Immunotherapy Using CAR T Cells: Current Challenges and Solutions to Overcome On-Target, Off-Tumor Toxicity

Abstract

Blood cancers like leukemia and lymphoma currently affect approximately 1.3 million Americans and account for about 10% of all cancer related deaths in the US. However, immunotherapies such as chimeric antigen receptor (CAR) T cells have been developed to provide a cure for many of these patients where refractory/relapsed disease was previously a death sentence. Current approaches for CAR T treatment involve the modification of autologous T cells ex vivo in order to engineer these cells with a CAR which binds to a B cell cancer antigen and results in T cell mediated clearance of the target tumor cell. With exception to CD19 and other B cell antigens, targeting other tumor cell types has been largely unsuccessful for many reasons, including antigen escape and on-target off-tumor toxicity (OTOT), which occurs when the target cancer antigen is co-expressed on healthy tissue cells and becomes targeted by the CAR T cell therapy. The purpose of this review is to understand the challenges in antigen escape and OTOT. We will discuss current strategies to overcome these obstacles which allow CAR T therapy to be more applicable to other tumor cell types. We will highlight novel approaches such as logic gated CARs and epitope editing as potential solutions to overcome antigen escape and OTOT.