CAR-T Cell Therapy: A Door Is Open to Find Innumerable Possibilities of Treatments for Cancer Patients

Abstract

Seven years ago a chronic lymphocytic leukemia patient was for the first time successfully treated with chimeric antigen receptor (CAR)-modified T cells (CAR-T cells) to target CD19 overexpression in tumor cells. This was the beginning of the development of a new type of immunotherapy treatment in cancer patients. Since then, identification of novel antigens expressed in tumor cells and optimization of both CAR constructs and protocols of administration have opened up new avenues for the successful treatment of other hematological malignancies. However, research still continues to avoid some problems such as toxicities associated with the treatment and to find strategies to avoid tumor cell immune evasion mechanisms. On the other hand, for solid tumors, CAR-T therapy results are still in an early phase. In contrast to hematological malignancies, the complex tumor heterogeneity of solid tumors has led to the research of novel and challenging strategies to improve CAR-T cell activity. Here, we will review the main clinical results obtained with CAR-T cells in hematological malignancies, specifically focusing on CAR-T-19 and CAR-T against B-cell maturation antigen (CAR-T-BCMA). Moreover, we will mention the main problems that decrease CAR-T cell activity in solid tumors and the strategies to overcome them. Finally, we will present some of the first clinical results obtained for solid tumors.

Keywords: CAR-T cell immunotherapy; CD19; BCMA; GD2; HER2; EGFRvIII.

Figure 1. Structure of different chimeric antigen receptor (CAR) generations. First-generation CARs contain the single-chain variable fragment bound to the spacer/hinge domain, a transmembrane domain region with CD8 being the most commonly used, and the T-cell receptor CD3z domain. Second-generation CARs add one costimulatory domain to the construct, and third-generation CARs contain more than one costimulatory domain. Fourth-generation CARs contain an inducible or constitutive domain for another protein such as cytokines or specific ligand receptors. scFv: Single-chain variable fragment.