Chimeric Antigen Receptors Modified T-Cells for Cancer Therapy

Abstract

The genetic modification and characterization of T-cells with chimeric antigen receptors (CARs) allow functionally distinct T-cell subsets to recognize specific tumor cells. The incorporation of costimulatory molecules or cytokines can enable engineered T-cells to eliminate tumor cells. CARs are generated by fusing the antigen-binding region of a monoclonal antibody (mAb) or other ligand to membrane-spanning and intracellular-signaling domains. They have recently shown clinical benefit in patients treated with CD19-directed autologous T-cells. Recent successes suggest that the modification of T-cells with CARs could be a powerful approach for developing safe and effective cancer therapeutics. Here, we briefly review early studies, consider strategies to improve the therapeutic potential and safety, and discuss the challenges and future prospects for CAR T-cells in cancer therapy.

Figure 1.

Schematic representation of the chimeric antigen receptor (CAR) structure. A) CARs target surface antigens in a major histocompatibility class–independent manner and are comprised of an extracellular portion typically derived from an antibody and intracellular signaling modules derived from T-cell signaling proteins. First-generation CARs contain a single cytoplasmic domain. Second- and third-generation CARs contain combinations of signaling domains. B) CAR T-cells redirected for universal cytokine killing (TRUCKs) employ a vector encoding the CAR construct that also possesses a cytokine expression cassette. These cytokines such as IL-12 can effectively recruit other components of the immune system to enhance the antitumor immune response toward those cancer cells that are invisible to CAR T-cells. C) To increase the specificity of the CAR T-cells, T-cell signal 1 is separated from signal 2. Both target antigens that are expressed on tumor cells must be engaged to deliver signals 1 and 2 and fully activate CAR T-cells. Normal cells that express only one of two antigens do not signal T-cells sufficiently to accomplish full activation. D) A CAR that delivers a dominant inhibitory signal such as PD-1 and CTLA-4 is coexpressed with a CAR capable of full T-cell activation. Engaging both antigens on normal cells could inhibit T-cell function, whereas encountering only the activating ligand on tumor cells generates a sustained T-cell response. CAR = chimeric antigen receptor; CCR = chimeric costimulatory receptor; iCAR = inhibitory CAR.

Figure 2.

Strategies to improve chimeric antigen receptor (CAR) T-cell therapy. There are various potential strategies to genetically modify T-cells for adoptive therapy to improve CAR T-cell efficacy and safety. Ultimately, combination therapy can be used to enhance the therapeutic potential of CAR T-cells. CAR = chimeric antigen receptor; CCR = chimeric costimulatory receptor; iCAR = inhibitory CAR; EGFR = epidermal growth factor receptor; HSV = herpes simplex virus; IDO = indoleamine 2, 3-dioxygenase; Treg = regulatory T-cell; TRUCKs = T-cells redirected for universal cytokine killing; VEGFR = vascular endothelial growth factor receptor.