Chimeric antigen receptor T-cesll therapy(CAR–T)has achieved groundbreaking advancements in clinical application,ushering in a new era for innovative cancer treatment.However,the challenges associated with implementi...Chimeric antigen receptor T-cesll therapy(CAR–T)has achieved groundbreaking advancements in clinical application,ushering in a new era for innovative cancer treatment.However,the challenges associated with implementing this novel targeted cell therapy are increasingly significant.Particularly in the clinical management of solid tumors,obstacles such as the immunosuppressive effects of the tumor microenvironment,limited local tumor infiltration capability of CAR–T cells,heterogeneity of tumor targeting antigens,uncertainties surrounding CAR–T quality,control,and clinical adverse reactions have contributed to increased drug resistance and decreased compliance in tumor therapy.These factors have significantly impeded the widespread adoption and utilization of this therapeutic approach.In this paper,we comprehensively analyze recent preclinical and clinical reports on CAR–T therapy while summarizing crucial factors influencing its efficacy.Furthermore,we aim to identify existing solution strategies and explore their current research status.Through this review article,our objective is to broaden perspectives for further exploration into CAR–T therapy strategies and their clinical applications.展开更多
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
γδT cells are a kind of innate immune T cell.They have not attracted sufficient attention because they account for only a small proportion of all immune cells,and many basic factors related to these cells remain unc...γδT cells are a kind of innate immune T cell.They have not attracted sufficient attention because they account for only a small proportion of all immune cells,and many basic factors related to these cells remain unclear.However,in recent years,with the rapid development of tumor immunotherapy,γδT cells have attracted increasing attention because of their ability to exert cytotoxic effects on most tumor cells without major histocompatibility complex(MHC)restriction.An increasing number of basic studies have focused on the development,antigen recognition,activation,and antitumor immune response ofγδT cells.Additionally,γδT cell-based immunotherapeutic strategies are being developed,and the number of clinical trials investigating such strategies is increasing.This review mainly summarizes the progress of basic research and the clinical application ofγδT cells in tumor immunotherapy to provide a theoretical basis for further the development ofγδT cell-based strategies in the future.展开更多
Diffuse large B-cell lymphoma(DLBCL)and follicular lymphoma(FL)are the most common forms of aggressive and indolent lymphoma,respectively.The majority of patients are cured by standard R-CHOP immunochemotherapy,but 30...Diffuse large B-cell lymphoma(DLBCL)and follicular lymphoma(FL)are the most common forms of aggressive and indolent lymphoma,respectively.The majority of patients are cured by standard R-CHOP immunochemotherapy,but 30%–40%of DLBCL and 20%of FL patients relapse or are refractory(R/R).DLBCL and FL are phenotypically and genetically hereterogenous B-cell neoplasms.To date,the diagnosis of DLBCL and FL has been based on morphology,immunophenotyping and cytogenetics.However,next-generation sequencing(NGS)is widening our understanding of the genetic basis of the B-cell lymphomas.In this review we will discuss how integrating the NGS-based characterization of somatic gene mutations with diagnostic or prognostic value in DLBCL and FL could help refine B-cell lymphoma classification as part of a multidisciplinary pathology work-up.We will also discuss how molecular testing can identify candidates for clinical trials with targeted therapies and help predict therapeutic outcome to currently available treatments,including chimeric antigen receptor T-cell,as well as explore the application of circulating cell-free DNA,a non-invasive method for patient monitoring.We conclude that molecular analyses can drive improvements in patient outcomes due to an increased understanding of the different pathogenic pathways affected by each DLBCL subtype and indolent FL vs R/R FL.展开更多
基金funded by 2023 Sichuan Scientific and Technological Achievements Transformation Project.Project Number:2023JDZH0024.
文摘Chimeric antigen receptor T-cesll therapy(CAR–T)has achieved groundbreaking advancements in clinical application,ushering in a new era for innovative cancer treatment.However,the challenges associated with implementing this novel targeted cell therapy are increasingly significant.Particularly in the clinical management of solid tumors,obstacles such as the immunosuppressive effects of the tumor microenvironment,limited local tumor infiltration capability of CAR–T cells,heterogeneity of tumor targeting antigens,uncertainties surrounding CAR–T quality,control,and clinical adverse reactions have contributed to increased drug resistance and decreased compliance in tumor therapy.These factors have significantly impeded the widespread adoption and utilization of this therapeutic approach.In this paper,we comprehensively analyze recent preclinical and clinical reports on CAR–T therapy while summarizing crucial factors influencing its efficacy.Furthermore,we aim to identify existing solution strategies and explore their current research status.Through this review article,our objective is to broaden perspectives for further exploration into CAR–T therapy strategies and their clinical applications.
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.
基金supported by grants from the National Natural Science Foundation of China(Nos.32270915,31970843,82071791,U20A20374,and 81972886)National Key Research and Development Program of China(No.2022YFC3602004)+4 种基金CAMS Initiative for Innovative Medicine(Nos.2021-I2M-1-005,2021-I2M-1-035,and 2021-I2M-1-053)Haihe Laboratory of Cell Ecosystem Innovation Fund(No.22HHXBSS00028)CAMS Central Public Welfare Scientific Research Institute Basal Research Expenses(No.3332020035)Changzhou Science and Technology Support Plan(No.CE20215008)Beijing Municipal Commission of Science and Technology Fund for Innovative Drug(No.Z221100007922040)
文摘γδT cells are a kind of innate immune T cell.They have not attracted sufficient attention because they account for only a small proportion of all immune cells,and many basic factors related to these cells remain unclear.However,in recent years,with the rapid development of tumor immunotherapy,γδT cells have attracted increasing attention because of their ability to exert cytotoxic effects on most tumor cells without major histocompatibility complex(MHC)restriction.An increasing number of basic studies have focused on the development,antigen recognition,activation,and antitumor immune response ofγδT cells.Additionally,γδT cell-based immunotherapeutic strategies are being developed,and the number of clinical trials investigating such strategies is increasing.This review mainly summarizes the progress of basic research and the clinical application ofγδT cells in tumor immunotherapy to provide a theoretical basis for further the development ofγδT cell-based strategies in the future.
文摘Diffuse large B-cell lymphoma(DLBCL)and follicular lymphoma(FL)are the most common forms of aggressive and indolent lymphoma,respectively.The majority of patients are cured by standard R-CHOP immunochemotherapy,but 30%–40%of DLBCL and 20%of FL patients relapse or are refractory(R/R).DLBCL and FL are phenotypically and genetically hereterogenous B-cell neoplasms.To date,the diagnosis of DLBCL and FL has been based on morphology,immunophenotyping and cytogenetics.However,next-generation sequencing(NGS)is widening our understanding of the genetic basis of the B-cell lymphomas.In this review we will discuss how integrating the NGS-based characterization of somatic gene mutations with diagnostic or prognostic value in DLBCL and FL could help refine B-cell lymphoma classification as part of a multidisciplinary pathology work-up.We will also discuss how molecular testing can identify candidates for clinical trials with targeted therapies and help predict therapeutic outcome to currently available treatments,including chimeric antigen receptor T-cell,as well as explore the application of circulating cell-free DNA,a non-invasive method for patient monitoring.We conclude that molecular analyses can drive improvements in patient outcomes due to an increased understanding of the different pathogenic pathways affected by each DLBCL subtype and indolent FL vs R/R FL.
