Immune-checkpoint inhibitor-mediated colitis(IMC)is an increasingly recognized adverse event in cancer immunotherapy,particularly associated with immune checkpoint inhibitors(ICIs)such as anti-cytotoxic T-lymphocyte a...Immune-checkpoint inhibitor-mediated colitis(IMC)is an increasingly recognized adverse event in cancer immunotherapy,particularly associated with immune checkpoint inhibitors(ICIs)such as anti-cytotoxic T-lymphocyte antigen-4 and anti-programmed cell death protein-1 antibodies.As this revolutionary immunotherapy gains prominence in cancer treatment,understanding,diagnosing,and effectively managing IMC becomes paramount.IMC represents a unique challenge due to its immune-mediated nature and potential for severe complications.However,a precise picture of IMC pathophysiology is currently unavailable.Therefore,we aimed to summarize the existing data while acknowledging the need for further research.This comprehensive review explores the mechanisms underlying ICIs,gastrointestinal adverse effects,and,in particular,IMC’s incidence,prevalence,and features.Our review also emphasizes the importance of recognizing IMC’s distinct clinical and histopathological features to differentiate it from other forms of colitis.Furthermore,this paper highlights the urgentneed for evolving diagnostic methods,therapeutic strategies,and a multidisciplinary approach to effectively manage IMC.展开更多
Great advances in immune checkpoint blockade have resulted in a paradigm shift in patients with lung cancer.Immune-checkpoint inhibitor(ICI)treatment,either as monotherapy or combination therapy,has been established a...Great advances in immune checkpoint blockade have resulted in a paradigm shift in patients with lung cancer.Immune-checkpoint inhibitor(ICI)treatment,either as monotherapy or combination therapy,has been established as the standard of care for patients with locally advanced/metastatic non-small cell lung cancer without EGFR/ALK alterations or extensive-stage small cell lung cancer.An increasing number of clinical trials are also ongoing to further investigate the role of ICIs in patients with early-stage lung cancer as neoadjuvant or adjuvant therapy.Although PD-L1 expression and tumor mutational burden have been widely studied for patient selection,both of these biomarkers are imperfect.Due to the complex cancer-immune interactions among tumor cells,the tumor microenvironment and host immunity,collaborative efforts are needed to establish a multidimensional immunogram to integrate complementary predictive biomarkers for personalized immunotherapy.Furthermore,as a result of the wide use of ICIs,managing acquired resistance to ICI treatment remains an inevitable challenge.A deeper understanding of the underlying biological mechanisms of acquired resistance to ICIs is helpful to overcome these obstacles.In this review,we describe the cutting-edge progress made in patients with lung cancer,the optimal duration of ICI treatment,ICIs in some special populations,the unique response patterns during ICI treatment,the emerging predictive biomarkers,and our understanding of primary and acquired resistance mechanisms to ICI treatment.展开更多
Introduction
Cancer cells can avoid being recognized and destroyed by the immune system by activating im-mune checkpoints, such as cytotoxic T lymphocyte-associated antigen 4 (CTLA4) and the programmed death-1 (PD-1)...Introduction
Cancer cells can avoid being recognized and destroyed by the immune system by activating im-mune checkpoints, such as cytotoxic T lymphocyte-associated antigen 4 (CTLA4) and the programmed death-1 (PD-1) receptor and its ligand PD-L1.展开更多
In 2030,pancreatic ductal adenocarcinoma(PDAC)will become the second leading cause of cancer-related mortality in the world.Unfortunately,neither conventional chemotherapy nor novel immunotherapeutic strategies can pr...In 2030,pancreatic ductal adenocarcinoma(PDAC)will become the second leading cause of cancer-related mortality in the world.Unfortunately,neither conventional chemotherapy nor novel immunotherapeutic strategies can provide durable responses and the survival prognosis remains very low.PDAC is notorious for its immuneresistant features and unique genomic landscape facilitating tumor escape from immunosurveillance.Novel immune-checkpoint inhibitors(ICI)failed to show promising efficacy and other multi-modal approaches are currently being validated in multiple clinical trials.In this paper,we provide our opinion on the major mechanisms responsible for PDAC resistance to ICI therapy and provide our view on future strategies which may overcome those barriers.展开更多
Mitochondria provides adenosine triphosphate for multiple vital movements to ensure tumor cell proliferation.Compared to the broadly used method of inducing DNA replication arrest to kill cancer,inducing mitochondria ...Mitochondria provides adenosine triphosphate for multiple vital movements to ensure tumor cell proliferation.Compared to the broadly used method of inducing DNA replication arrest to kill cancer,inducing mitochondria damage to cause energy shortage is quite promising as it can inhibit tumor cell bioactivities,increase intracellular accumulation of toxic drugs,eventually sensitize chemotherapy and even reverse drug resistance.Breaking the balance of glutathione(GSH)and reactive oxygen species(ROS)contents have been proven efficient in destroying mitochondria respectively.Herein,apigenin,a GSH efflux reagent,and 2-deoxy-5-fluorouridine 5-monophosphate sodium salt(FdUMP)that could induce toxic ROS were co-delivered by constructed lipid nanoparticles,noted as Lip@AF.An immune-checkpoint inhibition reagent CD276 antibody was modified onto the surface of Lip@AF with high reaction specificity(noted asαCD276-Lip@AF)to enhance the recognition of immune cells to tumor.Results showed that the redox balancewas destroyed,leading to severe injury to mitochondria and cell membrane.Furthermore,synergistic DNA/RNA replication inhibition caused by inhibiting the function of thymidylate synthase were observed.Eventually,significantly enhanced cytotoxicity was achieved by combining multiple mechanisms including ferroptosis,apoptosis and pyroptosis.In vivo,strengthen tumor growth inhibitionwas achieved byαCD276-Lip@AF with high biosafety,providing new sights in enhancing chemotherapy sensitiveness and achieving high-performance chemo-immunotherapy.展开更多
Colorectal cancer(CRC) is one of the most common cancers and a leading cause of cancer-related mortality worldwide. Although systemic therapy is the standard care for patients with recurrent or metastatic CRC, the pro...Colorectal cancer(CRC) is one of the most common cancers and a leading cause of cancer-related mortality worldwide. Although systemic therapy is the standard care for patients with recurrent or metastatic CRC, the prognosis is extremely poor. The optimal sequence of therapy remains unknown. Therefore, alternative strategies, such as immunotherapy, are needed for patients with advanced CRC. This review summarizes evidence from dendritic cell-based cancer immunotherapy strategies that are currently in clinical trials. In addition, we discuss the possibility of antitumor immune responses through immunoinhibitory PD-1/PD-L1 pathway blockade in CRC patients.展开更多
Glioblastoma remains as the most common and aggressive malignant brain tumor,standing with a poor prognosis and treatment prospective.Despite the aggressive standard care,such as surgical resection and chemoradiation,...Glioblastoma remains as the most common and aggressive malignant brain tumor,standing with a poor prognosis and treatment prospective.Despite the aggressive standard care,such as surgical resection and chemoradiation,median survival rates are low.In this regard,immunotherapeutic strategies aim to become more attractive for glioblastoma,considering its recent advances and approaches.In this review,we provide an overview of the current status and progress in immunotherapy for glioblastoma,going through the fundamental knowledge on immune targeting to promising strategies,such as Chimeric antigen receptor T-Cell therapy,immune checkpoint inhibitors,cytokine-based treatment,oncolytic virus and vaccine-based techniques.At last,it is discussed innovative methods to overcome diverse challenges,and future perspectives in this area.展开更多
Background:Recent clinical trials have shown that inhibitors targeting programmed cell death protein 1(PD-1)or its ligand(programmed cell death-ligand 1[PD-L1])provide significant efficacy and clinical benefit in the ...Background:Recent clinical trials have shown that inhibitors targeting programmed cell death protein 1(PD-1)or its ligand(programmed cell death-ligand 1[PD-L1])provide significant efficacy and clinical benefit in the treatment of advanced ormetastatic urothelial carcinoma(UC).This systematic review and meta-analysis aimed to compare the effectiveness and safety of PD-1/PD-L1 inhibitors in combination with chemotherapy or PD-1/PD-L1 inhibitor monotherapy versus platinum-based chemotherapy as a first-line treatment for advanced UC.Materials and methods:From the beginning of the database construction to February 4,2024,a combination of medical subject headings and free-text words was searched using the Population Intervention Comparison Outcome Study design framework.The PubMed,Cochrane Library,Embase,and Web of Science electronic databases were searched.Meta-analyses of progressionfree survival,overall survival,objective response rate(ORR),complete remission rate,duration of remission,and grade≥3 adverse events were performed.Results:Four studieswere included in the meta-analysis.The PD-1/PD-L1 inhibitors plus chemotherapy therapy is associated with significantly better ORR compared with chemotherapy.Unfortunately,there were no significant differences between PD-1/PD-L1 inhibitor monotherapy and chemotherapy in terms of ORR,duration of remission,or overall survival.Conclusions:Our findings indicate that PD-1/PD-L1 inhibitors plus chemotherapy therapy provides more oncological advantages than standard chemotherapy and should be recommended as a first-line treatment for advanced or metastatic UC.Attention must also be paid to the adverse effects of the combination of PD-1/PD-L1 inhibitors and chemotherapy.展开更多
With the improved understanding of driver mutations in non-small cell lung cancer (NSCLC), expanding the targeted therapeutic options improved the survival and safety. However, responses to these agents are commonly t...With the improved understanding of driver mutations in non-small cell lung cancer (NSCLC), expanding the targeted therapeutic options improved the survival and safety. However, responses to these agents are commonly temporary and incomplete. Moreover, even patients with the same oncogenic driver gene can respond diversely to the same agent. Furthermore, the therapeutic role of immune-checkpoint inhibitors (ICIs) in oncogene-driven NSCLC remains unclear. Therefore, this review aimed to classify the management of NSCLC with driver mutations based on the gene subtype, concomitant mutation, and dynamic alternation. Then, we provide an overview of the resistant mechanism of target therapy occurring in targeted alternations (“target-dependent resistance”) and in the parallel and downstream pathways (“target-independent resistance”). Thirdly, we discuss the effectiveness of ICIs for NSCLC with driver mutations and the combined therapeutic approaches that might reverse the immunosuppressive tumor immune microenvironment. Finally, we listed the emerging treatment strategies for the new oncogenic alternations, and proposed the perspective of NSCLC with driver mutations. This review will guide clinicians to design tailored treatments for NSCLC with driver mutations.展开更多
Cancer immunotherapy,especially immune checkpoint blockade(ICB),has revolutionized oncology.However,only a limited number of patients benefit from immunotherapy,and some cancers that initially respond to immunotherapy...Cancer immunotherapy,especially immune checkpoint blockade(ICB),has revolutionized oncology.However,only a limited number of patients benefit from immunotherapy,and some cancers that initially respond to immunotherapy can ultimately relapse and progress.Thus,some studies have investigated combining immunotherapy with other therapies to overcome resistance to monotherapy.Recently,multiple preclinical and clinical studies have shown that tumor vasculature is a determinant of whether immunotherapy will elicit an antitumor response;thus,vascular targeting may be a promising strategy to improve cancer immunotherapy outcomes.A successful antitumor immune response requires an intact“Cancer-Immunity Cycle,”including T cell priming and activation,immune cell recruitment,and recognition and killing of cancer cells.Angiogenic inducers,especially vascular endothelial growth factor(VEGF),can interfere with activation,infiltration,and function of T cells,thus breaking the“Cancer-Immunity Cycle.”Together with immunostimulation-regulated tumor vessel remodeling,VEGF-mediated immunosuppression provides a solid therapeutic rationale for combining immunotherapy with antiangiogenic agents to treat solid tumors.Following the successes of recent landmark phase III clinical trials,therapies combining immune checkpoint inhibitors(ICIs)with antiangiogenic agents have become first-line treatments for multiple solid tumors,whereas the efficacy of such combinations in other solid tumors remains to be validated in ongoing studies.In this review,we discussed synergies between antiangiogenic agents and cancer immunotherapy based on results from preclinical and translational studies.Then,we discussed recent progress in randomized clinical trials.ICI-containing combinations were the focus of this review because of their recent successes,but combinations containing other immunotherapies were also discussed.Finally,we attempted to define critical challenges in combining ICIs with antiangiogenic agents to promote coordination and stimulate collaboration within the research community.展开更多
Glioblastoma(GBM)is the most common and aggressive malignant brain tumor in adults and is poorly controlled.Previous studies have shown that both macrophages and angiogenesis play significant roles in GBM progression,...Glioblastoma(GBM)is the most common and aggressive malignant brain tumor in adults and is poorly controlled.Previous studies have shown that both macrophages and angiogenesis play significant roles in GBM progression,and co-targeting of CSF1R and VEGFR is likely to be an effective strategy for GBM treatment.Therefore,this study developed a novel and selective inhibitor of CSFIR and VEGFR,SYHA1813,possessing potent antitumor activity against GBM.SYHA1813 inhibited VEGFR and CSFIR kinase activities with high potency and selectivity and thus blocked the cell viability of HUVECs and macrophages and exhibited anti-angiogenetic effects both in vitro and in vivo.SYHA1813 also displayed potent in vivo antitumor activity against GBM in immune-competent and immune-deficient mouse models,including temozolomide(TMZ)insensitive tumors.Notably,SYHA1813 could penetrate the blood-brain barrier(BBB)and prolong the survival time of mice bearing intracranial GBM xenografts.Moreover,SYHA1813 treatment resulted in a synergistic antitumor efficacy in combination with the PD-1 antibody.As a clinical proof of concept,SYHA1813 achieved confirmed responses in patients with recurrent GBM in an ongoing first-in-human phase I trial.The data of this study support the rationale for an ongoing phase I clinical study(ChiCTR2100045380).展开更多
Pancreatic ductal adenocarcinoma(PDAC)is the most common type and composes about 90%of pancreatic cancer featured with high intra-tumoral heterogeneity and poor prognosis,which has been considered the least immunogeni...Pancreatic ductal adenocarcinoma(PDAC)is the most common type and composes about 90%of pancreatic cancer featured with high intra-tumoral heterogeneity and poor prognosis,which has been considered the least immunogenic cancer for decades.However,this characterization might be over-simplistic,and more sophisticated approaches are needed to develop effective treatment strategies.In this review,we aim to summarize studies involving PDAC immunity in different aspects to provide a multidimensional recognition and comprehensively understanding of the mechanisms underlying the tumor microenvironment(TME)of PDAC.A database search of peer-reviewed articles published in English between 2003 and 2022 in PubMed and the Web of Science was performed.Original articles and review articles relevant to the topic were selected.We emphasized the importance of investigating tumor-infiltrating lymphocytes(TILs)in pancreatic cancer,especially focusing on CD8+T cells,along with indicating potential therapeutic strategies to turn the immune-cold PDACs into the immune-hot ones.展开更多
Clinical guidelines for the prevention,diagnosis and management of human disease are evidence-based tools that rely on quality of clinical research,including data from randomized controlled clinical trials(RCTs)and re...Clinical guidelines for the prevention,diagnosis and management of human disease are evidence-based tools that rely on quality of clinical research,including data from randomized controlled clinical trials(RCTs)and real-world evidence.The Society for Immunotherapy of Cancer(SITC)recently published a clinical practice guideline on immunotherapy for the treatment of hepatocellular carcinoma(HCC)(1).展开更多
Pharmacogenetics is the study of therapeutic and adverse responses to drugs based on an individual’s genetic background.Monoclonal antibodies(mAbs)are a rapidly evolving field in cancer therapy,however a number of ne...Pharmacogenetics is the study of therapeutic and adverse responses to drugs based on an individual’s genetic background.Monoclonal antibodies(mAbs)are a rapidly evolving field in cancer therapy,however a number of newly developed and highly effective mAbs(e.g.,anti-CTLA-4 and anti-PD-1)possess pharmacogenomic profiles that remain largely undefined.Since the first chemotherapeutic mAb Rituximab was approved in 1997 by the US Food and Drug Administration for cancer treatment,a broad number of other mAbs have been successfully developed and implemented into oncological practice.Nowadays,mAbs are considered as one of the most promising new approaches for cancer treatment.The efficacy of mAb treatment can however be significantly affected by genetic background,where genes responsible for antibody presentation and metabolism,for example,can seriously affect patient outcome.This review will focus on current anticancer mAb treatments,patient genetics that shape their efficacy,and the molecular pathways that bridge the two.展开更多
Background:Metastatic triple-negative breast cancer(mTNBC)is an aggressive histological subtype with poor prognosis.Several first-line treatments are currently available for mTNBC.This study conducted a network meta-a...Background:Metastatic triple-negative breast cancer(mTNBC)is an aggressive histological subtype with poor prognosis.Several first-line treatments are currently available for mTNBC.This study conducted a network meta-analysis to compare these first-line regimens and to determine the regimen with the best efficacy.Methods:A systematic search of PubMed,EMBASE,the Cochrane Central Register of Controlled Bases,and mi-nutes of major conferences was performed.Progression-free survival(PFS),overall survival(OS),and objective response rate(ORR)were analyzed via network meta-analysis using the R software(R Core Team,Vienna,Austria).The efficacy of the treatment regimens was compared using hazard ratios and 95%confidence intervals.Results:A total of 29 randomized controlled trials involving 4607 patients were analyzed.The ranking was based on the surface under the cumulative ranking curve.Network meta-analysis results showed that cisplatin combined with nab-paclitaxel or paclitaxel was superior to docetaxel plus capecitabine in terms of PFS and ORR.For programmed death-ligand 1(PD-L1)and breast cancer susceptibility gene(BRCA)mutation-positive tumors,atezolizumab/pembrolizumab combined with nab-paclitaxel and talazoparib was superior to docetaxel plus capecitabine.No significant difference was observed among the treatments in Os.Neutropenia,diarrhea,and fatigue were common serious adverse events.Conclusion:Cisplatin combined with nab-paclitaxel or paclitaxel is the preferred first-line treatment for mTNBC.For PD-L1 and BRCA mutation-positive tumors,atezolizumab/pembrolizumab combined with nab-paclitaxel and talazoparib is an effective treatment option,Neutropenia,diarrhea,and fatigue are frequently occurring serious adverseevents.展开更多
Aim:Immune checkpoint inhibitors(ICIs)are proven to be an effective way to treat the disease of hematologic malignancies.But there is still plenty of uncertainty about the effectiveness of ICIs on hepatocellular carci...Aim:Immune checkpoint inhibitors(ICIs)are proven to be an effective way to treat the disease of hematologic malignancies.But there is still plenty of uncertainty about the effectiveness of ICIs on hepatocellular carcinoma.The Meta-analysis was conducted to evaluate the efficacy and safety of ICIs treatment in patients with HCC.Methods:Four electronic databases,including PubMed,Embase,Cochrane database,and ClinicalTrials.gov,were systematically retrieved for relevant observational studies published before November 1,2018.The objective response rate(ORR)and adverse events were analyzed.Meta and Metafor Packages in R were utilized to accomplish meta proportion analysis.Results:A total of 462 patients from 7 studies were included in this meta-analysis.The pooled estimated ORR of ICIs was 19.8%(95%CI 16.4%to 23.7%).No substantial heterogeneity was observed among studies(Q=2.0427,P=0.92,I 2=0.0%).The common adverse events on any grade were saw in increased AST(22.7%,95%CI 13.8%to 35.2%),fatigue(20.9%,95%CI 10.9%to 36.3%),rash(18.5%,95%CI 8.9%to 34.4%)and pruritus(17.3%,95%CI 13.5%to 21.8%).Increased AST(9.9%,95%CI 4.4%to 21.0%)and increased ALT(5.8%,95%CI 3.7%to 8.9%)were the most common adverse events on grade greater than 3.Conclusion:Although ICIs treatment has a certain efficacy on liver cancer,it also causes some adverse events which should be noticed by clinicians.展开更多
基金Supported by the European Union-NextGenerationEU,through the National Recovery and Resilience Plan of the Republic of Bulgaria,No.BG-RRP-2.004-0008.
文摘Immune-checkpoint inhibitor-mediated colitis(IMC)is an increasingly recognized adverse event in cancer immunotherapy,particularly associated with immune checkpoint inhibitors(ICIs)such as anti-cytotoxic T-lymphocyte antigen-4 and anti-programmed cell death protein-1 antibodies.As this revolutionary immunotherapy gains prominence in cancer treatment,understanding,diagnosing,and effectively managing IMC becomes paramount.IMC represents a unique challenge due to its immune-mediated nature and potential for severe complications.However,a precise picture of IMC pathophysiology is currently unavailable.Therefore,we aimed to summarize the existing data while acknowledging the need for further research.This comprehensive review explores the mechanisms underlying ICIs,gastrointestinal adverse effects,and,in particular,IMC’s incidence,prevalence,and features.Our review also emphasizes the importance of recognizing IMC’s distinct clinical and histopathological features to differentiate it from other forms of colitis.Furthermore,this paper highlights the urgentneed for evolving diagnostic methods,therapeutic strategies,and a multidisciplinary approach to effectively manage IMC.
基金This work was partly supported by grants from the National Natural Science Foundation of China(No.81703020,81871865,81972169)National R&D projects(2016YFC0902300)Shanghai Science and Technology Medical Guidance Project(16411964400).
文摘Great advances in immune checkpoint blockade have resulted in a paradigm shift in patients with lung cancer.Immune-checkpoint inhibitor(ICI)treatment,either as monotherapy or combination therapy,has been established as the standard of care for patients with locally advanced/metastatic non-small cell lung cancer without EGFR/ALK alterations or extensive-stage small cell lung cancer.An increasing number of clinical trials are also ongoing to further investigate the role of ICIs in patients with early-stage lung cancer as neoadjuvant or adjuvant therapy.Although PD-L1 expression and tumor mutational burden have been widely studied for patient selection,both of these biomarkers are imperfect.Due to the complex cancer-immune interactions among tumor cells,the tumor microenvironment and host immunity,collaborative efforts are needed to establish a multidimensional immunogram to integrate complementary predictive biomarkers for personalized immunotherapy.Furthermore,as a result of the wide use of ICIs,managing acquired resistance to ICI treatment remains an inevitable challenge.A deeper understanding of the underlying biological mechanisms of acquired resistance to ICIs is helpful to overcome these obstacles.In this review,we describe the cutting-edge progress made in patients with lung cancer,the optimal duration of ICI treatment,ICIs in some special populations,the unique response patterns during ICI treatment,the emerging predictive biomarkers,and our understanding of primary and acquired resistance mechanisms to ICI treatment.
文摘Introduction
Cancer cells can avoid being recognized and destroyed by the immune system by activating im-mune checkpoints, such as cytotoxic T lymphocyte-associated antigen 4 (CTLA4) and the programmed death-1 (PD-1) receptor and its ligand PD-L1.
文摘In 2030,pancreatic ductal adenocarcinoma(PDAC)will become the second leading cause of cancer-related mortality in the world.Unfortunately,neither conventional chemotherapy nor novel immunotherapeutic strategies can provide durable responses and the survival prognosis remains very low.PDAC is notorious for its immuneresistant features and unique genomic landscape facilitating tumor escape from immunosurveillance.Novel immune-checkpoint inhibitors(ICI)failed to show promising efficacy and other multi-modal approaches are currently being validated in multiple clinical trials.In this paper,we provide our opinion on the major mechanisms responsible for PDAC resistance to ICI therapy and provide our view on future strategies which may overcome those barriers.
基金financially supported by the National Natural Science Foundation of China(82173769)Tianjin Science Foundation for Distinguished Young Scholars(24JCJQJC00050)+2 种基金Applied Basic Research Multi-Investment Foundation of Tianjin(21JCYBJC01540)the National Natural Science Foundation of China(82300336)the Science&Technology Development Fund of Tianjin Education Commission for Higher Education(2019KJ178).
文摘Mitochondria provides adenosine triphosphate for multiple vital movements to ensure tumor cell proliferation.Compared to the broadly used method of inducing DNA replication arrest to kill cancer,inducing mitochondria damage to cause energy shortage is quite promising as it can inhibit tumor cell bioactivities,increase intracellular accumulation of toxic drugs,eventually sensitize chemotherapy and even reverse drug resistance.Breaking the balance of glutathione(GSH)and reactive oxygen species(ROS)contents have been proven efficient in destroying mitochondria respectively.Herein,apigenin,a GSH efflux reagent,and 2-deoxy-5-fluorouridine 5-monophosphate sodium salt(FdUMP)that could induce toxic ROS were co-delivered by constructed lipid nanoparticles,noted as Lip@AF.An immune-checkpoint inhibition reagent CD276 antibody was modified onto the surface of Lip@AF with high reaction specificity(noted asαCD276-Lip@AF)to enhance the recognition of immune cells to tumor.Results showed that the redox balancewas destroyed,leading to severe injury to mitochondria and cell membrane.Furthermore,synergistic DNA/RNA replication inhibition caused by inhibiting the function of thymidylate synthase were observed.Eventually,significantly enhanced cytotoxicity was achieved by combining multiple mechanisms including ferroptosis,apoptosis and pyroptosis.In vivo,strengthen tumor growth inhibitionwas achieved byαCD276-Lip@AF with high biosafety,providing new sights in enhancing chemotherapy sensitiveness and achieving high-performance chemo-immunotherapy.
基金Supported by Grants in Aid for Scientific Research (C) from the Japanese Ministry of Education, Culture, Sports, Science, and Technology.
文摘Colorectal cancer(CRC) is one of the most common cancers and a leading cause of cancer-related mortality worldwide. Although systemic therapy is the standard care for patients with recurrent or metastatic CRC, the prognosis is extremely poor. The optimal sequence of therapy remains unknown. Therefore, alternative strategies, such as immunotherapy, are needed for patients with advanced CRC. This review summarizes evidence from dendritic cell-based cancer immunotherapy strategies that are currently in clinical trials. In addition, we discuss the possibility of antitumor immune responses through immunoinhibitory PD-1/PD-L1 pathway blockade in CRC patients.
基金Supported by the Scientific Initiation Scholarship Programme(PIBIC)of National Council for Scientific and Technological Development,CNPq,Brazilthe Scientific Initiation Scholarship Programme(PIBIC)of Bahia State Research Support Foundation,FAPESB,Brazil.
文摘Glioblastoma remains as the most common and aggressive malignant brain tumor,standing with a poor prognosis and treatment prospective.Despite the aggressive standard care,such as surgical resection and chemoradiation,median survival rates are low.In this regard,immunotherapeutic strategies aim to become more attractive for glioblastoma,considering its recent advances and approaches.In this review,we provide an overview of the current status and progress in immunotherapy for glioblastoma,going through the fundamental knowledge on immune targeting to promising strategies,such as Chimeric antigen receptor T-Cell therapy,immune checkpoint inhibitors,cytokine-based treatment,oncolytic virus and vaccine-based techniques.At last,it is discussed innovative methods to overcome diverse challenges,and future perspectives in this area.
基金supported by the Guangxi Natural Science Foundation Program(no.2024GXNSFBA010036)the Scientific Research Foundation of Guangxi Health Commission(Z-B20220927)the Scientific Research Foundation of Guangxi Health Commission(Z-B20220930).
文摘Background:Recent clinical trials have shown that inhibitors targeting programmed cell death protein 1(PD-1)or its ligand(programmed cell death-ligand 1[PD-L1])provide significant efficacy and clinical benefit in the treatment of advanced ormetastatic urothelial carcinoma(UC).This systematic review and meta-analysis aimed to compare the effectiveness and safety of PD-1/PD-L1 inhibitors in combination with chemotherapy or PD-1/PD-L1 inhibitor monotherapy versus platinum-based chemotherapy as a first-line treatment for advanced UC.Materials and methods:From the beginning of the database construction to February 4,2024,a combination of medical subject headings and free-text words was searched using the Population Intervention Comparison Outcome Study design framework.The PubMed,Cochrane Library,Embase,and Web of Science electronic databases were searched.Meta-analyses of progressionfree survival,overall survival,objective response rate(ORR),complete remission rate,duration of remission,and grade≥3 adverse events were performed.Results:Four studieswere included in the meta-analysis.The PD-1/PD-L1 inhibitors plus chemotherapy therapy is associated with significantly better ORR compared with chemotherapy.Unfortunately,there were no significant differences between PD-1/PD-L1 inhibitor monotherapy and chemotherapy in terms of ORR,duration of remission,or overall survival.Conclusions:Our findings indicate that PD-1/PD-L1 inhibitors plus chemotherapy therapy provides more oncological advantages than standard chemotherapy and should be recommended as a first-line treatment for advanced or metastatic UC.Attention must also be paid to the adverse effects of the combination of PD-1/PD-L1 inhibitors and chemotherapy.
基金Beijing Natural Science Foundation(No.7222144)National Key Research and Development Project(No.2019YFC1315700)CAMS Key Laboratory of Translational Research on Lung Cancer(No.2018PT31035).
文摘With the improved understanding of driver mutations in non-small cell lung cancer (NSCLC), expanding the targeted therapeutic options improved the survival and safety. However, responses to these agents are commonly temporary and incomplete. Moreover, even patients with the same oncogenic driver gene can respond diversely to the same agent. Furthermore, the therapeutic role of immune-checkpoint inhibitors (ICIs) in oncogene-driven NSCLC remains unclear. Therefore, this review aimed to classify the management of NSCLC with driver mutations based on the gene subtype, concomitant mutation, and dynamic alternation. Then, we provide an overview of the resistant mechanism of target therapy occurring in targeted alternations (“target-dependent resistance”) and in the parallel and downstream pathways (“target-independent resistance”). Thirdly, we discuss the effectiveness of ICIs for NSCLC with driver mutations and the combined therapeutic approaches that might reverse the immunosuppressive tumor immune microenvironment. Finally, we listed the emerging treatment strategies for the new oncogenic alternations, and proposed the perspective of NSCLC with driver mutations. This review will guide clinicians to design tailored treatments for NSCLC with driver mutations.
基金National Key Research and Development Program,Grant/Award Number:2017YFSF090107National Natural Science Foundation of China,Grant/Award Numbers:82072996,81874131+1 种基金Hubei Province Natural Science Funds for Distinguished Young Scholar,Grant/Award Number:2017CFA062Innovative research team of high-level local universities in Shanghai,Grant/Award Number:ZLCX20180500。
文摘Cancer immunotherapy,especially immune checkpoint blockade(ICB),has revolutionized oncology.However,only a limited number of patients benefit from immunotherapy,and some cancers that initially respond to immunotherapy can ultimately relapse and progress.Thus,some studies have investigated combining immunotherapy with other therapies to overcome resistance to monotherapy.Recently,multiple preclinical and clinical studies have shown that tumor vasculature is a determinant of whether immunotherapy will elicit an antitumor response;thus,vascular targeting may be a promising strategy to improve cancer immunotherapy outcomes.A successful antitumor immune response requires an intact“Cancer-Immunity Cycle,”including T cell priming and activation,immune cell recruitment,and recognition and killing of cancer cells.Angiogenic inducers,especially vascular endothelial growth factor(VEGF),can interfere with activation,infiltration,and function of T cells,thus breaking the“Cancer-Immunity Cycle.”Together with immunostimulation-regulated tumor vessel remodeling,VEGF-mediated immunosuppression provides a solid therapeutic rationale for combining immunotherapy with antiangiogenic agents to treat solid tumors.Following the successes of recent landmark phase III clinical trials,therapies combining immune checkpoint inhibitors(ICIs)with antiangiogenic agents have become first-line treatments for multiple solid tumors,whereas the efficacy of such combinations in other solid tumors remains to be validated in ongoing studies.In this review,we discussed synergies between antiangiogenic agents and cancer immunotherapy based on results from preclinical and translational studies.Then,we discussed recent progress in randomized clinical trials.ICI-containing combinations were the focus of this review because of their recent successes,but combinations containing other immunotherapies were also discussed.Finally,we attempted to define critical challenges in combining ICIs with antiangiogenic agents to promote coordination and stimulate collaboration within the research community.
基金supported by grants from the Natural Science Foundation of China for Innovation Research Group(81821005)the National Natural Science Foundation of China(82273948 and 81573271)+2 种基金the"Personalized Medicines,Molecular Signaturebased Drug Discovery and Development",Strategic Priority Research Program of the Chinese Academy of Sciences(XDA12020203 and XDA12020228,China)the National Science&Technology Major Project"Key New Drug Creation and Manufacturing Program",China(2018ZX09711002-011-016)the Youth Innovation Promotion Association of CAS(2018324,China).
文摘Glioblastoma(GBM)is the most common and aggressive malignant brain tumor in adults and is poorly controlled.Previous studies have shown that both macrophages and angiogenesis play significant roles in GBM progression,and co-targeting of CSF1R and VEGFR is likely to be an effective strategy for GBM treatment.Therefore,this study developed a novel and selective inhibitor of CSFIR and VEGFR,SYHA1813,possessing potent antitumor activity against GBM.SYHA1813 inhibited VEGFR and CSFIR kinase activities with high potency and selectivity and thus blocked the cell viability of HUVECs and macrophages and exhibited anti-angiogenetic effects both in vitro and in vivo.SYHA1813 also displayed potent in vivo antitumor activity against GBM in immune-competent and immune-deficient mouse models,including temozolomide(TMZ)insensitive tumors.Notably,SYHA1813 could penetrate the blood-brain barrier(BBB)and prolong the survival time of mice bearing intracranial GBM xenografts.Moreover,SYHA1813 treatment resulted in a synergistic antitumor efficacy in combination with the PD-1 antibody.As a clinical proof of concept,SYHA1813 achieved confirmed responses in patients with recurrent GBM in an ongoing first-in-human phase I trial.The data of this study support the rationale for an ongoing phase I clinical study(ChiCTR2100045380).
基金supported by grants from the Chongqing Talents Program(CN)(CQYC2021059730 to Y.Zhang)Chongqing Returnee Talents Innovation Program(CN)(CX2022081 to Y.Zhang)the National Natural Science Foundation of China(31800763 to Y.Zhang)
文摘Pancreatic ductal adenocarcinoma(PDAC)is the most common type and composes about 90%of pancreatic cancer featured with high intra-tumoral heterogeneity and poor prognosis,which has been considered the least immunogenic cancer for decades.However,this characterization might be over-simplistic,and more sophisticated approaches are needed to develop effective treatment strategies.In this review,we aim to summarize studies involving PDAC immunity in different aspects to provide a multidimensional recognition and comprehensively understanding of the mechanisms underlying the tumor microenvironment(TME)of PDAC.A database search of peer-reviewed articles published in English between 2003 and 2022 in PubMed and the Web of Science was performed.Original articles and review articles relevant to the topic were selected.We emphasized the importance of investigating tumor-infiltrating lymphocytes(TILs)in pancreatic cancer,especially focusing on CD8+T cells,along with indicating potential therapeutic strategies to turn the immune-cold PDACs into the immune-hot ones.
文摘Clinical guidelines for the prevention,diagnosis and management of human disease are evidence-based tools that rely on quality of clinical research,including data from randomized controlled clinical trials(RCTs)and real-world evidence.The Society for Immunotherapy of Cancer(SITC)recently published a clinical practice guideline on immunotherapy for the treatment of hepatocellular carcinoma(HCC)(1).
文摘Pharmacogenetics is the study of therapeutic and adverse responses to drugs based on an individual’s genetic background.Monoclonal antibodies(mAbs)are a rapidly evolving field in cancer therapy,however a number of newly developed and highly effective mAbs(e.g.,anti-CTLA-4 and anti-PD-1)possess pharmacogenomic profiles that remain largely undefined.Since the first chemotherapeutic mAb Rituximab was approved in 1997 by the US Food and Drug Administration for cancer treatment,a broad number of other mAbs have been successfully developed and implemented into oncological practice.Nowadays,mAbs are considered as one of the most promising new approaches for cancer treatment.The efficacy of mAb treatment can however be significantly affected by genetic background,where genes responsible for antibody presentation and metabolism,for example,can seriously affect patient outcome.This review will focus on current anticancer mAb treatments,patient genetics that shape their efficacy,and the molecular pathways that bridge the two.
文摘Background:Metastatic triple-negative breast cancer(mTNBC)is an aggressive histological subtype with poor prognosis.Several first-line treatments are currently available for mTNBC.This study conducted a network meta-analysis to compare these first-line regimens and to determine the regimen with the best efficacy.Methods:A systematic search of PubMed,EMBASE,the Cochrane Central Register of Controlled Bases,and mi-nutes of major conferences was performed.Progression-free survival(PFS),overall survival(OS),and objective response rate(ORR)were analyzed via network meta-analysis using the R software(R Core Team,Vienna,Austria).The efficacy of the treatment regimens was compared using hazard ratios and 95%confidence intervals.Results:A total of 29 randomized controlled trials involving 4607 patients were analyzed.The ranking was based on the surface under the cumulative ranking curve.Network meta-analysis results showed that cisplatin combined with nab-paclitaxel or paclitaxel was superior to docetaxel plus capecitabine in terms of PFS and ORR.For programmed death-ligand 1(PD-L1)and breast cancer susceptibility gene(BRCA)mutation-positive tumors,atezolizumab/pembrolizumab combined with nab-paclitaxel and talazoparib was superior to docetaxel plus capecitabine.No significant difference was observed among the treatments in Os.Neutropenia,diarrhea,and fatigue were common serious adverse events.Conclusion:Cisplatin combined with nab-paclitaxel or paclitaxel is the preferred first-line treatment for mTNBC.For PD-L1 and BRCA mutation-positive tumors,atezolizumab/pembrolizumab combined with nab-paclitaxel and talazoparib is an effective treatment option,Neutropenia,diarrhea,and fatigue are frequently occurring serious adverseevents.
基金This work was supported by National Key Basic Research Program of China(No.2015CB554000).
文摘Aim:Immune checkpoint inhibitors(ICIs)are proven to be an effective way to treat the disease of hematologic malignancies.But there is still plenty of uncertainty about the effectiveness of ICIs on hepatocellular carcinoma.The Meta-analysis was conducted to evaluate the efficacy and safety of ICIs treatment in patients with HCC.Methods:Four electronic databases,including PubMed,Embase,Cochrane database,and ClinicalTrials.gov,were systematically retrieved for relevant observational studies published before November 1,2018.The objective response rate(ORR)and adverse events were analyzed.Meta and Metafor Packages in R were utilized to accomplish meta proportion analysis.Results:A total of 462 patients from 7 studies were included in this meta-analysis.The pooled estimated ORR of ICIs was 19.8%(95%CI 16.4%to 23.7%).No substantial heterogeneity was observed among studies(Q=2.0427,P=0.92,I 2=0.0%).The common adverse events on any grade were saw in increased AST(22.7%,95%CI 13.8%to 35.2%),fatigue(20.9%,95%CI 10.9%to 36.3%),rash(18.5%,95%CI 8.9%to 34.4%)and pruritus(17.3%,95%CI 13.5%to 21.8%).Increased AST(9.9%,95%CI 4.4%to 21.0%)and increased ALT(5.8%,95%CI 3.7%to 8.9%)were the most common adverse events on grade greater than 3.Conclusion:Although ICIs treatment has a certain efficacy on liver cancer,it also causes some adverse events which should be noticed by clinicians.
