The technique of chimeric antigen receptor (CAR) T-cell for cancer immunotherapy has shown very encouraging results in early clinical trials against some advanced, hard-to-treat types of leukemias and lymphomas. What is Chimeric Antigen Receptor (CAR) T-cell for Cancer Immunotherapy? It ia about that T cells are removed from the patient's blood and genetically altered in the lab to have specific antigen receptors (called chimeric antigen receptors, or CARs) on their surface. These receptors could attach to antigens on the surface of cancer cells. The T cells are then multiplied in the lab and infused back into the patient's blood, where they can now seek out the cancer cells and launch a precise immune attack against them.
The basic design of CAR T cells consists of two fundamental domains: (1)the antigen-binding portion(commonly composed of a single-chain variable fragment [scFv] derived from a monoclonal antibody [mAb]) joined to (2) one or more intracellular T-cell signaling domains.
CAR T-cell for cancer immunotherapy: target antigen
The ideal target tumor antigen for CAR T cells has the following key characteristics: expression on all tumor cells including the cancer stem cell, expression on the tumor cell surface, affecting tumor cell survival, and lack of expression on normal tissues.
CAR T-cell for cancer immunotherapy: intracellular signaling
Early CAR designs incorporated one intracellular signaling domain, most commonly the immunoreceptor tyrosine-based activation motif of the CD3ζ chain. However, these first-generation CARs suboptimally activated the T cells and failed to demonstrate clinical benefit in early clinical trials. Enhancementof T-cell activation, persistence,and antitumor efficacy was mediated in second-generation CARs by including additional signaling domains within the CAR construct, most commonly the CD28 or 4-1BB costimulatory signaling domains. The dramatic complete response rates of 70% to 90% in adult and pediatric patients with relapsed/refractory B-cell acute lymphatic leukemia (B-ALL) following infusion of CD19-specific second-generation CAR T cells has resulted in renewed vigor for expanding CAR T-cell technology to other malignancies
To be effective after infusion, CAR T cells must expand, persist, exhibit enduring antitumor cytotoxicity, withstand and/or counteract an immunosuppressive tumor microenvironment, and overcome targeted tumor antigen escape. In designing CAR T cells for cancer immunotherapy, all of these factors must be harmonized to generate the optimal CAR T cell.
Curran K J et al. Chimeric antigen receptor T cells for cancer immunotherapy[J]. Journal of Clinical Oncology, 2015, 33(15): 1703-1706.
Curran KJ et al. Chimeric antigen receptors for T cell immunotherapy. Current understanding and future directions. J Gene Med 14:405-415, 2012.