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 surfa...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. In that context,CARs are generally targeted against the ubiquitous B-cell antigen,CD19. 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. Finally,there is increasing interest in the application of this technology to the treatment of non-malignant disease states,such as autoimmunity,chronic infection and in the suppression of allograft rejection. Here,we consider the background and direction of travel of this emerging and highly promising treatment for malignant and other disease types.展开更多
基金Supported by The Wellcome TrustCancer Research UK+9 种基金Bayerthe Medical Research CouncilBreast Cancer NowLeukaemia and Lymphoma ResearchWorldwide Cancer ResearchJune Hancock Mesothelioma FoundationJon Moulton Charitable FoundationPancreatic Cancer United Kingdomthe Experimental Cancer Medicine Centre at King’s College Londonthe National Institute for Health Research(NIHR) Biomedical Research Centre based at Guy’s and St Thomas’NHS Foundation Trust and King’s College London
文摘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. In that context,CARs are generally targeted against the ubiquitous B-cell antigen,CD19. 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. Finally,there is increasing interest in the application of this technology to the treatment of non-malignant disease states,such as autoimmunity,chronic infection and in the suppression of allograft rejection. Here,we consider the background and direction of travel of this emerging and highly promising treatment for malignant and other disease types.
