Challenges and strategies of clinical application of CAR-T therapy in the treatment of tumors-a narrative review

Abstract

Chimeric antigen receptor T-cell (CAR-T) therapy has achieved good therapeutic efficacy in the treatment of hematological malignancies. In August 2017, Novartis Kymriah (CAR-T cells targeting CD19) was approved by the FDA, indicating the real entry of CAR-T cell therapy into clinical applications and making CAR-T cell therapy the most attractive technology in the field of tumor treatment. In October 2017, the FDA approved the world's second CAR-T cell therapy-Yescarta. The launch of these products has attracted wide attention to CAR-T cell therapy. CAR-T cell therapy has achieved significant effect in the treatment of tumors, however, CAR-T therapy also faces clinical problems, such as cytokine release syndrome (CRS), poor therapeutic efficacy in solid tumors, and high rates of tumor recurrence. At present, the side effects of CAR-T therapy have attracted a large amount of attention, which has resulted in investigations into strategy establishment. With a deepening understanding of CAR-T therapy and the continuous optimization of therapeutic regimens, its toxicity and side effects have been partially controlled. This study set out to analyze the problems in the clinical application of CAR-T therapy encountered in recent years and to introduce corresponding strategies, with the aim of providing a basis of reference for clinicians and scientists in the management of CAR-T therapy in clinical practice and in the CAR-T therapy research.

Keywords: Chimeric antigen receptor T-cell (CAR-T); cytokine release syndrome (CRS); solid tumor treatment; strategy; tumor recurrence.

Figure 1

Chimeric antigen receptor (CAR) generations. First generation CARs were composed of the single-chain variable region (scFv) linked to intracellular CD3 zeta (ζ). Second generation CARs incorporated an intracellular signaling motif from a T-cell costimulatory molecule followed by CD3ζ, while third generation CARs include more than one costimulatory molecule in addition to CD3ζ.