that significantly limits the successful outcome of HCT. We have developed innovative preclinical models of CMV reactivation and both leukemia and multiple myeloma (MM) relapse after ACT. In the HCT setting, we have modelled the two most promising platforms to improve transplant outcome that were developed within the current P01, namely naïve T cell (Tn) depletion and post-transplant cyclophosphamide (PT-Cy). We demonstrate profound effects on alloantigen driven T cell exhaustion, residual stem-like memory T cell populations and NK cell expansion in the bone marrow. We plan to utilize our unique, but well-established preclinical models to define the impact of these new clinical HCT platforms on the cellular and molecular pathways that mediate pathogen and leukemia specific immune responses, with the aim of using new synthetic cytokines to enhance critical protective immunity. We will expand these studies to new fully murine CAR T cell models of B cell leukemia and MM, focussing on identification of pathways of both toxicity and immune escape, again with the aim of generating new therapeutic approaches to optimize outcomes. These preclinical studies will be leveraged to expand and optimize those planned in Projects 2 and 3. In this manner we will facilitate the development of a new generation of cell therapies.