Immune checkpoint inhibitors(ICIs)are new and promising therapeutic agents for non-small cell lung cancer(NSCLC).However,along with demonstrating remarkable efficacy,ICIs can also trigger immune-related adverse events...Immune checkpoint inhibitors(ICIs)are new and promising therapeutic agents for non-small cell lung cancer(NSCLC).However,along with demonstrating remarkable efficacy,ICIs can also trigger immune-related adverse events.Checkpoint inhibitor pneumonitis(CIP)has been reported to have a morbidity rate of 3%to 5%and a mortality rate of 10%to 17%.Moreover,the incidence of CIP in NSCLC is higher than that in other tumor types,reaching 7%to 13%.With the increased use of ICIs in NSCLC,CIP has drawn extensive attention from oncologists and cancer researchers.Identifying high risk factors for CIP and the potential mechanism of CIP are key points in preventing and monitoring serious adverse events.In this review,the results of our analysis and summary of previous studies suggested that the risk factors for CIP may include previous lung disease,prior thoracic irradiation,and combinations with other drugs.Our review also explored potential mechanisms closely related toCIP,including increasedT cell activity against associated antigens in tumor and normal tissues,preexisting autoantibodies,and inflammatory cytokines.展开更多
Hepatocellular carcinoma(HCC)arises on the background of chronic liver disease.Despite the development of effective anti-viral therapeutics HCC is continuing to rise,in part driven by the epidemic of non-alcoholic fat...Hepatocellular carcinoma(HCC)arises on the background of chronic liver disease.Despite the development of effective anti-viral therapeutics HCC is continuing to rise,in part driven by the epidemic of non-alcoholic fatty liver disease.Many patients present with advanced disease out with the criteria for transplant,resection or even locoregional therapy.Currently available therapeutics for HCC are effective in a small minority of individuals.However,there has been a major global interest in immunotherapies for cancer and although HCC has lagged behind other cancers,great opportunities now exist for treating HCC with newer and more sophisticated agents.Whilst checkpoint inhibitors are at the forefront of this revolution,other therapeutics such as inhibitory cytokine blockade,oncolytic viruses,adoptive cellular therapies and vaccines are emerging.Broadly these may be categorized as either boosting existing immune response or stimulating de novo immune response.Although some of these agents have shown promising results as monotherapy in early phase trials it may well be that their future role will be as combination therapy,either in combination with one another or in combination with treatment modalities such as locoregional therapy.Together these agents are likely to generate new and exciting opportunities for treating HCC,which are summarized in this review.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
In recent years immune checkpoint inhibitors have garnered attention as being one of the most promising types of immunotherapy on the horizon. There has been particular focus on the immune checkpoint molecules, cytoto...In recent years immune checkpoint inhibitors have garnered attention as being one of the most promising types of immunotherapy on the horizon. There has been particular focus on the immune checkpoint molecules, cytotoxic Tlymphocyte antigen-4（CTLA-4） and programmed cell death protein 1（PD-1） which have been shown to have potent immunomodulatory effects through their function as negative regulators of T cell activation. CTLA-4, through engagement with its ligands B7-1（CD80） and B7-2（CD86）, plays a pivotal role in attenuating the activation of naive and memory T cells. In contrast, PD-1 is primarily involved in modulating T cell activity in peripheral tissues via its interaction with PD-L1 and PD-L2. The discovery of these negative regulators of the immune response was crucial in the development of checkpoint inhibitors. This shifted the focus from developing therapies that targeted activation of the host immune system against cancer to checkpoint inhibitors, which aimed to mediate tumor cell destruction through the removal of coinhibitory signals blocking anti-tumor T cell responses.展开更多
Immuno-oncology is a fast evolving field of cancer therapy and immune checkpoint inhibitors (ICIs) are clearly a breakthrough in this field. Cardiotoxicity with conventional anti-cancer therapies has been well studied...Immuno-oncology is a fast evolving field of cancer therapy and immune checkpoint inhibitors (ICIs) are clearly a breakthrough in this field. Cardiotoxicity with conventional anti-cancer therapies has been well studied in the past and clear guidelines for management of these side effects are available in the literature. However, cardiotoxicity with novel agents such as ICIs has been fairly under-reported and/or underestimated and we are yet to formulate clear guidelines for management of these rare side effects. In the last few years, there has been an overall increase in the number of cases of cardiotoxicity related to ICIs. In this literature review, we describe the mechanism of action of the most widely used ICIs and their related cardiotoxicities. The increase in number of case reports about the potential of cardiotoxicities with these novel agents clearly indicates the need for a new insight into the field of cardio-immuno-oncology.展开更多
Background:Treatment of hepatocellular carcinoma(HCC)is challenging as most patients are diagnosed at advanced stage with underlying chronic liver conditions.Conventional systemic chemotherapy has failed in HCC,and th...Background:Treatment of hepatocellular carcinoma(HCC)is challenging as most patients are diagnosed at advanced stage with underlying chronic liver conditions.Conventional systemic chemotherapy has failed in HCC,and the clinical efficacy of FDA-approved molecular targeted agents such as sorafenib and lenvatinib remains unsatisfactory.Data sources:Literature search was conducted in Pub Med for relevant articles published before January 2021.The search aimed to identify recent developments in immune-based treatment approaches for HCC.Information of clinical trials was obtained from https://clinicaltrials.gov/.Results:Two immune checkpoint inhibitors(ICIs),nivolumab and pembrolizumab were approved as monotherapies,which has revolutionized HCC treatment.Besides,combination ICIs have also got accelerated FDA approval recently.Immune-based therapies have challenged targeted drugs owing to their safety,tolerability,and survival benefits.In addition to the significant success in ICIs,other immunotherapeutic strategies such as cancer vaccine,chimeric antigen receptor T-cells,natural killer cells,cytokines,and combination therapy,have also shown promising outcomes in clinical trials.Various diagnostic and prognostic biomarkers have been identified which can help in clinical decision making when starting treatment with ICIs.Conclusions:Immunotherapy has emerged as one of the mainstream treatment modalities for advanced HCC in recent years.However,challenges such as low response rate and acquired resistance in previously respondent patients still exist.Further research is needed to understand the unique resistance mechanism to immunotherapy and to discover more predictive biomarkers to guide clinical decision making.展开更多
Pancreatic ductal adenocarcinoma(PDAC)is one of the deadliest cancers,mostly due to its resistance to treatment.Of these,checkpoint inhibitors(CPI)are inefficient when used as monotherapy,except in the case of a rare ...Pancreatic ductal adenocarcinoma(PDAC)is one of the deadliest cancers,mostly due to its resistance to treatment.Of these,checkpoint inhibitors(CPI)are inefficient when used as monotherapy,except in the case of a rare subset of tumors harboring microsatellite instability(<2%).This inefficacy mainly resides in the low immunogenicity and non-inflamed phenotype of PDAC.The abundant stroma generates a hypoxic microenvironment and drives the recruitment of immunosuppressive cells through cancerassociated-fibroblast activation and transforming growth factorβsecretion.Several strategies have recently been developed to overcome this immunosuppressive microenvironment.Combination therapies involving CPI aim at increasing tumor immunogenicity and promoting the recruitment and activation of effector T cells.Ongoing studies are therefore exploring the association of CPI with vaccines,oncolytic viruses,MEK inhibitors,cytokine inhibitors,and hypoxia-and stroma-targeting agents.Adoptive T-cell transfer is also under investigation.Moreover,translational studies on tumor tissue and blood,prior to and during treatment may lead to the identification of biomarkers with predictive value for both clinical outcome and response to immunotherapy.展开更多
Immune checkpoint inhibitors(ICIs)are widely used due to their effectiveness in treating various tumors.Immune-related adverse events(irAEs)are defined as adverse effects resulting from ICI treatment.Gastrointestinal ...Immune checkpoint inhibitors(ICIs)are widely used due to their effectiveness in treating various tumors.Immune-related adverse events(irAEs)are defined as adverse effects resulting from ICI treatment.Gastrointestinal irAEs are a common type of irAEs characterized by intestinal side effects,such as diarrhea and colitis,which may lead to the cessation of ICIs.Although irAE gastritis is rarely reported,it may lead to serious complications such as gastrorrhagia.Furthermore,irAE gastritis is often difficult to identify early due to its diverse symptoms.Although steroid hormones and immunosuppressants are commonly used to reverse irAEs,the best regimen and dosage for irAE gastritis remains uncertain.In addition,the risk of recurrence of irAE gastritis after the reuse of ICIs should be considered.In this editorial,strategies such as early identification,pathological diagnosis,mana-gement interventions,and immunotherapy rechallenge are discussed to enable clinicians to better manage irAE gastritis and improve the prognosis of these patients.展开更多
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
Immunological evasion is one of the defining characteristics of cancers,as the immune modification of an immune checkpoint(IC)confers immune evasion capabilities to tumor cells.Multiple ICs,such as programmed cell dea...Immunological evasion is one of the defining characteristics of cancers,as the immune modification of an immune checkpoint(IC)confers immune evasion capabilities to tumor cells.Multiple ICs,such as programmed cell death protein-1(PD-1)and cytotoxic T-lymphocyte-associated antigen-4(CTLA-4),can bind to their respective receptors and reduce tumor immunity in a variety of ways,including blocking immune cell activation signals.IC blockade(ICB)therapies targeting these checkpoint molecules have demonstrated significant clinical benefits.This is because antibody-based IC inhibitors and a variety of specific small molecule inhibitors can inhibit key oncogenic signaling pathways and induce durable tumor remission in patients with a variety of cancers.Deciphering the roles and regulatory mechanisms of these IC molecules will provide crucial theoretical guidance for clinical treatment.In this review,we summarize the current knowledge on the functional and regulatory mechanisms of these IC molecules at multiple levels,including epigenetic regulation,transcriptional regulation,and post-translational modifications.In addition,we provide a summary of the medications targeting various nodes in the regulatory pathway,and highlight the potential of newly identified IC molecules,focusing on their potential implications for cancer diagnostics and immunotherapy.展开更多
In recent years,immune checkpoint inhibitors(ICIs)have made breakthroughs in the field of lung cancer and have become a focal point for research.Programmed death-1(PD-1)or programmed death-ligand 1(PD-L1)inhibitor mon...In recent years,immune checkpoint inhibitors(ICIs)have made breakthroughs in the field of lung cancer and have become a focal point for research.Programmed death-1(PD-1)or programmed death-ligand 1(PD-L1)inhibitor monotherapy was the first to break the treatment pattern for non-small cell lung cancer(NSCLC).However,owing to the limited benefit of ICI monotherapy at the population level and its hyper-progressive phenomenon,it may not meet clinical needs.To expand the beneficial range of immunotherapy and improve its efficacy,several research strategies have adopted the use of combination immunotherapy.At present,multiple strategies,such as PD-1/PD-L1 inhibitors combined with chemotherapy,anti-angiogenic therapy,cytotoxic T-lymphocyte-associated protein 4 inhibitors,and radiotherapy,as well as combined treatment with new target drugs,have been evaluated for clinical practice.To further understand the current status and future development direction of immunotherapy,herein,we review the recent progress of ICI combination therapies for NSCLC.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 展开更多
Over the past few years,immune checkpoint inhibitors(ICIs)have greatly improved the survival for patients with non-small cell lung cancer(NSCLC)without driver mutations.Compared with wild-type tumors,tumors with epide...Over the past few years,immune checkpoint inhibitors(ICIs)have greatly improved the survival for patients with non-small cell lung cancer(NSCLC)without driver mutations.Compared with wild-type tumors,tumors with epidermal growth factor receptor(EGFR)mutations show more heterogeneity in the expression level of programmed cell death-ligand 1(PD-L1),tumor mutational burden(TMB),and other immune microenvironment characteristics.Whether ICIs are suitable for NSCLC patients with EGFR mutations is still worth exploring.In previous studies,no significantly improved benefits were observed with immunotherapy monotherapy in NSCLC patients with EGFR mutation.Here,we summarized and analyzed data from the clinical trials of ICIs or combined therapy in NSCLC patients with EGFR mutations.We also focused on the mechanisms affecting the efficacy of ICIs in NSCLC patients with EGFR mutations,the characteristics of potential responders,and provided insights into areas worth further investigations in future studies.展开更多
Immunotherapy with checkpoint inhibitors has revolutionized cancer therapy and is now the standard treatment for several different types of cancer,supported by favorable outcomes and good tolerance.However,it is linke...Immunotherapy with checkpoint inhibitors has revolutionized cancer therapy and is now the standard treatment for several different types of cancer,supported by favorable outcomes and good tolerance.However,it is linked to multiple immune manifestations,referred to as immune-related adverse events(irAEs).These adverse events frequently affect the skin,colon,endocrine glands,lungs,and liver.The gastrointestinal system is one of the most commonly affected organ systems and is responsible for the most frequent emergency visits resulting from irAEs.However,because immune checkpoint inhibitors are a recent addition to our arsenal of cancer drugs,many health-care providers remain unfamiliar with the management of irAEs.Gastroenterologists involved in the treatment of oncology patients who have received checkpoint inhibitors are currently encountering cases of abdominal pain,diarrhea,and other nonspecific symptoms that may be challenging to manage.This article reviews the gastrointestinal,hepatic,and pancreatic toxicities of checkpoint inhibitors and provides an approach to their diagnosis and recommended workup.It also highlights the management of irAEs according to their toxicity grading and specifically discusses the instances in which corticosteroids should be administered and/or the immune checkpoint inhibitors should be withheld.展开更多
基金This work was supported by a grant from the Wu Jieping Medical Foundation(Grant No.320675018288).
文摘Immune checkpoint inhibitors(ICIs)are new and promising therapeutic agents for non-small cell lung cancer(NSCLC).However,along with demonstrating remarkable efficacy,ICIs can also trigger immune-related adverse events.Checkpoint inhibitor pneumonitis(CIP)has been reported to have a morbidity rate of 3%to 5%and a mortality rate of 10%to 17%.Moreover,the incidence of CIP in NSCLC is higher than that in other tumor types,reaching 7%to 13%.With the increased use of ICIs in NSCLC,CIP has drawn extensive attention from oncologists and cancer researchers.Identifying high risk factors for CIP and the potential mechanism of CIP are key points in preventing and monitoring serious adverse events.In this review,the results of our analysis and summary of previous studies suggested that the risk factors for CIP may include previous lung disease,prior thoracic irradiation,and combinations with other drugs.Our review also explored potential mechanisms closely related toCIP,including increasedT cell activity against associated antigens in tumor and normal tissues,preexisting autoantibodies,and inflammatory cytokines.
文摘Hepatocellular carcinoma(HCC)arises on the background of chronic liver disease.Despite the development of effective anti-viral therapeutics HCC is continuing to rise,in part driven by the epidemic of non-alcoholic fatty liver disease.Many patients present with advanced disease out with the criteria for transplant,resection or even locoregional therapy.Currently available therapeutics for HCC are effective in a small minority of individuals.However,there has been a major global interest in immunotherapies for cancer and although HCC has lagged behind other cancers,great opportunities now exist for treating HCC with newer and more sophisticated agents.Whilst checkpoint inhibitors are at the forefront of this revolution,other therapeutics such as inhibitory cytokine blockade,oncolytic viruses,adoptive cellular therapies and vaccines are emerging.Broadly these may be categorized as either boosting existing immune response or stimulating de novo immune response.Although some of these agents have shown promising results as monotherapy in early phase trials it may well be that their future role will be as combination therapy,either in combination with one another or in combination with treatment modalities such as locoregional therapy.Together these agents are likely to generate new and exciting opportunities for treating HCC,which are summarized in this review.
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.
基金supported by The MRC DPFS grant (MR/M015696/1)Ministry of Sciences and Technology of China (2013DFG32080)
文摘In recent years immune checkpoint inhibitors have garnered attention as being one of the most promising types of immunotherapy on the horizon. There has been particular focus on the immune checkpoint molecules, cytotoxic Tlymphocyte antigen-4（CTLA-4） and programmed cell death protein 1（PD-1） which have been shown to have potent immunomodulatory effects through their function as negative regulators of T cell activation. CTLA-4, through engagement with its ligands B7-1（CD80） and B7-2（CD86）, plays a pivotal role in attenuating the activation of naive and memory T cells. In contrast, PD-1 is primarily involved in modulating T cell activity in peripheral tissues via its interaction with PD-L1 and PD-L2. The discovery of these negative regulators of the immune response was crucial in the development of checkpoint inhibitors. This shifted the focus from developing therapies that targeted activation of the host immune system against cancer to checkpoint inhibitors, which aimed to mediate tumor cell destruction through the removal of coinhibitory signals blocking anti-tumor T cell responses.
文摘Immuno-oncology is a fast evolving field of cancer therapy and immune checkpoint inhibitors (ICIs) are clearly a breakthrough in this field. Cardiotoxicity with conventional anti-cancer therapies has been well studied in the past and clear guidelines for management of these side effects are available in the literature. However, cardiotoxicity with novel agents such as ICIs has been fairly under-reported and/or underestimated and we are yet to formulate clear guidelines for management of these rare side effects. In the last few years, there has been an overall increase in the number of cases of cardiotoxicity related to ICIs. In this literature review, we describe the mechanism of action of the most widely used ICIs and their related cardiotoxicities. The increase in number of case reports about the potential of cardiotoxicities with these novel agents clearly indicates the need for a new insight into the field of cardio-immuno-oncology.
基金supported by grants from the National S&T Major Project(2017ZX10203205)Key Research&Development Plan of Zhejiang Province(2019C03050)。
文摘Background:Treatment of hepatocellular carcinoma(HCC)is challenging as most patients are diagnosed at advanced stage with underlying chronic liver conditions.Conventional systemic chemotherapy has failed in HCC,and the clinical efficacy of FDA-approved molecular targeted agents such as sorafenib and lenvatinib remains unsatisfactory.Data sources:Literature search was conducted in Pub Med for relevant articles published before January 2021.The search aimed to identify recent developments in immune-based treatment approaches for HCC.Information of clinical trials was obtained from https://clinicaltrials.gov/.Results:Two immune checkpoint inhibitors(ICIs),nivolumab and pembrolizumab were approved as monotherapies,which has revolutionized HCC treatment.Besides,combination ICIs have also got accelerated FDA approval recently.Immune-based therapies have challenged targeted drugs owing to their safety,tolerability,and survival benefits.In addition to the significant success in ICIs,other immunotherapeutic strategies such as cancer vaccine,chimeric antigen receptor T-cells,natural killer cells,cytokines,and combination therapy,have also shown promising outcomes in clinical trials.Various diagnostic and prognostic biomarkers have been identified which can help in clinical decision making when starting treatment with ICIs.Conclusions:Immunotherapy has emerged as one of the mainstream treatment modalities for advanced HCC in recent years.However,challenges such as low response rate and acquired resistance in previously respondent patients still exist.Further research is needed to understand the unique resistance mechanism to immunotherapy and to discover more predictive biomarkers to guide clinical decision making.
文摘Pancreatic ductal adenocarcinoma(PDAC)is one of the deadliest cancers,mostly due to its resistance to treatment.Of these,checkpoint inhibitors(CPI)are inefficient when used as monotherapy,except in the case of a rare subset of tumors harboring microsatellite instability(<2%).This inefficacy mainly resides in the low immunogenicity and non-inflamed phenotype of PDAC.The abundant stroma generates a hypoxic microenvironment and drives the recruitment of immunosuppressive cells through cancerassociated-fibroblast activation and transforming growth factorβsecretion.Several strategies have recently been developed to overcome this immunosuppressive microenvironment.Combination therapies involving CPI aim at increasing tumor immunogenicity and promoting the recruitment and activation of effector T cells.Ongoing studies are therefore exploring the association of CPI with vaccines,oncolytic viruses,MEK inhibitors,cytokine inhibitors,and hypoxia-and stroma-targeting agents.Adoptive T-cell transfer is also under investigation.Moreover,translational studies on tumor tissue and blood,prior to and during treatment may lead to the identification of biomarkers with predictive value for both clinical outcome and response to immunotherapy.
基金Supported by Joint Funds for the Innovation of Science and Technology,Fujian Province,China,No.2021Y9227Natural Science Foundation of Fujian Province,China,No.2023J011254+2 种基金The Science Foundation for The Excellent Youth Scholars of Fujian Provincial Health Commission,China,No.2022ZQNZD009The Special Research Funds for Local Science and Technology Development Guided by Central Government,Fujian Province,China,No.2023L3020Fujian Medical University Student Innovation and Entrepreneurship Training Project,China,No.JC2023191.
文摘Immune checkpoint inhibitors(ICIs)are widely used due to their effectiveness in treating various tumors.Immune-related adverse events(irAEs)are defined as adverse effects resulting from ICI treatment.Gastrointestinal irAEs are a common type of irAEs characterized by intestinal side effects,such as diarrhea and colitis,which may lead to the cessation of ICIs.Although irAE gastritis is rarely reported,it may lead to serious complications such as gastrorrhagia.Furthermore,irAE gastritis is often difficult to identify early due to its diverse symptoms.Although steroid hormones and immunosuppressants are commonly used to reverse irAEs,the best regimen and dosage for irAE gastritis remains uncertain.In addition,the risk of recurrence of irAE gastritis after the reuse of ICIs should be considered.In this editorial,strategies such as early identification,pathological diagnosis,mana-gement interventions,and immunotherapy rechallenge are discussed to enable clinicians to better manage irAE gastritis and improve the prognosis of these patients.
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supported by the National Key Research and Development Program of China(No.2021YFC2700903)the National Natural Science Foundation of China(Nos.81672791 and 81872300)+2 种基金the Zhejiang Provincial Natural Science Fund for Distinguished Young Scholars of China(No.LR18C060002)the Huadong Medicine Joint Funds of the Zhejiang Provincial Natural Science Foundation of China(No.LHDMY22H160006)the ZJU-QILU Joint Research Institute and Qilu Group.
文摘Immunological evasion is one of the defining characteristics of cancers,as the immune modification of an immune checkpoint(IC)confers immune evasion capabilities to tumor cells.Multiple ICs,such as programmed cell death protein-1(PD-1)and cytotoxic T-lymphocyte-associated antigen-4(CTLA-4),can bind to their respective receptors and reduce tumor immunity in a variety of ways,including blocking immune cell activation signals.IC blockade(ICB)therapies targeting these checkpoint molecules have demonstrated significant clinical benefits.This is because antibody-based IC inhibitors and a variety of specific small molecule inhibitors can inhibit key oncogenic signaling pathways and induce durable tumor remission in patients with a variety of cancers.Deciphering the roles and regulatory mechanisms of these IC molecules will provide crucial theoretical guidance for clinical treatment.In this review,we summarize the current knowledge on the functional and regulatory mechanisms of these IC molecules at multiple levels,including epigenetic regulation,transcriptional regulation,and post-translational modifications.In addition,we provide a summary of the medications targeting various nodes in the regulatory pathway,and highlight the potential of newly identified IC molecules,focusing on their potential implications for cancer diagnostics and immunotherapy.
基金the Special Project for Significant New Drug Research and Development in the Major National Science and Technology Projects of China(No.2020ZX09201-024).
文摘In recent years,immune checkpoint inhibitors(ICIs)have made breakthroughs in the field of lung cancer and have become a focal point for research.Programmed death-1(PD-1)or programmed death-ligand 1(PD-L1)inhibitor monotherapy was the first to break the treatment pattern for non-small cell lung cancer(NSCLC).However,owing to the limited benefit of ICI monotherapy at the population level and its hyper-progressive phenomenon,it may not meet clinical needs.To expand the beneficial range of immunotherapy and improve its efficacy,several research strategies have adopted the use of combination immunotherapy.At present,multiple strategies,such as PD-1/PD-L1 inhibitors combined with chemotherapy,anti-angiogenic therapy,cytotoxic T-lymphocyte-associated protein 4 inhibitors,and radiotherapy,as well as combined treatment with new target drugs,have been evaluated for clinical practice.To further understand the current status and future development direction of immunotherapy,herein,we review the recent progress of ICI combination therapies for NSCLC.
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
基金The study was funded by the National Natural Science Foundation of China(81972796 and 81972863)Radiation Oncology Innovate Unit,Chinese Academy of Medical Sciences(2019RU071)+1 种基金the Academic Promotion Program of Shandong First Medical University(2019ZL002)the Natural Science Foundation of Shandong(ZR2019MH010 and ZR2020MH289).
文摘Over the past few years,immune checkpoint inhibitors(ICIs)have greatly improved the survival for patients with non-small cell lung cancer(NSCLC)without driver mutations.Compared with wild-type tumors,tumors with epidermal growth factor receptor(EGFR)mutations show more heterogeneity in the expression level of programmed cell death-ligand 1(PD-L1),tumor mutational burden(TMB),and other immune microenvironment characteristics.Whether ICIs are suitable for NSCLC patients with EGFR mutations is still worth exploring.In previous studies,no significantly improved benefits were observed with immunotherapy monotherapy in NSCLC patients with EGFR mutation.Here,we summarized and analyzed data from the clinical trials of ICIs or combined therapy in NSCLC patients with EGFR mutations.We also focused on the mechanisms affecting the efficacy of ICIs in NSCLC patients with EGFR mutations,the characteristics of potential responders,and provided insights into areas worth further investigations in future studies.
文摘Immunotherapy with checkpoint inhibitors has revolutionized cancer therapy and is now the standard treatment for several different types of cancer,supported by favorable outcomes and good tolerance.However,it is linked to multiple immune manifestations,referred to as immune-related adverse events(irAEs).These adverse events frequently affect the skin,colon,endocrine glands,lungs,and liver.The gastrointestinal system is one of the most commonly affected organ systems and is responsible for the most frequent emergency visits resulting from irAEs.However,because immune checkpoint inhibitors are a recent addition to our arsenal of cancer drugs,many health-care providers remain unfamiliar with the management of irAEs.Gastroenterologists involved in the treatment of oncology patients who have received checkpoint inhibitors are currently encountering cases of abdominal pain,diarrhea,and other nonspecific symptoms that may be challenging to manage.This article reviews the gastrointestinal,hepatic,and pancreatic toxicities of checkpoint inhibitors and provides an approach to their diagnosis and recommended workup.It also highlights the management of irAEs according to their toxicity grading and specifically discusses the instances in which corticosteroids should be administered and/or the immune checkpoint inhibitors should be withheld.
