Chimeric antigen receptor T-cell lymphoma immunotherapy: the next questions.

Abstract

Chimeric antigen receptor (CAR) T-cell therapy is an innovative form of adoptive cellular immunotherapy targeting CD19 in its most advanced form. Up to 30% of infused patients achieve long-term survival, meaning that 70% of patients still fail to respond or relapse after therapy. This review will address the unresolved issues relating to responders' characterization, relapse prediction, and prevention, CAR T-cell construct optimization, rational combination with other therapies and treatment toxicity, focusing on the management of relapsed/refractory lymphoma patients. Many new antigenic targets are currently investigated and raise the hope of broader successes. However, literature data report that treatment failure is not only related to CAR T construct and infusion but is also due to hostile tumor microenvironment and poor interaction with the host effector cells. Further research should not only target CAR T structure, toxicity and associated therapies, but also tumor-related and host-related microenvironment interactions that lead to treatment failure in relapsed/refractory lymphoma patients. Poor persistence of CAR T and loss of CD19 antigen are well established mechanisms of relapse in Acute Lymphoblastic Leukemia (ALL). A fourth generation of CAR T construct is currently investigated to overcome this issue. In non-Hodgkin lymphoma, mechanisms of treatment failure remain poorly understood but tumor and host microenvironment are undoubtedly involved and should be further investigated. A deeper understanding of CAR T-cell therapy failure in individuals will help personalize CAR T-cell therapy in the future.