Children's Hospital Colorado Foundation Archives

2019

Young Investigator

Mark Kohler

Aurora, CO

Executive Summary:
As relapsed and/or chemotherapy-refractory acute lymphoblastic leukemia (ALL) remains a leading cause of death in pediatric oncology, novel therapies are needed for these patients. Chimeric Antigen Receptor (CAR) expressing T cells have demonstrated great success in putting such patients into remission. However, despite the promise of this therapy, long-term remissions are only achieved in 50% of patients. Thus, strategies to improve the duration of remission induced by CAR T cell therapy are critical to improving outcomes in children with relapsed ALL

When we examine the causes of ALL relapse after CAR T cell therapy, we see that in many patients the CAR T cells do not perform all of the functions expected of unmanipulated T cells when they are activated by their natural T cell receptor (TCR), including the ability to persist long-term and to recognize target cells expressing low levels of antigen. As the behavior of a T cell is dictated by the signals produced by its TCR, we hypothesize that the CAR is unable to recapitulate the signaling of a TCR, leading to suboptimal T cell functions, and ultimately relapse of leukemia. As little is known about the exact nature of CAR signaling, we aim to identify the aspects of the CAR signal that are deficient, with the ultimate goal of rationally re-engineering CAR T cell therapy to increase the number of pediatric ALL patients that achieve long-term remission. To carry out this project we propose the following aims:

Aim 1: To identify differences in the signal transduction pathways of Chimeric Antigen Receptors (CARs) relative to endogenous T Cell Receptors (TCRs) in human T cells.
Aim 2: To identify deficits in CAR signaling upon encountering antigen-low leukemia cells.
Aim 3: To identify interventions to enhance the response of CAR T cells to antigen-low leukemia cells.