File Name: designing chimeric antigen receptors to effectively and safely target tumors .zip
Protocol DOI: The expression of synthetic receptors in primary T cells enables the programming of user-defined responses when designing T-cell therapies. Chimeric antigen receptors CARs are synthetic receptors that have demonstrated efficacy in cancer therapy by. Chimeric antigen receptors CARs are synthetic receptors that have demonstrated efficacy in cancer therapy by targeting immobilized antigens on the surface of malignant cells. Recently, we showed they can also rewire T-cell responses to soluble ligands. In contrast to other synthetic receptors, CARs are not only readily engineered by rational design, but also clinically translatable, with robust function in primary human T cells.
Due to their cytotoxic capacity, T cells emerged as attractive candidates for specific immunotherapy of cancer. A promising approach is the genetic modification of T cells with chimeric antigen receptors CARs. First generation CARs consist of a binding moiety specifically recognizing a tumor cell surface antigen and a lymphocyte activating signaling chain. The CAR-mediated recognition induces cytokine production and tumor-directed cytotoxicity of T cells. Second and third generation CARs include signal sequences from various costimulatory molecules resulting in enhanced T-cell persistence and sustained antitumor reaction. Clinical trials revealed that the adoptive transfer of T cells engineered with first generation CARs represents a feasible concept for the induction of clinical responses in some tumor patients.
Chimeric antigen receptors CARs are fusion molecules that may be genetically delivered ex-vivo to T-cells and other immune cell populations, thereby conferring specificity for native target antigens found on the surface of tumour and other target cell types. Antigen recognition by CARs is neither restricted by nor dependent upon human leukocyte antigen antigen expression, favouring widespread use of this technology across transplantation barriers. Signalling is delivered by a designer endodomain that provides a tailored and target-dependent activation signal to polyclonal circulating T-cells. Recent clinical data emphasise the enormous promise of this emerging immunotherapeutic strategy for B-cell malignancy, notably acute lymphoblastic leukaemia. However, CAR T-cell immunotherapy is limited by potential for severe on-target toxicity, notably due to cytokine release syndrome. Furthermore, efficacy in the context of solid tumours remains unproven, owing in part to lack of availability of safe tumour-specific targets, inadequate CAR T-cell homing and hostility of the tumour microenvironment to immune effector deployment. Manufacture and commercial development of this strategy also impose new challenges not encountered with more traditional drug products.
Metrics details. Especially in hematological malignancies, CAR-T cells have achieved exciting results. However, the application of CAR-T cells is obviously hampered by the adverse effects, such as cytokines release syndrome and on-target off-tumor toxicity. In some clinical trials, patients quitted the treatment of CAR-T cells due to life-threatening toxicity. Seeking to alleviate these toxicities or prevent the occurrence, researchers have developed a number of safety strategies of CAR-T cells, including suicide genes, synthetic Notch receptor, on-switch CAR, combinatorial target-antigen recognition, bispecific T cell engager and inhibitory CAR.
Chimeric antigen receptor T cells also known as CAR T cells are T cells that have been genetically engineered to produce an artificial T-cell receptor for use in immunotherapy. Chimeric antigen receptors CARs , also known as chimeric immunoreceptors , chimeric T cell receptors or artificial T cell receptors are receptor proteins that have been engineered to give T cells the new ability to target a specific protein. The receptors are chimeric because they combine both antigen-binding and T-cell activating functions into a single receptor.
Metrics details. Natural killer NK cells are a critical component of the innate immune system. Chimeric antigen receptors CARs re-direct NK cells toward tumor cells carrying corresponding antigens, creating major opportunities in the fight against cancer.