Advances in chimeric antigen receptor(CAR)-T cell therapy have significantly improved clinical outcomes of patients with relapsed or refractory hematologic malignancies.However,progress is still hindered as clinical b...Advances in chimeric antigen receptor(CAR)-T cell therapy have significantly improved clinical outcomes of patients with relapsed or refractory hematologic malignancies.However,progress is still hindered as clinical benefit is only available for a fraction of patients.A lack of understanding of CAR-T cell behaviors in vivo at the single-cell level impedes their more extensive application in clinical practice.Mounting evidence suggests that single-cell sequencing techniques can help perfect the receptor design,guide gene-based T cell modification,and optimize the CAR-T manufacturing conditions,and all of them are essential for long-term immunosurveillance and more favorable clinical outcomes.The information generated by employing these methods also potentially informs our understanding of the numerous complex factors that dictate therapeutic efficacy and toxicities.In this review,we discuss the reasons why CAR-T immunotherapy fails in clinical practice and what this field has learned since the milestone of single-cell sequencing technologies.We further outline recent advances in the application of single-cell analyses in CAR-T immunotherapy.Specifically,we provide an overview of single-cell studies focusing on target antigens,CAR-transgene integration,and preclinical research and clinical applications,and then discuss how it will affect the future of CAR-T cell therapy.展开更多
Adoptive cellular immunotherapy with chimeric antigen receptor(CAR)T cells has emerged as a novel modality for treating relapsed and/or refractory B-cell non-Hodgkin lymphoma(B-NHL).With increasing approval of CAR T-c...Adoptive cellular immunotherapy with chimeric antigen receptor(CAR)T cells has emerged as a novel modality for treating relapsed and/or refractory B-cell non-Hodgkin lymphoma(B-NHL).With increasing approval of CAR T-cell products and advances in CAR T cell therapy,CAR T cells are expected to be used in a growing number of cases.However,CAR T-cell-associated toxicities can be severe or even fatal,thus compromising the survival benefit from this therapy.Standardizing and studying the clinical management of these toxicities are imperative.In contrast to other hematological malignancies,such as acute lymphoblastic leukemia and multiple myeloma,anti-CD19 CAR T-cell-associated toxicities in B-NHL have several distinctive features,most notably local cytokine-release syndrome(CRS).However,previously published guidelines have provided few specific recommendations for the grading and management of toxicities associated with CAR T-cell treatment for B-NHL.Consequently,we developed this consensus for the prevention,recognition,and management of these toxicities,on the basis of published literature regarding the management of anti-CD19 CAR T-cell-associated toxicities and the clinical experience of multiple Chinese institutions.This consensus refines a grading system and classification of CRS in B-NHL and corresponding measures for CRS management,and delineates comprehensive principles and exploratory recommendations for managing anti-CD19 CAR T-cell-associated toxicities in addition to CRS.展开更多
In this study,we used plasma factor V activity and parameters of the thrombin generation test to discuss their diagnostic and prognostic value for disseminated intravascular coagulation (DIC) in patients with hematolo...In this study,we used plasma factor V activity and parameters of the thrombin generation test to discuss their diagnostic and prognostic value for disseminated intravascular coagulation (DIC) in patients with hematological malignancies.A total of 164 patients who were diagnosed with hematological malignancies in the Department of Hematology,Union Hospital,between Apr 2014 and Dec.2014 were enrolled in this study.There were 131 patients in the study group and 33 patients in the control group in terms of the laboratory results for DIC.The patients in the study group were divided into a DIC subgroup (n=59) and a non-DIC subgroup (n=72) based on the International Society of Thrombosis and Hemostasis (ISTH) Integral System,and they were divided into four subgroups [score ≤3 (n=35),score=4 (n=37),score=5 (n=47),and score >6 (n=12)] according to ISTH scores.Using 28-day mortality as the endpoint,the patients in the study group were divided into a survival subgroup (n=111) and a non-survival subgroup (n=20).The results showed that the plasma factor V activity was significantly weaker,and lag time and time to peak were significantly shorter in the study group than in the control group (P<0.01).The factor V activity,peak and endogenous thrombin potential (ETP) were significantly decreased in the DIC subgroup as compared with those in the non-DIC subgroup (P<0.01).Among factor V activity,lag time,peak,ETP,and ttPeak,only the factor V activity was significantly decreased in the nonsurvival subgroup compared with the survival subgroup (P<0.01).With the increase in ISTH score,the ETP and peak decreased gradually.The binary logistic regression analysis revealed that PLT,D-dimer,factor V activity and ETP had linear relationship with DIC diagnosed by ISTH Integral System.Using DIC diagnosed by ISTH Integral System as the endpoint,the area under curve (AUC) of factor V activity was found to be similar to that of blood platelet count (PLT) and prothrombin time (PT).In conclusion,factor V activity,ETP and peak had diagnostic value for DIC in patients with hematological malignancies,and only factor V activity had limited prognostic value.展开更多
The efficacy and safety of recombinant tissue plasminogen activator （rtPA） need to be improved due to its low bioavailability and requirement of large dose administration. The purpose of this study was to develop a ...The efficacy and safety of recombinant tissue plasminogen activator （rtPA） need to be improved due to its low bioavailability and requirement of large dose administration. The purpose of this study was to develop a fibrin-targeted nanoparticle （NP） drug delivery system for thrombosis combination therapy. We conjugated rtPA to poly（ethylene glycol）- poly（ε-caprolactone） （PEG-PCL） nanoparticles （rtPA-NP） and investigated its physicochemical characteristics such as particle size, zeta potential, enzyme activity of conjugated rtPA and its storage stability at 4℃. The thrombolytic activity of rtPA-NP was evaluated in vitro and in vivo as well as the half-life of rtPA-NP, the properties to fibrin targeting and its influences on systemic hemostasis in vivo. The results showed that rtPA-NP equivalent to 10% of a typical dose of rtPA could dissolve fibrin clots and were demonstrated to have a neuroprotective effect after focal cerebral ischemia as evidenced by decreased infarct volume and improved neurological deficit （P〈0.001）. RtPA-NP did not influence the in vivo hemostasis or coagulation system. The half-life of conjugated rtPA was shown to be approximately 18 times longer than that of free rtPA. These experiments suggested that rtPA-conjugated PEG-PCL nanoparticles might be a promising fibrin-targeted delivery system for a combination treatment of thrombosis.展开更多
Objective:The systemic inflammatory response is regarded as the major cause of endotoxin-induced coagulopathy,which is a strong predictor of mortality in patients with severe sepsis.Simvastatin plays an important role...Objective:The systemic inflammatory response is regarded as the major cause of endotoxin-induced coagulopathy,which is a strong predictor of mortality in patients with severe sepsis.Simvastatin plays an important role in reducing inflammation.In addition,the gut has long been hypothesized to be the“motor”of critical illness,driving or aggravating sepsis by the increased intestinal permeability and bacterial translocation.展开更多
Background:Chimeric antigen receptor T(CAR-T)therapy has substantially revolutionized the clinical outcomes of patients with hematologic malignan-cies,but the cancer-intrinsic mechanisms underlying resistance to CAR-T...Background:Chimeric antigen receptor T(CAR-T)therapy has substantially revolutionized the clinical outcomes of patients with hematologic malignan-cies,but the cancer-intrinsic mechanisms underlying resistance to CAR-T cells remain yet to be fully understood.This study aims to explore the molecular deter-minants of cancer cell sensitivity to CAR-T cell-mediated killing and to provide a better understanding of the underlying mechanisms and potential modulation to improve clinical efficacy.Methods:The human whole-genome CRISPR/Cas9-based knockout screening was conducted to identify key genes that enable cancer cells to evade CD19 CAR-T-cell-mediated killing.The in vitro cytotoxicity assays and evaluation of tumor tissue and bone marrow specimens were further conducted to confirm the role of the key genes in cancer cell susceptibility to CAR-T cells.In addition,the specific mechanisms influencing CAR-T cell-mediated cancer clearance were elucidated in mouse and cellular models.Results:The CRISPR/Cas9-based knockout screening showed that the enrich-ment of autophagy-related genes(ATG3,BECN1,and RB1CC1)provided protec-tion of cancer cells from CD19 CAR-T cell-mediated cytotoxicity.These findings were further validated by in vitro cytotoxicity assays in cells with genetic and pharmacological inhibition of autophagy.Notably,higher expression of the three autophagy-related proteins in tumor samples was correlated with poorer respon-siveness and worse survival in patients with relapsed/refractory B-cell lymphoma after CD19 CAR-T therapy.Bulk RNA sequencing analysis of bone marrow samples from B-cell leukemia patients also suggested the clinical relevance of autophagy to the therapeutic response and relapse after CD19 CAR-T cell ther-apy.Pharmacological inhibition of autophagy and knockout of RB1CC1 could dramatically sensitize tumor cells to CD19 CAR-T cell-mediated killing in mouse models of both B-cell leukemia and lymphoma.Moreover,our study revealed that cancer-intrinsic autophagy mediates evasion of CAR-T cells via the TNF-α-TNFR1 axis-mediated apoptosis and STAT1/IRF1-induced chemokine signaling activation.Conclusions:These findings confirm that autophagy signaling in B-cell malig-nancies is essential for the effective cytotoxic function of CAR-T cells and thereby pave the way for the development of autophagy-targeting strategies to improve the clinical efficacy of CAR-T cell immunotherapy.展开更多
The immune-cell origin of hematologic malignancies provides a unique avenue for the understanding of both the mechanisms of immune responsiveness and immune escape,which has accelerated the progress of immunotherapy.S...The immune-cell origin of hematologic malignancies provides a unique avenue for the understanding of both the mechanisms of immune responsiveness and immune escape,which has accelerated the progress of immunotherapy.Several categories of immunotherapies have been developed and are being further evaluated in clinical trials for the treatment of blood cancers,including stem cell transplantation,immune checkpoint inhibitors,antigen-targeted antibodies,antibody-drug conjugates,tumor vaccines,and adoptive cell therapies.These immunotherapies have shown the potential to induce long-term remission in refractory or relapsed patients and have led to a paradigm shift in cancer treatment with great clinical success.Different immunotherapeutic approaches have their advantages but also shortcomings that need to be addressed.To provide clinicians with timely information on these revolutionary therapeutic approaches,the comprehensive review provides historical perspectives on the applications and clinical considerations of the immunotherapy.Here,we first outline the recent advances that have been made in the understanding of the various categories of immunotherapies in the treatment of hematologic malignancies.We further discuss the specific mechanisms of action,summarize the clinical trials and outcomes of immunotherapies in hematologic malignancies,as well as the adverse effects and toxicity management and then provide novel insights into challenges and future directions.展开更多
Over the last decade,epidemiological studies have discovered a link between hepatitis C virus(HCV)and hepatitis B virus(HBV)infection and non-Hodgkin lymphoma(NHL).The regression of HCV-associated NHL after HCV eradic...Over the last decade,epidemiological studies have discovered a link between hepatitis C virus(HCV)and hepatitis B virus(HBV)infection and non-Hodgkin lymphoma(NHL).The regression of HCV-associated NHL after HCV eradication is the most compelling proof supporting HCV infection’s role in lymphoproliferative diseases.HBV infection was found to significantly enhance the incidence of NHL,according to the epidemiological data.The exact mechanism of HCV leading to NHL has not been fully clarified,and there are mainly the following possible mechanisms:(1)Indirect mechanisms:stimulation of B lymphocytes by extracellular HCV and cytokines;(2)Direct mechanisms:oncogenic effects mediated by intracellular HCV proteins;(3)hit-and-run mechanism:permanent genetic B lymphocytes damage by the transitional entry of HCV.The specific role of HBV in the occurrence of NHL is still unclear,and the research on its mechanism is less extensively explored than HCV,and there are mainly the following possible mechanisms:(1)Indirect mechanisms:stimulation of B lymphocytes by extracellular HBV;(2)Direct mechanisms:oncogenic effects mediated by intracellular HBV DNA.In fact,it is reasonable to consider direct-acting antivirals(DAAs)as first-line therapy for indolent HCV-associated BNHL patients who do not require immediate chemotherapy.Chemotherapy for NHL is affected by HBV infection and replication.At the same time,chemotherapy can also activate HBV replication.Following recent guidelines,all patients withHBsAg positive/HBV DNA≥2,000IU/mL should be treated for HBV.The data on epidemiology,interventional studies,and molecular mechanisms of HCV and HBV-associated B-NHL are systematically summarized in this review.展开更多
The considerable development of carrier-free nanodrugs has been achieved due to their high drug-loading capability,simple preparation method,and offering“all-in-one”functional platform features.However,the native de...The considerable development of carrier-free nanodrugs has been achieved due to their high drug-loading capability,simple preparation method,and offering“all-in-one”functional platform features.However,the native defects of carrier-free nanodrugs limit their delivery and release behavior throughout the in vivo journey,which significantly compromise the therapeutic efficacy and hinder their further development in cancer treatment.In this review,we summarized and discussed the recent strategies to enhance drug delivery and release of carrier-free nanodrugs for improved cancer therapy,including optimizing the intrinsic physicochemical properties and external modification.Finally,the corresponding challenges that carrier-free nanodrugs faced are discussed and the future perspectives for its application are presented.We hope this review will provide constructive information for the rational design of more effective carrier-free nanodrugs to advance therapeutic treatment.展开更多
Chimeric antigen receptor T-cell(CAR-T)therapy has greatly improved the disease remission rate and long-term survival rate of patients with relapsed/refractory hematological malignancies.[1-3]Currently,several commerc...Chimeric antigen receptor T-cell(CAR-T)therapy has greatly improved the disease remission rate and long-term survival rate of patients with relapsed/refractory hematological malignancies.[1-3]Currently,several commercial CAR-T products are available in the market and numerous CAR-T clinical trials have been conducted.Attention should be paid to the safety of CAR-T therapy.The main adverse effects of CAR-T therapy are cytokine release syndrome(CRS)and immune effector cell-associated neurotoxicity syndrome(ICANS).[4]展开更多
Chimeric antigen receptor(CAR)-T therapy was first described in 1989 and has revolutionized the management of hematological cancers with its great potential in reinforcing T cells against tumors[1].CAR-T therapies are...Chimeric antigen receptor(CAR)-T therapy was first described in 1989 and has revolutionized the management of hematological cancers with its great potential in reinforcing T cells against tumors[1].CAR-T therapies are mechanistically different from more traditional approaches to the treatment of hematological cancers such as surgery,chemoradiotherapy,and monoclonal antibody therapy.To date,six CAR-T products have been approved by the US Food and Drug Administration(FDA)and successfully applied to the treatment of B-cell acute lymphoblastic leukemia(B-ALL),diffuse large B cell lymphoma(DLBCL),follicular lymphoma(FL),and multiple myeloma(MM).Whilst there has been progress in the identification of new targets and related technologies for solid tumors,commercial products are not yet available.展开更多
The SARS-CoV-2 infection causes severe immune disruption.However,it is unclear if disrupted immune regulation still exists and pertains in recovered COVID-19 patients.In our study,we have characterized the immunephe n...The SARS-CoV-2 infection causes severe immune disruption.However,it is unclear if disrupted immune regulation still exists and pertains in recovered COVID-19 patients.In our study,we have characterized the immunephe no type of B cells from 15 recovered COVID-19 patients,and found that healthy controls and recovered patients had similar B-cell populations before and after BCR stimulation,but the frequencies of PBC in patients were significantly increased when compared to healthy controls before stimulation.However,the percentage of unswitched memory B cells was decreased in recovered patients but not changed in healthy controls upon BCR stimulation.Interestingly,we found that CD19 expression was significantly reduced in almost all the B-cell subsets in recovered patients.Moreover,the BCR signaling and early B-cell response were disrupted upon BCR stimulation.Mechanistically,we found that the reduced CD19 expression was caused by the dysregulation of cell metabolism.In conclusion,we found that SARS-CoV-2 infection causes immunodeficiency in recovered patients by downregulating CD19 expression in B cells via enhandng B-cell metabolism,which may provide a new intervention target to cure COVID-19.展开更多
Unsatisfactory drug loading capability,potential toxicity of the inert carrier and the limited therapeutic effect of a single chemotherapy drug are all vital inhibitory factors of carrier-assisted drug delivery system...Unsatisfactory drug loading capability,potential toxicity of the inert carrier and the limited therapeutic effect of a single chemotherapy drug are all vital inhibitory factors of carrier-assisted drug delivery systems for chemotherapy.To address the above obstacles,a series of carrier-free nanoplatforms self-assembled by dual-drug conjugates was constructed to reinforce chemotherapy against tumors by simultaneously disrupting intratumoral DNA activity and inhibiting mitochondria function.In this nanoplatform,the mitochondria-targeting small-molecular drug,a-tocopheryl succinate(TOS),firstly self-assembled into nanoparticles,which then were used as the carrier to conjugate cisplatin(CDDP).Systematic characterization results showed that this nanoplatform exhibited suitable particle size and a negative surface charge with good stability in physicochemical environments,as well as pH-sensitive drug release and efficient cellular uptake.Due to the combined effects of reactive oxygen species(ROS)generation by TOS and DNA damage by CDDP,the developed nanoplatform could induce mitochondrial dysfunction and elevated cell apoptosis,resulting in highly efficient anti-tumor outcomes in vitro.Collectively,the combined design principles adopted for carrier-free nanodrugs construction in this study aimed at targeting different intracellular organelles for facilitating ROS production and DNA disruption can be extended to other carrier-free nanodrugs-dependent therapeutic systems.展开更多
Challenges associated with low-drug-loading capacity,lack of active targeting of tumor cells and unspecific drug release of nanocarriers synchronously plague the success of cancer therapy.Herein,we constructed active-...Challenges associated with low-drug-loading capacity,lack of active targeting of tumor cells and unspecific drug release of nanocarriers synchronously plague the success of cancer therapy.Herein,we constructed active-targeting,redox-activated polymeric micelles(HPGssML)selfassembled aptamer-decorated,amphiphilic biodegradable poly(benzyl malolactonate-co-e-caprolactone)copolymer with disulfide linkage and p-conjugated moieties.HPGssML with a homogenous spherical shape and nanosized diameter(-150 nm)formed a low critical micellar concentration(10^-3mg/mL),suggesting good stability of polymeric micelles.The anticancer drug,doxorubicin(DOX),can be efficiently loaded into the core of micelles with high-drug-loading content via strong π-π interaction,which was verified by a decrease in fluorescence intensity and redshift in UV adsorption of DOX in micelles.The redox sensitivity of polymeric micelles was confirmed by size change and in vitro drug release in a reducing environment.Confocal microscopy and flow cytometry assay demonstrated that conjugating aptamers could enhance specific uptake of HPGssML by cancer cells.An in vitro cytotoxicity study showed that the half-maximal inhibitory concentration(IC50)of DOX-loaded HPGssML was two times lower than that of the control group,demonstrating improved antitumor efficacy.Therefore,the multifunctional biodegradable polymeric micelles can be exploited as a desirable drug carrier for effective cancer treatment.展开更多
基金National Key Research and Development Program of China(2022YFC2502700)National Natural Science Foundation of China(8187343482100190).
文摘Advances in chimeric antigen receptor(CAR)-T cell therapy have significantly improved clinical outcomes of patients with relapsed or refractory hematologic malignancies.However,progress is still hindered as clinical benefit is only available for a fraction of patients.A lack of understanding of CAR-T cell behaviors in vivo at the single-cell level impedes their more extensive application in clinical practice.Mounting evidence suggests that single-cell sequencing techniques can help perfect the receptor design,guide gene-based T cell modification,and optimize the CAR-T manufacturing conditions,and all of them are essential for long-term immunosurveillance and more favorable clinical outcomes.The information generated by employing these methods also potentially informs our understanding of the numerous complex factors that dictate therapeutic efficacy and toxicities.In this review,we discuss the reasons why CAR-T immunotherapy fails in clinical practice and what this field has learned since the milestone of single-cell sequencing technologies.We further outline recent advances in the application of single-cell analyses in CAR-T immunotherapy.Specifically,we provide an overview of single-cell studies focusing on target antigens,CAR-transgene integration,and preclinical research and clinical applications,and then discuss how it will affect the future of CAR-T cell therapy.
基金supported by funds from the National Natural Science Foundation of China(Grant Nos.81830002,81830004,82070168,and 32070951)the Translational Research grant of NCRCH(Grant No.2020ZKZC04)National Key R&D Program of China(Grant No.2021YFA1100800)。
文摘Adoptive cellular immunotherapy with chimeric antigen receptor(CAR)T cells has emerged as a novel modality for treating relapsed and/or refractory B-cell non-Hodgkin lymphoma(B-NHL).With increasing approval of CAR T-cell products and advances in CAR T cell therapy,CAR T cells are expected to be used in a growing number of cases.However,CAR T-cell-associated toxicities can be severe or even fatal,thus compromising the survival benefit from this therapy.Standardizing and studying the clinical management of these toxicities are imperative.In contrast to other hematological malignancies,such as acute lymphoblastic leukemia and multiple myeloma,anti-CD19 CAR T-cell-associated toxicities in B-NHL have several distinctive features,most notably local cytokine-release syndrome(CRS).However,previously published guidelines have provided few specific recommendations for the grading and management of toxicities associated with CAR T-cell treatment for B-NHL.Consequently,we developed this consensus for the prevention,recognition,and management of these toxicities,on the basis of published literature regarding the management of anti-CD19 CAR T-cell-associated toxicities and the clinical experience of multiple Chinese institutions.This consensus refines a grading system and classification of CRS in B-NHL and corresponding measures for CRS management,and delineates comprehensive principles and exploratory recommendations for managing anti-CD19 CAR T-cell-associated toxicities in addition to CRS.
文摘In this study,we used plasma factor V activity and parameters of the thrombin generation test to discuss their diagnostic and prognostic value for disseminated intravascular coagulation (DIC) in patients with hematological malignancies.A total of 164 patients who were diagnosed with hematological malignancies in the Department of Hematology,Union Hospital,between Apr 2014 and Dec.2014 were enrolled in this study.There were 131 patients in the study group and 33 patients in the control group in terms of the laboratory results for DIC.The patients in the study group were divided into a DIC subgroup (n=59) and a non-DIC subgroup (n=72) based on the International Society of Thrombosis and Hemostasis (ISTH) Integral System,and they were divided into four subgroups [score ≤3 (n=35),score=4 (n=37),score=5 (n=47),and score >6 (n=12)] according to ISTH scores.Using 28-day mortality as the endpoint,the patients in the study group were divided into a survival subgroup (n=111) and a non-survival subgroup (n=20).The results showed that the plasma factor V activity was significantly weaker,and lag time and time to peak were significantly shorter in the study group than in the control group (P<0.01).The factor V activity,peak and endogenous thrombin potential (ETP) were significantly decreased in the DIC subgroup as compared with those in the non-DIC subgroup (P<0.01).Among factor V activity,lag time,peak,ETP,and ttPeak,only the factor V activity was significantly decreased in the nonsurvival subgroup compared with the survival subgroup (P<0.01).With the increase in ISTH score,the ETP and peak decreased gradually.The binary logistic regression analysis revealed that PLT,D-dimer,factor V activity and ETP had linear relationship with DIC diagnosed by ISTH Integral System.Using DIC diagnosed by ISTH Integral System as the endpoint,the area under curve (AUC) of factor V activity was found to be similar to that of blood platelet count (PLT) and prothrombin time (PT).In conclusion,factor V activity,ETP and peak had diagnostic value for DIC in patients with hematological malignancies,and only factor V activity had limited prognostic value.
基金This work was supported by the National Basic Scientific Research Program of China （973 Program, No. 2007CB935803）, the National Natural Science Foundation of China （No. 30825018） and the Key Clinical Program of the Ministry of Health of China （No. 2010439）.
文摘The efficacy and safety of recombinant tissue plasminogen activator （rtPA） need to be improved due to its low bioavailability and requirement of large dose administration. The purpose of this study was to develop a fibrin-targeted nanoparticle （NP） drug delivery system for thrombosis combination therapy. We conjugated rtPA to poly（ethylene glycol）- poly（ε-caprolactone） （PEG-PCL） nanoparticles （rtPA-NP） and investigated its physicochemical characteristics such as particle size, zeta potential, enzyme activity of conjugated rtPA and its storage stability at 4℃. The thrombolytic activity of rtPA-NP was evaluated in vitro and in vivo as well as the half-life of rtPA-NP, the properties to fibrin targeting and its influences on systemic hemostasis in vivo. The results showed that rtPA-NP equivalent to 10% of a typical dose of rtPA could dissolve fibrin clots and were demonstrated to have a neuroprotective effect after focal cerebral ischemia as evidenced by decreased infarct volume and improved neurological deficit （P〈0.001）. RtPA-NP did not influence the in vivo hemostasis or coagulation system. The half-life of conjugated rtPA was shown to be approximately 18 times longer than that of free rtPA. These experiments suggested that rtPA-conjugated PEG-PCL nanoparticles might be a promising fibrin-targeted delivery system for a combination treatment of thrombosis.
基金This study was supported by grants from the National Natural Science Foundation of China(No.81873434)and the Natural Science Foundation of Hubei Province(No.2020CFA065).
文摘Objective:The systemic inflammatory response is regarded as the major cause of endotoxin-induced coagulopathy,which is a strong predictor of mortality in patients with severe sepsis.Simvastatin plays an important role in reducing inflammation.In addition,the gut has long been hypothesized to be the“motor”of critical illness,driving or aggravating sepsis by the increased intestinal permeability and bacterial translocation.
基金National Key R&D Program of China,Grant/Award Number:2022YFC2502700National Natural Science Foundation of China,Grant/Award Numbers:81873434,82100190,82200145China Postdoctoral Innovative Talent Support Foundation,Grant/Award Number:BX2021106
文摘Background:Chimeric antigen receptor T(CAR-T)therapy has substantially revolutionized the clinical outcomes of patients with hematologic malignan-cies,but the cancer-intrinsic mechanisms underlying resistance to CAR-T cells remain yet to be fully understood.This study aims to explore the molecular deter-minants of cancer cell sensitivity to CAR-T cell-mediated killing and to provide a better understanding of the underlying mechanisms and potential modulation to improve clinical efficacy.Methods:The human whole-genome CRISPR/Cas9-based knockout screening was conducted to identify key genes that enable cancer cells to evade CD19 CAR-T-cell-mediated killing.The in vitro cytotoxicity assays and evaluation of tumor tissue and bone marrow specimens were further conducted to confirm the role of the key genes in cancer cell susceptibility to CAR-T cells.In addition,the specific mechanisms influencing CAR-T cell-mediated cancer clearance were elucidated in mouse and cellular models.Results:The CRISPR/Cas9-based knockout screening showed that the enrich-ment of autophagy-related genes(ATG3,BECN1,and RB1CC1)provided protec-tion of cancer cells from CD19 CAR-T cell-mediated cytotoxicity.These findings were further validated by in vitro cytotoxicity assays in cells with genetic and pharmacological inhibition of autophagy.Notably,higher expression of the three autophagy-related proteins in tumor samples was correlated with poorer respon-siveness and worse survival in patients with relapsed/refractory B-cell lymphoma after CD19 CAR-T therapy.Bulk RNA sequencing analysis of bone marrow samples from B-cell leukemia patients also suggested the clinical relevance of autophagy to the therapeutic response and relapse after CD19 CAR-T cell ther-apy.Pharmacological inhibition of autophagy and knockout of RB1CC1 could dramatically sensitize tumor cells to CD19 CAR-T cell-mediated killing in mouse models of both B-cell leukemia and lymphoma.Moreover,our study revealed that cancer-intrinsic autophagy mediates evasion of CAR-T cells via the TNF-α-TNFR1 axis-mediated apoptosis and STAT1/IRF1-induced chemokine signaling activation.Conclusions:These findings confirm that autophagy signaling in B-cell malig-nancies is essential for the effective cytotoxic function of CAR-T cells and thereby pave the way for the development of autophagy-targeting strategies to improve the clinical efficacy of CAR-T cell immunotherapy.
基金This work was supported by grants from the National Key R&D Program of China(2022YFC2502700)the National Natural Science Foundation of China(81873434+1 种基金82100190)the China Postdoctoral Innovative Talent Support Foundation(BX2021106).All the figures were created by the website tool BioRender(https://www.biorender.com/).
文摘The immune-cell origin of hematologic malignancies provides a unique avenue for the understanding of both the mechanisms of immune responsiveness and immune escape,which has accelerated the progress of immunotherapy.Several categories of immunotherapies have been developed and are being further evaluated in clinical trials for the treatment of blood cancers,including stem cell transplantation,immune checkpoint inhibitors,antigen-targeted antibodies,antibody-drug conjugates,tumor vaccines,and adoptive cell therapies.These immunotherapies have shown the potential to induce long-term remission in refractory or relapsed patients and have led to a paradigm shift in cancer treatment with great clinical success.Different immunotherapeutic approaches have their advantages but also shortcomings that need to be addressed.To provide clinicians with timely information on these revolutionary therapeutic approaches,the comprehensive review provides historical perspectives on the applications and clinical considerations of the immunotherapy.Here,we first outline the recent advances that have been made in the understanding of the various categories of immunotherapies in the treatment of hematologic malignancies.We further discuss the specific mechanisms of action,summarize the clinical trials and outcomes of immunotherapies in hematologic malignancies,as well as the adverse effects and toxicity management and then provide novel insights into challenges and future directions.
基金funded by the Wuhan Municipal Health Commission(grant number WX17Q06).
文摘Over the last decade,epidemiological studies have discovered a link between hepatitis C virus(HCV)and hepatitis B virus(HBV)infection and non-Hodgkin lymphoma(NHL).The regression of HCV-associated NHL after HCV eradication is the most compelling proof supporting HCV infection’s role in lymphoproliferative diseases.HBV infection was found to significantly enhance the incidence of NHL,according to the epidemiological data.The exact mechanism of HCV leading to NHL has not been fully clarified,and there are mainly the following possible mechanisms:(1)Indirect mechanisms:stimulation of B lymphocytes by extracellular HCV and cytokines;(2)Direct mechanisms:oncogenic effects mediated by intracellular HCV proteins;(3)hit-and-run mechanism:permanent genetic B lymphocytes damage by the transitional entry of HCV.The specific role of HBV in the occurrence of NHL is still unclear,and the research on its mechanism is less extensively explored than HCV,and there are mainly the following possible mechanisms:(1)Indirect mechanisms:stimulation of B lymphocytes by extracellular HBV;(2)Direct mechanisms:oncogenic effects mediated by intracellular HBV DNA.In fact,it is reasonable to consider direct-acting antivirals(DAAs)as first-line therapy for indolent HCV-associated BNHL patients who do not require immediate chemotherapy.Chemotherapy for NHL is affected by HBV infection and replication.At the same time,chemotherapy can also activate HBV replication.Following recent guidelines,all patients withHBsAg positive/HBV DNA≥2,000IU/mL should be treated for HBV.The data on epidemiology,interventional studies,and molecular mechanisms of HCV and HBV-associated B-NHL are systematically summarized in this review.
基金supported by grants from the National Key Research and Development Program of China(No.2018YFC1106103)the National Natural Science Foundation of China(Grant No.51973135).
文摘The considerable development of carrier-free nanodrugs has been achieved due to their high drug-loading capability,simple preparation method,and offering“all-in-one”functional platform features.However,the native defects of carrier-free nanodrugs limit their delivery and release behavior throughout the in vivo journey,which significantly compromise the therapeutic efficacy and hinder their further development in cancer treatment.In this review,we summarized and discussed the recent strategies to enhance drug delivery and release of carrier-free nanodrugs for improved cancer therapy,including optimizing the intrinsic physicochemical properties and external modification.Finally,the corresponding challenges that carrier-free nanodrugs faced are discussed and the future perspectives for its application are presented.We hope this review will provide constructive information for the rational design of more effective carrier-free nanodrugs to advance therapeutic treatment.
文摘Chimeric antigen receptor T-cell(CAR-T)therapy has greatly improved the disease remission rate and long-term survival rate of patients with relapsed/refractory hematological malignancies.[1-3]Currently,several commercial CAR-T products are available in the market and numerous CAR-T clinical trials have been conducted.Attention should be paid to the safety of CAR-T therapy.The main adverse effects of CAR-T therapy are cytokine release syndrome(CRS)and immune effector cell-associated neurotoxicity syndrome(ICANS).[4]
基金supported by the National Key R&D Program of China(2019YFC1316200)the Natural Science Foundation of Hubei Province(2020CFA065)the National Natural Science Foundation of China(82070124)。
文摘Chimeric antigen receptor(CAR)-T therapy was first described in 1989 and has revolutionized the management of hematological cancers with its great potential in reinforcing T cells against tumors[1].CAR-T therapies are mechanistically different from more traditional approaches to the treatment of hematological cancers such as surgery,chemoradiotherapy,and monoclonal antibody therapy.To date,six CAR-T products have been approved by the US Food and Drug Administration(FDA)and successfully applied to the treatment of B-cell acute lymphoblastic leukemia(B-ALL),diffuse large B cell lymphoma(DLBCL),follicular lymphoma(FL),and multiple myeloma(MM).Whilst there has been progress in the identification of new targets and related technologies for solid tumors,commercial products are not yet available.
基金supported by the National Natural Science Foundation of China(31970839)the National Key R&D Program of China(1316203)+1 种基金Independent Innovation Research Fund of Huazhong University of Science and Technology(2020kfyXGYJ017)the HUST Academic Frontier Youth Team(2018QYTD10).
文摘The SARS-CoV-2 infection causes severe immune disruption.However,it is unclear if disrupted immune regulation still exists and pertains in recovered COVID-19 patients.In our study,we have characterized the immunephe no type of B cells from 15 recovered COVID-19 patients,and found that healthy controls and recovered patients had similar B-cell populations before and after BCR stimulation,but the frequencies of PBC in patients were significantly increased when compared to healthy controls before stimulation.However,the percentage of unswitched memory B cells was decreased in recovered patients but not changed in healthy controls upon BCR stimulation.Interestingly,we found that CD19 expression was significantly reduced in almost all the B-cell subsets in recovered patients.Moreover,the BCR signaling and early B-cell response were disrupted upon BCR stimulation.Mechanistically,we found that the reduced CD19 expression was caused by the dysregulation of cell metabolism.In conclusion,we found that SARS-CoV-2 infection causes immunodeficiency in recovered patients by downregulating CD19 expression in B cells via enhandng B-cell metabolism,which may provide a new intervention target to cure COVID-19.
基金This work was supported by grants from the National Key Research and Development Program of China(No.2018YFC1106103,2018YFC1106103-1)National Natural Science Foundation of China(Grant No.51973135).
文摘Unsatisfactory drug loading capability,potential toxicity of the inert carrier and the limited therapeutic effect of a single chemotherapy drug are all vital inhibitory factors of carrier-assisted drug delivery systems for chemotherapy.To address the above obstacles,a series of carrier-free nanoplatforms self-assembled by dual-drug conjugates was constructed to reinforce chemotherapy against tumors by simultaneously disrupting intratumoral DNA activity and inhibiting mitochondria function.In this nanoplatform,the mitochondria-targeting small-molecular drug,a-tocopheryl succinate(TOS),firstly self-assembled into nanoparticles,which then were used as the carrier to conjugate cisplatin(CDDP).Systematic characterization results showed that this nanoplatform exhibited suitable particle size and a negative surface charge with good stability in physicochemical environments,as well as pH-sensitive drug release and efficient cellular uptake.Due to the combined effects of reactive oxygen species(ROS)generation by TOS and DNA damage by CDDP,the developed nanoplatform could induce mitochondrial dysfunction and elevated cell apoptosis,resulting in highly efficient anti-tumor outcomes in vitro.Collectively,the combined design principles adopted for carrier-free nanodrugs construction in this study aimed at targeting different intracellular organelles for facilitating ROS production and DNA disruption can be extended to other carrier-free nanodrugs-dependent therapeutic systems.
基金supported by the Natural Science Foundation of China(Grant No.51973135)National Key Research and Development Program of China(Grant Nos.2018YFC1106103,2017YFB0702600,2017YFB0702603)Science and Technology Foundation of Sichuan Province(Grant No.2018RZ0044).
文摘Challenges associated with low-drug-loading capacity,lack of active targeting of tumor cells and unspecific drug release of nanocarriers synchronously plague the success of cancer therapy.Herein,we constructed active-targeting,redox-activated polymeric micelles(HPGssML)selfassembled aptamer-decorated,amphiphilic biodegradable poly(benzyl malolactonate-co-e-caprolactone)copolymer with disulfide linkage and p-conjugated moieties.HPGssML with a homogenous spherical shape and nanosized diameter(-150 nm)formed a low critical micellar concentration(10^-3mg/mL),suggesting good stability of polymeric micelles.The anticancer drug,doxorubicin(DOX),can be efficiently loaded into the core of micelles with high-drug-loading content via strong π-π interaction,which was verified by a decrease in fluorescence intensity and redshift in UV adsorption of DOX in micelles.The redox sensitivity of polymeric micelles was confirmed by size change and in vitro drug release in a reducing environment.Confocal microscopy and flow cytometry assay demonstrated that conjugating aptamers could enhance specific uptake of HPGssML by cancer cells.An in vitro cytotoxicity study showed that the half-maximal inhibitory concentration(IC50)of DOX-loaded HPGssML was two times lower than that of the control group,demonstrating improved antitumor efficacy.Therefore,the multifunctional biodegradable polymeric micelles can be exploited as a desirable drug carrier for effective cancer treatment.
