The Advent of CAR T-Cell Therapy for Lymphoproliferative Neoplasms: Integrating Research Into Clinical Practice

Abstract

Research on CAR T cells has achieved enormous progress in recent years. After the impressive results obtained in relapsed and refractory B-cell acute lymphoblastic leukemia and aggressive B-cell lymphomas, two constructs, tisagenlecleucel and axicabtagene ciloleucel, were approved by FDA. The role of CAR T cells in the treatment of B-cell disorders, however, is rapidly evolving. Ongoing clinical trials aim at comparing CAR T cells with standard treatment options and at evaluating their efficacy earlier in the disease course. The use of CAR T cells is still limited by the risk of relevant toxicities, most commonly cytokine release syndrome and neurotoxicity, whose management has nonetheless significantly improved. Some patients do not respond or relapse after treatment, either because of poor CAR T-cell expansion, lack of anti-tumor effects or after the loss of the target antigen on tumor cells. Investigators are trying to overcome these hurdles in many ways: by testing constructs which target different and/or multiple antigens or by improving CAR T-cell structure with additional functions and synergistic molecules. Alternative cell sources including allogeneic products (off-the-shelf CAR T cells), NK cells, and T cells obtained from induced pluripotent stem cells are also considered. Several trials are exploring the curative potential of CAR T cells in other malignancies, and recent data on multiple myeloma and chronic lymphocytic leukemia are encouraging. Given the likely expansion of CAR T-cell indications and their wider availability over time, more and more highly specialized clinical centers, with dedicated clinical units, will be required. Overall, the costs of these cell therapies will also play a role in the sustainability of many health care systems. This review will focus on the major clinical trials of CAR T cells in B-cell malignancies, including those leading to the first FDA approvals, and on the new settings in which these constructs are being tested. Besides, the most promising approaches to improve CAR T-cell efficacy and early data on alternative cell sources will be reviewed. Finally, we will discuss the challenges and the opportunities that are emerging with the advent of CAR T cells into clinical routine.

Keywords: CAR T cells; adoptive immunotherapy; cellular therapy; leukemia; lymphoma.

Figure 1

Axicabtagene ciloleucel (axi-cel or KTE-C19) and tisagenlecleucel (tisa-cel or CTL019) structure. The 2 constructs share identical recognition (FMC63-scFv) and signaling (CD3ζ) domains but the co-stimulatory domains differ: CD28 for axi-cel and 4-1BB for tisa-cel.

Figure 2

Possible strategies to improve CAR T-cell efficacy. (A) Pooled CAR T cells, consisting of two or more T-cell populations expressing CAR with distinct antigen specificities. (B) Dual CAR T cells are engineered to co-express CAR molecules with different antigen specificities. (C) Tandem CAR T cells express a bispecific CAR construct harboring two ligand-binding domains with different antigen specificities. (D) The murine-derived scFv is replaced in fully human CAR T cells, in order to limit the occurrence of immune rejection. (E) Armored CAR T cells are modified to secrete cytokines or to express immunomodulatory ligands together with the CAR. (F) CAR T cells can be co-administered with pharmacological agents with immunomodulatory properties.