CAR-T: What Is Next?

Abstract

The year 2017 was marked by the Food and Drug Administration (FDA) approval of the first two chimeric antigen receptor-T (CAR-T) therapies. The approved indications were for the treatment of relapsed or refractory diffuse large B-cell lymphoma (DLBCL) and for the treatment of patients up to 25 years of age with acute lymphoblastic leukemia (ALL) that is refractory or in a second or later relapse. Since then, extensive research activities have been ongoing globally on different hematologic and solid tumors to assess the safety and efficacy of CAR-T therapy for these diseases. Limitations to CAR-T therapy became apparent from, e.g., the relapse in up to 60% of patients and certain side effects such as cytokine release syndrome (CRS). This led to extensive clinical activities aimed at overcoming these obstacles, so that the use of CAR-T therapy can be expanded. Attempts to improve on efficacy and safety include changing the CAR-T administration schedule, combining it with chemotherapy, and the development of next-generation CAR-T therapies, e.g., through the use of CAR-natural killer (CAR-NK) and CAR macrophages (CAR-Ms). This review will focus on new CAR-T treatment strategies in hematologic malignancies, clinical trials aimed at improving efficacy and addressing side effects, the challenges that CAR-T therapy faces in solid tumors, and the ongoing research aimed at overcoming these challenges.

Keywords: CAR macrophages (CAR-Ms); CAR-NK; CAR-T therapy; CAR-natural killer; chimeric antigen receptor-t.

Figure 1

(a) The T cell, CAR (chimeric antigen receptor), and CAR-T cell. (b) Structure of the CAR-T cell and how it recognizes the tumor cell. The primary construct of a CAR consists of three parts: an antigen recognition domain, a transmembrane domain, and a signaling domain. When the antigen recognition domain of CAR binds to the antigen on the tumor cell, the CAR-T cell will be activated and serve as a ‘living drug’ that attacks and eliminates the tumor cell.

Figure 2

Constitution of general CARs and the third-generation CARs. Left: The primary construct of a CAR consists of three parts: an ectodomain, a transmembrane domain, and an endodomain. An ectodomain contains a single-chain variable antibody domain (scFv) to recognize tumor antigens and a spacer to provide flexibility for binding. The transmembrane region connects the ectodomain and endodomain. The endodomain is responsible for transducing signals, and it is composed of one or more costimulatory molecules, such as cluster of differentiation (CD)28 and 4-1BB, and a stimulatory molecule, CD3ζ. Right: The costimulatory domain of the third-generation CARs includes two costimulatory molecules, CD28 and 4-1BB.