Chimeric Antigen Receptor-Modified T Cell Therapy in Multiple Myeloma: Beyond B Cell Maturation Antigen

Abstract

Chimeric antigen receptor (CAR)-modified T cell therapy is a rapidly emerging immunotherapeutic approach that is revolutionizing cancer treatment. The impressive clinical results obtained with CAR-T cell therapy in patients with acute lymphoblastic leukemia and lymphoma have fueled the development of CAR-T cells targeting other malignancies, including multiple myeloma (MM). The field of CAR-T cell therapy for MM is still in its infancy, but remains promising. To date, most studies have been performed with B cell maturation antigen (BCMA)-targeted CARs, for which high response rates have been obtained in early-phase clinical trials. However, responses are usually temporary, and relapses have frequently been observed. One of the major reasons for relapse is the loss or downregulation of BCMA expression following CAR-T therapy. This has fostered a search for alternative target antigens that are expressed on the MM cell surface. In this review, we provide an overview of myeloma target antigens other than BCMA that are currently being evaluated in pre-clinical and clinical studies.

Keywords: B cell maturation antigen; CD138; CD19; CD38; SLAMF7/CS1; chimeric antigen receptor-modified T cells; immunotherapy; multiple myeloma.

Figure 1

Chimeric antigen receptor (CAR)-T cells from multiple myeloma (MM) patients are usually manufactured from autologous T cells collected through leukapheresis or venipuncture (step 1). Apart from autologous cells, allogeneic cells or cell lines have been used as starting material (11). Natural killer (NK) cells, γδ T cells, and NK/T cells have been used as alternative lymphocyte subsets for CAR-T manufacturing. In a next step, the cells are expanded ex vivo (step 2) and loaded (step 3) with a lentiviral or retroviral vector carrying the CAR gene. CAR loading can also be accomplished by non-viral methods, including messenger RNA (mRNA) electroporation or using the Sleeping-Beauty (SB) DNA transposon system. The CAR-loaded T cells are administered by intravenous infusion (step 4) to the patient, who has usually received prior lympodepleting chemotherapy (such as cyclophosphamide or fludarabine). The different MM antigens that can serve as targets for CAR-T cell-based immunotherapy are schematically depicted, including their stage of clinical development (published clinical trials, ongoing clinical trials, pre-clinical studies). The insert shows the common structure of a second-generation CAR construct. The extracellular part of a CAR is composed of the antigen-recognition domain from a monoclonal antibody (usually with the V_H and V_L chains in single-chain variable fragment [scFv] format), and an extracellular spacer. The transmembrane (TM) and intracellular domains are the other CAR constituting parts. The latter contains a costimulatory (CO+) domain (e.g., 4-1BB or CD28), and the CD3ζ chain of the T-cell receptor.