Chimeric Antigen Receptor T Cells: A Race to Revolutionize Cancer Therapy

Abstract

For years, cancer treatment was dominated by chemotherapy, radiation therapy, and stem cell transplantation. New insights into genetic characteristics of leukemic cells have initiated the development of the chimeric antigen receptor (CAR) T-cell therapy. This type of adoptive cell immunotherapy has been a breakthrough in the treatment of aggressive B-cell lymphoma and B-cell precursor acute lymphoblastic leukemia. In August 2018, the European Commission has approved the first CAR T-cell products - tisagenlecleucel (Kymriah®, Novartis) and axicabtagene ciloleucel (Yescarta®, Gilead) - for hematological neoplasms in Europe. As CAR T cells are a living drug, its benefits can last for many years. The administration of CAR T cells is a complex and costly endeavor involving cell manufacture, shipping of apheresis products, and management of novel and severe adverse reactions. The most common toxicities observed after CAR T-cell therapy are cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome. Current research focuses on improved safety and efficacy in hematological malignancies as well as the translation of CAR T-cell therapy to solid tumors. This review covers the development and current status of CAR T-cell therapy in a clinical setting with focus on challenges and future opportunities.

Keywords: Cancer immunotherapy; Chimeric antigen receptor T cells; Lymphoma; Toxicities.

Fig. 1

Evolution of CAR generations. First-generation CARs consist of the CD3ζ alone, whereas the second generation includes additional costimulatory signaling domains (CD28 or 4-1BB). The third generation combines two costimulatory domains (e.g., CD28 and 4-1BB). Fourth-generation CARs are additionally armored with genes that enable, for example, the expression of cytokines. scFV, single-chain variable fragment; CD3ζ, cluster of differentiation 3 zeta; CD28 + 4-1BB, costimulatory signaling domains. Adapted from Brentjens and Curran [13].

Fig. 2

CAR T-cell therapy. T cells are collected from the patient and genetically modified to include antigen receptors that combine the single-chain variable fragment of an antibody with intracellular signaling domains. Thus, they can recognize tumor cells expressing a tumor-associated antigen using lentiviral-vector technology. Engineered CAR T cells are expanded in the laboratory and transfused back into the patient.