Chimeric Antigen Receptor-T-Cell Therapy for B-Cell Hematological Malignancies: An Update of the Pivotal Clinical Trial Data

Abstract

Chimeric antigen receptor (CAR)-T-cell therapy is an innovative form of adoptive cell therapy that has revolutionized the treatment of certain hematological malignancies, including B-cell non-Hodgkin lymphoma (NHL) and B-cell acute lymphoblastic leukemia (ALL). The treatment is currently also being studied in other B-cell neoplasms, including multiple myeloma (MM) and chronic lymphocytic leukemia (CLL). CD19 and B-cell maturation antigen (BCMA) have been the most popular target antigens for CAR-T-cell immunotherapy of these malignancies. This review will discuss the efficacy and toxicity data from the pivotal clinical studies of CD19- and BCMA-targeted CAR-T-cell therapies in relapsed/refractory B-cell malignancies (NHL, ALL, CLL) and MM, respectively.

Keywords: B-cell malignancies; BCMA; CAR-T cells; CD19; immunotherapy.

Figure 1

Overview of CD19-targeted chimeric antigen receptor (CAR)-T-cell therapies axicabtagene ciloleucel (axi-cel), tisagenlecleucel (tisa-cel), and lisocabtagene maraleucel (liso-cel) in CD19⁺ non-Hodgkin lymphoma (NHL). T cells are collected from the patient by leukapheresis (1) after which they are loaded with the CD19 CAR gene by means of lentiviral or retroviral transduction (2), and ex vivo expanded (3). The resultant CAR-T cells are then administered back to the patient by intravenous (i.v.) infusion (4). Lymphodepleting chemotherapy is usually administered prior to CAR-T-cell infusion in order to promote in vivo CAR-T-cell expansion and persistence. Axi-cel, tisa-cel, and liso-cel are second-generation CARs, of which the intracellular part contains the T-cell receptor ζ chain (CD3ζ) and a co-stimulatory (-CS) domain (CD28 or 4-1BB). The intracellular part is linked by the transmembrane domain (-TM) with the extracellular part of the CAR which is composed of the hinge and the antigen-recognition domain. The three constructs bear a different hinge (-H) but share the same murine FMC63-derived single chain variable fragment (scFv) as antigen-binding domain. B, bendamustine; CD3/CD28, anti-CD3/CD28 microbeads; Cy, cyclophosphamide; Flu, fludarabine; IL-2, interleukin-2; ND, no data; OKT3, anti-CD3 monoclonal antibody; PBMC, peripheral blood mononuclear cells.