CAR T cells: driving the road from the laboratory to the clinic

Abstract

Blockbuster antibody therapies have catapulted immune-based approaches to treat cancer into the consciousness of mainstay clinical research. On the back of this, other emerging immune-based therapies are providing great promise. T-cell therapy is one such area where recent trials using T cells genetically modified to express an antibody-based chimeric antigen receptor (CAR) targeted against the CD19 antigen have demonstrated impressive responses when adoptively transferred to patients with advanced chronic lymphocytic leukemia. The general concept of the CAR T cell was devised some 20 years ago. In this relatively short period of time, the technology to redirect T-cell function has moved at pace facilitating clinical translation; however, many questions remain with respect to developing the approach to improve CAR T-cell therapeutic activity and also to broaden the range of tumors that can be effectively targeted by this approach. This review highlights some of the underlying principles and compromises of CAR T-cell technology using the CD19-targeted CAR as a paradigm and discusses some of the issues that relate to targeting solid tumors with CAR T cells.

Functional Tuning of CARs Reveals Signaling Threshold above Which CD8+ CTL Antitumor Potency Is Attenuated due to Cell Fas–FasL-Dependent AICD

“…CARs are capable of mediating multiplexed signaling outputs that trigger redirected antitumor T-cell effector function (24)(25)(26). It stands to reason that the tuning of CARs for effective T-cell antitumor activity will be more stringent in solid tumor applications, and that empiric designs of CARs based on limited understanding of the impact of their composition on in vivo antitumor function will only hamper progress in human clinical applications.…”

Metabolic regulation of immune responses: therapeutic opportunities

“…Ho and colleagues demonstrated that recombinant expression of PCK1 in tumor-infiltrating CD4 T cells restores PEP levels and normal TCR signaling (21). An exciting prospect would be the use of this strategy in adoptive transfer-based immunotherapies, such as CAR T cell therapies or allogeneic NK cell therapies, which, despite impressive responses in hematological malignancies, have not been effective in the treatment of solid tumors (29,106). As these therapeutic approaches involve manipulation of isolated lymphocytes in the lab, it is entirely feasible to further engineer these cells to express recombinant PCK1.…”

Spotlight on chimeric antigen receptor engineered T cell research and clinical trials in China

“…Also, the limited expression time is preferable for CARs targeting antigens with potential risk (Kenderian et al, 2015;Krug et al, 2014). Theoretically, lentiviruses and transposons can transfect undivided cells, and thus avoid stimulation induced T cell differentiation; however, stimulation with mitogenic agents is still needed to change the resistant state of primary T cells (Cheadle et al, 2014;Morgan and Kakarla, 2014). Besides, transcription activator-like effector nuclease (TALEN) system is used to knock out TCR and CD52, in order to achieve "off the shelf" CAR-T cells (Couzin-Frankel, 2015;Poirot et al, 2015).…”