Cytokine release syndrome(CRS)is a major obstacle to the widespread clinical application of chimeric antigen receptor(CAR)T cell therapies.CRS can also be induced by infections(such as SARS-CoV-2),drugs(such as therap...Cytokine release syndrome(CRS)is a major obstacle to the widespread clinical application of chimeric antigen receptor(CAR)T cell therapies.CRS can also be induced by infections(such as SARS-CoV-2),drugs(such as therapeutic antibodies),and some autoimmune diseases.Myeloid-derived macrophages play key roles in the pathogenesis of CRS,and participate in the production and release of the core CRS cytokines,including interleukin(IL)-1,IL-6,and interferon-γ.In this review,we summarize the roles of macrophages in CRS and discuss new developments in macrophage activation and the related mechanisms of cytokine regulation in CRS.展开更多
BACKGROUND Cytokine release syndrome(CRS)is defined as systemic inflammation that usually occurs following chimeric antigen receptor T-cell therapy administration;however,it has not been reported in patients with untr...BACKGROUND Cytokine release syndrome(CRS)is defined as systemic inflammation that usually occurs following chimeric antigen receptor T-cell therapy administration;however,it has not been reported in patients with untreated non-small cell lung cancer to date.CASE SUMMARY A 44-year-old nonsmoking woman presented to the hospital due to fever,palpitation,nausea,and cough for 1 mo and was diagnosed with stage cT3N3M0(IIIc)adenocarcinoma of the lung.Auxiliary examinations revealed elevated cytokine[tumor necrosis factor-α,interleukin(IL)-1β,and IL-6]and inflammatory factor levels,which decreased after treatment with corticosteroids and immunoglobulin and when tumor growth was controlled following chemotherapy,radiotherapy,and antiangiogenesis therapy.However,tumor recurrence was observed.After administration of nivolumab as third-line treatment,the patient’s condition was transiently controlled;however,CRS-like symptoms suddenly emerged,which led to a resurgence of cytokines and inflammatory factors and rapid death.CONCLUSION CRS can develop in treatment-naïve lung cancer patients.Patients with tumorrelated CRS may be at risk of CRS recurrence,aggravation,and onset of immune checkpoint inhibitor-related adverse events.展开更多
BACKGROUND Chimeric antigen receptor T-Cell(CAR-T)therapy is an effective new treatment for hematologic malignancies.Cytokine release syndrome(CRS)and neurologic toxicity are main toxicities.CRS-induced rhabdomyolysis...BACKGROUND Chimeric antigen receptor T-Cell(CAR-T)therapy is an effective new treatment for hematologic malignancies.Cytokine release syndrome(CRS)and neurologic toxicity are main toxicities.CRS-induced rhabdomyolysis(RM)followed by CART therapy treatment has not been previously reported.CASE SUMMARY We report a case of a 22-year-old woman with relapsed acute lymphoblastic leukemia obtained sequential cluster of differentiation(CD)19 and CD22 CAR-T infusion.This patient experienced grade 3 CRS with RM,mild hypotension requiring intravenous fluids,and mild hypoxia and was managed effectively with the IL-6 receptor antagonist tocilizumab.This patient had no signs of immune effector cell-associated neurologic syndrome.Restaging scans 30 d postCAR-T therapy demonstrated a complete remission,and the symptoms of muscle weakness improved through rehabilitation.CONCLUSION Myalgia is an easily overlooked symptom of severe CRS after CAR-T therapy.It is necessary to monitor myoglobin levels when a patient presents with symptoms of myalgia or acute renal insufficiency.展开更多
OBJECTIVE:To verify the efficacy of glucocorticoids,chloroquine and vitamin A in the treatment of cytokine release syndrome(CRS),and to investigate the underlying mechanisms,based on network pharmacology.METHODS:We us...OBJECTIVE:To verify the efficacy of glucocorticoids,chloroquine and vitamin A in the treatment of cytokine release syndrome(CRS),and to investigate the underlying mechanisms,based on network pharmacology.METHODS:We used network pharmacology analysis and found 20 co-targeted genes of glucocorticoids,chloroquine,vitamin A and CRS.The pharmacological functions and therapeutic pathways of the genes were analyzed by gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment.The candidate naturally bioactive compounds against the key genes were predicted by Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform.The anti-inflammatory activity of luteolin was assessed by real-time polymerase chain reaction.RESULTS:Among the 20 co-targeted genes of glucocorticoids,chloroquine and vitamin A,interleukin 10(IL-10),interleukin 2(IL-2),interleukin 4(IL-4)and tumor necrosis factor-α(TNF-α)were the key cytokines against CRS.The key pathway involved in the pharmacological mechanism could be cytokine-cytokine receptor interaction pathway,T cell receptor signaling pathway,Janus Kinase-signal transducer and activator of transcription signaling pathway and phosphatidylinositol 3-kinase-protein kinase B signaling pathway.Luteolin targeted by IL-10,IL-4,IL-2 and TNF-αcould be one candidate drug for the treatment of CRS.CONCLUSION:This study comprehensively elucidates the pharmacological mechanism for the treatment of CRS and provides a new method for the discovery of drugs for this disease.展开更多
Despite the tremendous progress of chimeric antigen receptor T(CAR-T)cell therapy in hematological malignancies,their application in solid tumors has been limited largely due to T-cell exhaustion in the tumor microenv...Despite the tremendous progress of chimeric antigen receptor T(CAR-T)cell therapy in hematological malignancies,their application in solid tumors has been limited largely due to T-cell exhaustion in the tumor microenvironment(TME)and systemic toxicity caused by excessive cytokine release.As a key regulator of the immunosuppressive TME,TGF-βpromotes cytokine synthesis via the NF-κB pathway.Here,we coexpressed SMAD7,a suppressor of TGF-βsignaling,with a HER2-targeted CAR in engineered T cells.These novel CAR-T cells displayed high cytolytic efficacy and were resistant to TGF-β-triggered exhaustion,which enabled sustained tumoricidal capacity after continuous antigen exposure.Moreover,SMAD7 substantially reduced the production of inflammatory cytokines by antigen-primed CAR-T cells.Mechanistically,SMAD7 downregulated TGF-βreceptor I and abrogated the interplay between the TGF-βand NF-κB pathways in CAR-T cells.As a result,these CAR-T cells persistently inhibited tumor growth and promoted the survival of tumor-challenged mice regardless of the hostile tumor microenvironment caused by a high concentration of TGF-β.SMAD7 coexpression also enhanced CAR-T-cell infiltration and persistent activation in patient-derived tumor organoids.Therefore,our study demonstrated the feasibility of SMAD7 coexpression as a novel approach to improve the efficacy and safety of CAR-T-cell therapy for solid tumors.展开更多
The coronavirus disease 2019(COVID-19)pandemic is a major public health event caused by severe acute respiratory syndrome coronavirus 2(SARS-Co V-2).COVID-19 has spread widely all over the world.A high proportion of p...The coronavirus disease 2019(COVID-19)pandemic is a major public health event caused by severe acute respiratory syndrome coronavirus 2(SARS-Co V-2).COVID-19 has spread widely all over the world.A high proportion of patients become severely or critically ill,and suffer high mortality due to respiratory failure and multiple organ dysfunction.Therefore,providing timely and effective treatment for critically ill patients is essential to reduce overall mortality.Convalescent plasma therapy and pharmacological treatments,such as aerosol inhalation of interferon-α(IFN-α),corticosteroids,and tocilizumab,have all been applied in clinical practice;however,their effects remain controversial.Recent studies have shown that extracorporeal therapies might have a potential role in treating critically ill COVID-19 patients.In this review,we examine the application of continuous renal replacement therapy(CRRT),therapeutic plasma exchange(TPE),hemoadsorption(HA),extracorporeal membrane oxygenation(ECMO),and extracorporeal carbon dioxide removal(ECCO2 R)in critically ill COVID-19 patients to provide support for the further diagnosis and treatment of COVID-19.展开更多
Anti-CD 19 chimeric antigen receptor(CAR)T cell therapy has shown impressive efficacy in treating B-cell malignancies.A single-center phase I dose-escalation study was conducted to evaluate the safety and efficacy of ...Anti-CD 19 chimeric antigen receptor(CAR)T cell therapy has shown impressive efficacy in treating B-cell malignancies.A single-center phase I dose-escalation study was conducted to evaluate the safety and efficacy of T cells transduced with CBM.CD19 CAR,a second-generation anti-CD19 CAR bearing 4-1BB costimulatory molecule,for the treatment of patients with refractory diffuse large B-cell lymphoma(DLBCL).Ten heavily treated patients with refractory DLBCL were given CBM.CD19 CAR-T cell(C-CAR011)treatment.The overall response rate was 20%and 50%at 4 and 12 weeks after the infusion of C-CAR011,respectively,and the disease control rate was 60%at 12 weeks after infusion.Treatment-emergent adverse events occurred in all patients.The incidence of cytokine release syndrome in all grades and grade^3 was 90%and 0,respectively,which is consistent with the safety profile of axicabtagene ciloleucel and tisagenlecleucel.Neurotoxicity or other dose-limiting toxicides was not observed in any dose cohort of C-CAR011 therapy.Antitumor efficacy was apparent across dose cohorts.Therefore,C-CAR011 is a safe and effective therapeutic option for Chinese patients with refractory DLBCL,and further large-scale clinical trials are warranted.展开更多
The combination of the immunotherapy(i.e.,the use of monoclonal antibodies)and the conventional chemotherapy increases the long-term survival of patients with lymphoma.However,for patients with relapsed or treatment-r...The combination of the immunotherapy(i.e.,the use of monoclonal antibodies)and the conventional chemotherapy increases the long-term survival of patients with lymphoma.However,for patients with relapsed or treatment-resistant lymphoma,a novel treatment approach is urgently needed.Chimeric antigen receptor T(CAR-T)cells were introduced as a treatment for these patients.Based on recent clinical data,approximately 50%of patients with relapsed or refractory B-cell lymphoma achieved complete remission after receiving the CD19 CAR-T cell therapy.Moreover,clinical data revealed that some patients remained in remission for more than two years after the CAR-T cell therapy.Other than the CD19-targeted CAR-T,the novel target antigens,such as CD20,CD22,CD30,and CD37,which were greatly expressed on lymphoma cells,were studied under preclinical and clinical evaluations for use in the treatment of lymphoma.Nonetheless,the CAR-T therapy was usually associated with potentially lethal adverse effects,such as the cytokine release syndrome and the neurotoxicity.Therefore,optimizing the structure of CAR,creating new drugs,and combining CAR-T cell therapy with stem cell transplantation are potential solutions to increase the effectiveness of treatment and reduce the toxicity in patients with lymphoma after the CAR-T cell therapy.展开更多
Chimeric antigen receptor(CAR)-T-cell therapies have exhibited remarkable efficacy in the treatment of hematologic malignancies,with 9 CAR-T-cell products currently available.Furthermore,CAR-T cells have shown promisi...Chimeric antigen receptor(CAR)-T-cell therapies have exhibited remarkable efficacy in the treatment of hematologic malignancies,with 9 CAR-T-cell products currently available.Furthermore,CAR-T cells have shown promising potential for expanding their therapeutic applications to diverse areas,including solid tumors,myocardial fibrosis,and autoimmune and infectious diseases.Despite these advancements,significant challenges pertaining to treatment-related toxic reactions and relapses persist.Consequently,current research efforts are focused on addressing these issues to enhance the safety and efficacy of CAR-T cells and reduce the relapse rate.This article provides a comprehensive overview of the present state of CAR-T-cell therapies,including their achievements,existing challenges,and potential future developments.展开更多
基金supported by grants from the National Key Research and Development Program of China(Grant No.2020YFA0707704)the National Key Research and Development Program of China(Grant No.2016YFC1303800)+1 种基金the Jilin Scientific and Technological Development Program(CN)(Grant No.20190303146SF)the National Natural Science Foundation of China(Grant No.81874052).
文摘Cytokine release syndrome(CRS)is a major obstacle to the widespread clinical application of chimeric antigen receptor(CAR)T cell therapies.CRS can also be induced by infections(such as SARS-CoV-2),drugs(such as therapeutic antibodies),and some autoimmune diseases.Myeloid-derived macrophages play key roles in the pathogenesis of CRS,and participate in the production and release of the core CRS cytokines,including interleukin(IL)-1,IL-6,and interferon-γ.In this review,we summarize the roles of macrophages in CRS and discuss new developments in macrophage activation and the related mechanisms of cytokine regulation in CRS.
基金Supported by National Multidisciplinary Cooperative Diagnosis and Treatment Capacity Building Project for Major Diseases(Lung Cancer)National Key R&D Program of China,No.2016YFC1303300Xiangya Clinical Big Data Project of Central South University(Clinical big data project of lung cancer).
文摘BACKGROUND Cytokine release syndrome(CRS)is defined as systemic inflammation that usually occurs following chimeric antigen receptor T-cell therapy administration;however,it has not been reported in patients with untreated non-small cell lung cancer to date.CASE SUMMARY A 44-year-old nonsmoking woman presented to the hospital due to fever,palpitation,nausea,and cough for 1 mo and was diagnosed with stage cT3N3M0(IIIc)adenocarcinoma of the lung.Auxiliary examinations revealed elevated cytokine[tumor necrosis factor-α,interleukin(IL)-1β,and IL-6]and inflammatory factor levels,which decreased after treatment with corticosteroids and immunoglobulin and when tumor growth was controlled following chemotherapy,radiotherapy,and antiangiogenesis therapy.However,tumor recurrence was observed.After administration of nivolumab as third-line treatment,the patient’s condition was transiently controlled;however,CRS-like symptoms suddenly emerged,which led to a resurgence of cytokines and inflammatory factors and rapid death.CONCLUSION CRS can develop in treatment-naïve lung cancer patients.Patients with tumorrelated CRS may be at risk of CRS recurrence,aggravation,and onset of immune checkpoint inhibitor-related adverse events.
文摘BACKGROUND Chimeric antigen receptor T-Cell(CAR-T)therapy is an effective new treatment for hematologic malignancies.Cytokine release syndrome(CRS)and neurologic toxicity are main toxicities.CRS-induced rhabdomyolysis(RM)followed by CART therapy treatment has not been previously reported.CASE SUMMARY We report a case of a 22-year-old woman with relapsed acute lymphoblastic leukemia obtained sequential cluster of differentiation(CD)19 and CD22 CAR-T infusion.This patient experienced grade 3 CRS with RM,mild hypotension requiring intravenous fluids,and mild hypoxia and was managed effectively with the IL-6 receptor antagonist tocilizumab.This patient had no signs of immune effector cell-associated neurologic syndrome.Restaging scans 30 d postCAR-T therapy demonstrated a complete remission,and the symptoms of muscle weakness improved through rehabilitation.CONCLUSION Myalgia is an easily overlooked symptom of severe CRS after CAR-T therapy.It is necessary to monitor myoglobin levels when a patient presents with symptoms of myalgia or acute renal insufficiency.
基金Supported by the“Double-First Class”project of Beijing(No.1000041510155)。
文摘OBJECTIVE:To verify the efficacy of glucocorticoids,chloroquine and vitamin A in the treatment of cytokine release syndrome(CRS),and to investigate the underlying mechanisms,based on network pharmacology.METHODS:We used network pharmacology analysis and found 20 co-targeted genes of glucocorticoids,chloroquine,vitamin A and CRS.The pharmacological functions and therapeutic pathways of the genes were analyzed by gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment.The candidate naturally bioactive compounds against the key genes were predicted by Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform.The anti-inflammatory activity of luteolin was assessed by real-time polymerase chain reaction.RESULTS:Among the 20 co-targeted genes of glucocorticoids,chloroquine and vitamin A,interleukin 10(IL-10),interleukin 2(IL-2),interleukin 4(IL-4)and tumor necrosis factor-α(TNF-α)were the key cytokines against CRS.The key pathway involved in the pharmacological mechanism could be cytokine-cytokine receptor interaction pathway,T cell receptor signaling pathway,Janus Kinase-signal transducer and activator of transcription signaling pathway and phosphatidylinositol 3-kinase-protein kinase B signaling pathway.Luteolin targeted by IL-10,IL-4,IL-2 and TNF-αcould be one candidate drug for the treatment of CRS.CONCLUSION:This study comprehensively elucidates the pharmacological mechanism for the treatment of CRS and provides a new method for the discovery of drugs for this disease.
基金supported by a grant from the National Natural Science Foundation of China(No.81972870)the Independent Research Topic of State Key Laboratory of Cancer Biology of Fourth Military Medical University(CBSKL2022ZZ20)+2 种基金Shaanxi Innovative Research Team for Key Science and Technology(S2022-ZC-TD-0065)the Natural Science Foundation of Henan Province(No.222300420264)Tangdu Hospital-key research project(2022TDGS007).
文摘Despite the tremendous progress of chimeric antigen receptor T(CAR-T)cell therapy in hematological malignancies,their application in solid tumors has been limited largely due to T-cell exhaustion in the tumor microenvironment(TME)and systemic toxicity caused by excessive cytokine release.As a key regulator of the immunosuppressive TME,TGF-βpromotes cytokine synthesis via the NF-κB pathway.Here,we coexpressed SMAD7,a suppressor of TGF-βsignaling,with a HER2-targeted CAR in engineered T cells.These novel CAR-T cells displayed high cytolytic efficacy and were resistant to TGF-β-triggered exhaustion,which enabled sustained tumoricidal capacity after continuous antigen exposure.Moreover,SMAD7 substantially reduced the production of inflammatory cytokines by antigen-primed CAR-T cells.Mechanistically,SMAD7 downregulated TGF-βreceptor I and abrogated the interplay between the TGF-βand NF-κB pathways in CAR-T cells.As a result,these CAR-T cells persistently inhibited tumor growth and promoted the survival of tumor-challenged mice regardless of the hostile tumor microenvironment caused by a high concentration of TGF-β.SMAD7 coexpression also enhanced CAR-T-cell infiltration and persistent activation in patient-derived tumor organoids.Therefore,our study demonstrated the feasibility of SMAD7 coexpression as a novel approach to improve the efficacy and safety of CAR-T-cell therapy for solid tumors.
基金supported by the 1.3.5 Project for Disciplines of Excellence,West China Hospital,Sichuan University(Nos.2018HXFH018 and ZYGD18027),China。
文摘The coronavirus disease 2019(COVID-19)pandemic is a major public health event caused by severe acute respiratory syndrome coronavirus 2(SARS-Co V-2).COVID-19 has spread widely all over the world.A high proportion of patients become severely or critically ill,and suffer high mortality due to respiratory failure and multiple organ dysfunction.Therefore,providing timely and effective treatment for critically ill patients is essential to reduce overall mortality.Convalescent plasma therapy and pharmacological treatments,such as aerosol inhalation of interferon-α(IFN-α),corticosteroids,and tocilizumab,have all been applied in clinical practice;however,their effects remain controversial.Recent studies have shown that extracorporeal therapies might have a potential role in treating critically ill COVID-19 patients.In this review,we examine the application of continuous renal replacement therapy(CRRT),therapeutic plasma exchange(TPE),hemoadsorption(HA),extracorporeal membrane oxygenation(ECMO),and extracorporeal carbon dioxide removal(ECCO2 R)in critically ill COVID-19 patients to provide support for the further diagnosis and treatment of COVID-19.
基金This study was sponsored by Cellular Biomedicine Group Inc.and partly by National Natural Science Foundation of China(No.81720108002)Major Program of National Natural Science Foundation of China(No.2018ZX09734-007)Jiangsu Provincial Special Program of Medical Science(No.BE2017751).
文摘Anti-CD 19 chimeric antigen receptor(CAR)T cell therapy has shown impressive efficacy in treating B-cell malignancies.A single-center phase I dose-escalation study was conducted to evaluate the safety and efficacy of T cells transduced with CBM.CD19 CAR,a second-generation anti-CD19 CAR bearing 4-1BB costimulatory molecule,for the treatment of patients with refractory diffuse large B-cell lymphoma(DLBCL).Ten heavily treated patients with refractory DLBCL were given CBM.CD19 CAR-T cell(C-CAR011)treatment.The overall response rate was 20%and 50%at 4 and 12 weeks after the infusion of C-CAR011,respectively,and the disease control rate was 60%at 12 weeks after infusion.Treatment-emergent adverse events occurred in all patients.The incidence of cytokine release syndrome in all grades and grade^3 was 90%and 0,respectively,which is consistent with the safety profile of axicabtagene ciloleucel and tisagenlecleucel.Neurotoxicity or other dose-limiting toxicides was not observed in any dose cohort of C-CAR011 therapy.Antitumor efficacy was apparent across dose cohorts.Therefore,C-CAR011 is a safe and effective therapeutic option for Chinese patients with refractory DLBCL,and further large-scale clinical trials are warranted.
基金This work was supported by grants from the National Natural Science Foundation of China(Nos.81230014,81470341,81520108002,and 81500157)the Key Project of Science and Technology Department of Zhejiang Province(No.2018C03016-2)the Key Research and Development Program of Zhejiang Province(No.2019C03016).
文摘The combination of the immunotherapy(i.e.,the use of monoclonal antibodies)and the conventional chemotherapy increases the long-term survival of patients with lymphoma.However,for patients with relapsed or treatment-resistant lymphoma,a novel treatment approach is urgently needed.Chimeric antigen receptor T(CAR-T)cells were introduced as a treatment for these patients.Based on recent clinical data,approximately 50%of patients with relapsed or refractory B-cell lymphoma achieved complete remission after receiving the CD19 CAR-T cell therapy.Moreover,clinical data revealed that some patients remained in remission for more than two years after the CAR-T cell therapy.Other than the CD19-targeted CAR-T,the novel target antigens,such as CD20,CD22,CD30,and CD37,which were greatly expressed on lymphoma cells,were studied under preclinical and clinical evaluations for use in the treatment of lymphoma.Nonetheless,the CAR-T therapy was usually associated with potentially lethal adverse effects,such as the cytokine release syndrome and the neurotoxicity.Therefore,optimizing the structure of CAR,creating new drugs,and combining CAR-T cell therapy with stem cell transplantation are potential solutions to increase the effectiveness of treatment and reduce the toxicity in patients with lymphoma after the CAR-T cell therapy.
文摘Chimeric antigen receptor(CAR)-T-cell therapies have exhibited remarkable efficacy in the treatment of hematologic malignancies,with 9 CAR-T-cell products currently available.Furthermore,CAR-T cells have shown promising potential for expanding their therapeutic applications to diverse areas,including solid tumors,myocardial fibrosis,and autoimmune and infectious diseases.Despite these advancements,significant challenges pertaining to treatment-related toxic reactions and relapses persist.Consequently,current research efforts are focused on addressing these issues to enhance the safety and efficacy of CAR-T cells and reduce the relapse rate.This article provides a comprehensive overview of the present state of CAR-T-cell therapies,including their achievements,existing challenges,and potential future developments.
