Next frontiers in CAR T-cell therapy

Chimeric antigen receptor (CAR) T-cell therapy is entering a new era, transitioning from an experimental approach being tested in a handful of centers to a more mainstream and broadly investigated therapeutic platform with significant efforts directed towards commercial translation. CARs are synthetic receptors engineered and transduced into T cells to redirect T-cell cytotoxicity by recognition of cell surface antigens expressed on cancer cells. Ongoing innovations into the design and application of CAR T cells are aimed at improving antitumor potency and, at the same time, ensuring safety of this promising therapy. 3 In this issue of Molecular Therapy – Oncolytics, we have invited preeminent authors to focus on the specific issues that comprise the next frontiers in CAR T-cell therapy. The concept and clinical promise of CAR T-cell therapy is best illustrated in the success of CD19-targeted therapies for refractory/ relapsed B-cell malignancies (reviewed in refs. 4–6). The remarkable clinical efficacy demonstrated with CD19-CARs has been achieved at multiple institutions, each evaluating their own CAR T-cell platforms and trial designs. Founding principles that have arisen from this wealth of clinical experience has helped shape our thinking about the parameters key to achieving therapeutic success, as well as management of potential toxicity risks. The application of these concepts to other malignancies is a major focus of current investigations. The reviews presented in this Special Issue address challenges facing successful CAR T-cell therapy: CAR bioengineering, 7 T-cell manufacturing, 8 application of CAR T cells for the treatment of solid tumors, 9 toxicity and safety management (Curran et al. 10), and immune monitoring to gain comprehensive understanding of therapeutic outcomes (Kalos et al. 7 discuss the structure of the CAR as a hybrid antigen receptor, part antibody and part T-cell receptor, comprising an extracelluar antigen-binding domain and intra-cellular signaling domain(s). The antibody single chain variable fragment (scFv) directs T-cell binding to a tumor antigen and the intracellular domain, usually consisting of costimulatory and CD3ζ endodomains, initiates T-cell activation. The modifications of scFv, hinge/spacer length, and intracellular domains can influence T-cell recognition of differential antigen expressed on cancer cells versus normal cells, affinity, proliferation, persistence, and prevention of exhaustion. New generations of CARs, such as ligand CARs (IL-13 receptor), universal CAR systems, and bispecific CARs that can either be activated by two different antigens or inhibi-tory bispecific CARs that can prevent normal tissue destruction, are discussed. Additionally, third-generation CARs or TRUCKs (joint expression of …