CART Cell Toxicities: New Insight into Mechanisms and Management
Anas Zahid, Elizabeth L. Siegler, Saad S. Kenderian
Abstract
Immunotherapy has shown substantial promise as a cancer treatment.Significant clinical responses have been achieved through the genetic engineering of autologous T cells with chimeric antigen receptors (CARTs).In CART cell therapy, a patient's T cells are extracted and modified ex vivo to confer greater potency and efficiency in attacking tumor cells.CARs are synthetic receptors made of an extracellular antigen-binding single chain variable fragment (scFv) domain joined to the intracellular signaling components of a T cell receptor [1].CART cells are redirected to the tumor when the antibody-derived scFv binds to its cognate antigen on the cancer cell surface, which triggers T cell activation through the intracellular costimulatory and CD3ζ signaling domains of the CAR.The modular nature of the CAR enables targeting a broad range of tumor cell surface antigens by tailoring the antigen-binding domain on the CAR [2].CD19 is an ideal antigen to target in B cell malignancies, as it is expressed on nearly all B cells and is not expressed on bone marrow stem cells, lowering the risk of offtarget effects of anti-CD19 CART cell therapy [3].The general method of manufacturing CART cells starts with the isolation and collection of a patient's T cells via leukapheresis.The isolated T cells are activated with antibody-coated beads which serve as artificial antigen presenting cells.The activated T cells are genetically modified to express the CAR, most commonly through lentiviral transduction.The resulting CART cells are further expanded ex vivo.The patient typically undergoes a lymphodepleting regimen prior to CART cell reinfusion [4].This is the framework most commonly used to develop CART cells, but there may be significant variations in manufacturing techniques. CART CELLS IN THE CLINICT cells with chimeric antigen receptors cell therapy has led to exceptional success in treating certain hematological cancers, and the Food and Drug Administration (FDA) has approved three CART products, tisagenlecleucel, axicabtagene ciloleucel, and brexucabtagene autoleucel, for B-cell acute lymphoblastic leukemia (ALL), non-Hodgkin lymphoma, and mantle cell lymphoma, respectively.Real-world data are increasingly demonstrating the feasibility of CART cell therapy in patients otherwise ineligible for clinical trials and are signifying the need for novel strategies to mitigate CART-related toxicities [5].