BACKGROUND Programmed death receptor-1(PD-1)inhibitors have been approved as secondline treatment regimen in hepatocellular carcinoma(HCC),but it is still worth studying whether patients can benefit from PD-1 inhibito...BACKGROUND Programmed death receptor-1(PD-1)inhibitors have been approved as secondline treatment regimen in hepatocellular carcinoma(HCC),but it is still worth studying whether patients can benefit from PD-1 inhibitors as first-line drugs combined with targeted drugs and locoregional therapy.AIM To estimate the clinical outcome of transarterial chemoembolization(TACE)and lenvatinib plus PD-1 inhibitors for patients with unresectable HCC(uHCC).METHODS We carried out retrospective research of 65 patients with uHCC who were treated at Peking Union Medical College Hospital from September 2017 to February 2022.45 patients received the PD-1 inhibitors,lenvatinib,TACE(PD-1-Lenv-T)therapy,and 20 received the lenvatinib,TACE(Lenv-T)therapy.In terms of the dose of lenvatinib,8 mg was given orally for patients weighing less than 60 kg and 12 mg for those weighing more than 60 kg.Of the patients in the PD-1 inhibitor combination group,15 received Toripalimab,14 received Toripalimab,14 received Camrelizumab,4 received Pembrolizumab,9 received Sintilimab,and 2 received Nivolumab,1 with Tislelizumab.According to the investigators’assessment,TACE was performed every 4-6 wk when the patient had good hepatic function(Child-Pugh class A or B)until disease progression occurred.We evaluated the efficacy by the modified Response Evaluation Criteria in Solid Tumors(mRECIST criteria).We accessd the safety by the National Cancer Institute Common Terminology Criteria for Adverse Events,v 5.0.The key adverse events(AEs)after the initiation of combination therapy were observed.RESULTS Patients with uHCC who received PD-1-Lenv-T therapy(n=45)had a clearly longer overall survival than those who underwent Lenv-T therapy(n=20,26.8 vs 14.0 mo;P=0.027).The median progression-free survival time between the two treatment regimens was also measured{11.7 mo[95%confidence interval(CI):7.7-15.7]in the PD-1-Lenv-T group vs 8.5 mo(95%CI:3.0-13.9)in the Lenv-T group(P=0.028)}.The objective response rates of the PD-1-Lenv-T group and Lenv-T group were 44.4%and 20%(P=0.059)according to the mRECIST criteria,meanwhile the disease control rates were 93.3%and 64.0%(P=0.003),respectively.The type and frequency of AEs showed little distinction between patients received the two treatment regimens.CONCLUSION Our results suggest that the early combination of PD-1 inhibitors has manageable toxicity and hopeful efficacy in patients with uHCC.展开更多
Immune checkpoints release suppressive signals for T cells,which enable the tumors to escape from immune destruction and provide a new concept that uses the capabilities of the immune system as a therapeutic target fo...Immune checkpoints release suppressive signals for T cells,which enable the tumors to escape from immune destruction and provide a new concept that uses the capabilities of the immune system as a therapeutic target for tumors.At present,programmed death receptor 1(PD-1)/programmed death ligand-1(PDL1) has become the most promising therapeutic target.PD-1/PD-L1 blockades exhibit long-lasting antitumor efficacy and safety in patients with various cancers,such as melanoma and non-small-cell lung cancer.Moreover,PD-L1 is highly expressed in the peripheral blood and tumor specimens of patients with cancer,and the expression of PD-L1 is positively correlated with various pathological features and may serve as a predictor of poor prognosis or a diagnostic tool.Clinical trials have verified that PD-1/PD-L1 blockade therapy benefits patients with advanced gastric cancer or gastroesophageal junction cancer.Furthermore,there are many molecules involved in the regulation of PD-1/PD-L1 expression,and the modification of these molecules via drugs and combinations with PD-1/PD-L1 inhibitors may further improve the efficacy of immunotherapy for gastric cancer.In this review,the efficacy,safety,and possible combination treatment options of PD-1/PD-L1 in gastric cancer are reviewed in experimental and clinical settings.展开更多
Although tumor cell membranes with broad-spectrum antigens have been explored for cancer vaccines for decades,their relatively poor capacity to stimulate immune responses,especially cellular immune responses,has limit...Although tumor cell membranes with broad-spectrum antigens have been explored for cancer vaccines for decades,their relatively poor capacity to stimulate immune responses,especially cellular immune responses,has limited their application.Here,we presented a novel bacterial and cancerous cell membrane fusogenic liposome for co-delivering cell membrane-derived antigens and adjuvants.Meanwhile,a programmed death-ligand 1(PD-L1)inhibitor,JQ-1,was incorporated into the formulation to tackle the up-regulated PD-L1 expression of antigen-presenting cells(APCs)upon vaccination,thereby augmenting its anti-tumor efficacy.The fusogenic liposomes demonstrated significantly improved cellular uptake by APCs and effectively suppressed PD-L1 expression in bone marrow-derived dendritic cells(BMDCs)in vitro.Following subcutaneous vaccination,the nano-vaccines efficiently drained to the tumor-draining lymph nodes(TDLNs),and significantly inhibited PD-L1 expression of both dendritic cells(DCs)and macrophages within the TDLNs and tumors.As a result,the liposomal vaccine induced robust innate and cellular immune responses and inhibited tumor growth in a colorectal carcinoma-burden mouse model.In summary,the fabricated cell membrane-based fusogenic liposomes offer a safe,effective,and easily applicable strategy for tumor immunotherapy and hold potential for personalized cancer immunotherapy.展开更多
Background:To address the need for immunotherapy in patients with advanced primary hepatocellular carcinoma(HCC),combination with radiotherapy(RT)has emerged as a promising strategy.In preclinical studies,irradiated t...Background:To address the need for immunotherapy in patients with advanced primary hepatocellular carcinoma(HCC),combination with radiotherapy(RT)has emerged as a promising strategy.In preclinical studies,irradiated tumors released tumor antigens to synergistically increase the antitumor effect of immunotherapy.Hence,we investigated whether RT enhances the efficacy of anti-programmed death receptor-1(PD-1)inhibitors in advanced HCC in real-world practice.Methods:Between August 2018 and June 2021,172 patients with advanced primary HCC were enrolled in the tertiary center(Zhongshan Hospital of Fudan University);95 were treated with a combination of RT and the inhibitor of PD-1(RT-PD1 cohort),and 77 were administered anti-PD-1 therapy(PD1 cohort).The first cycle of PD-1 inhibitors was administered within 60 days or concurrently with RT.Propensity score matching for bias reduction was used to evaluate the clinical outcomes.Results:Among 71 propensity-matched pairs,median progression-free survival was 5.7 months in the RT-PD1 cohort vs.2.9 months in the PD1 cohort(P<0.001).Median overall survival was 20.9 months in the RT-PD1 cohort vs.11.2 months in the PD1 cohort(P=0.018).Compared with patients in the PD1 cohort,patients in the RT-PD1 cohort had significantly higher objective response rates(40.8%,29/71 vs.19.7%,14/71,P=0.006)and disease control rates(62.0%,44/71 vs.31.0%,22/71,P<0.001).The incidences of toxic effects were not significantly different between the two cohorts.Conclusions:RT plus anti-PD-1 therapy is well tolerated.RT enhances the efficacy of anti-PD-1 therapy in patients with advanced primary HCC by improving survival outcomes without increased toxic effects.展开更多
Despite therapeutic advancements,the prognosis of locally advanced non-small cell lung cancer(LANSCLC),which has invaded multiple lobes or the other lung and intrapulmonary lymph nodes,remains poor.The emergence of im...Despite therapeutic advancements,the prognosis of locally advanced non-small cell lung cancer(LANSCLC),which has invaded multiple lobes or the other lung and intrapulmonary lymph nodes,remains poor.The emergence of immunotherapy with immune checkpoint blockade(ICB)is transforming cancer treatment.However,only a fraction of lung cancer patients benefit from ICB.Significant clinical evidence suggests that the proinflammatory tumor microenvironment(TME)and programmed death-ligand 1(PD-L1)expression correlate positively with response to the PD-1/PD-L1 blockade.We report here a liposomal nanoparticle loaded with cyclic dinucleotide and aerosolized(AeroNP-CDN)for inhalation delivery to deep-seated lung tumors and target CDN to activate stimulators of interferon(IFN)genes in macrophages and dendritic cells(DCs).Using a mouse model that recapitulates the clinical LANSCLC,we show that AeroNP-CDN efficiently mitigates the immunosuppressive TME by reprogramming tumor-associated macrophage from the M2 to M1 phenotype,activating DCs for effective tumor antigen presentation and increasing tumor-infiltrating CD8+T cells for adaptive anticancer immunity.Intriguingly,activation of interferons by AeroNP-CDN also led to increased PD-L1 expression in lung tumors,which,however,set a stage for response to anti-PD-L1 treatment.Indeed,anti-PD-L1 antibody-mediated blockade of IFNs-induced immune inhibitory PD-1/PD-L1 signaling further prolonged the survival of the LANSCLC-bearing mice.Importantly,AeroNP-CDN alone or combination immunotherapy was safe without local or systemic immunotoxicity.In conclusion,this study demonstrates a potential nano-immunotherapy strategy for LANSCLC,and mechanistic insights into the evolution of adaptive immune resistance provide a rational combination immunotherapy to overcome it.展开更多
In recent years,with the extensive application of immunotherapy in clinical practice,it has achieved encouraging therapeutic effects.While enhancing clinical efficacy,however,it can also cause autoimmune damage,trigge...In recent years,with the extensive application of immunotherapy in clinical practice,it has achieved encouraging therapeutic effects.While enhancing clinical efficacy,however,it can also cause autoimmune damage,triggering immunerelated adverse events(irAEs).Reports of immunotherapy-induced gastritis have been increasing annually,but due to its atypical clinical symptoms,early diagnosis poses a certain challenge.Furthermore,it can lead to severe complications such as gastric bleeding,elevating the risk of adverse outcomes for solid tumor patients if immunotherapy is interrupted.Therefore,gaining a thorough understanding of the pathogenesis,clinical manifestations,diagnostic criteria,and treatment of immune-related gastritis is of utmost importance for early identification,diagnosis,and treatment.Additionally,the treatment of immune-related gastritis should be personalized according to the specific condition of each patient.For patients with grade 2-3 irAEs,restarting immune checkpoint inhibitors(ICIs)therapy may be considered when symptoms subside to grade 0-1.When restarting ICIs therapy,it is often recommended to use different types of ICIs.For grade 4 irAEs,permanent discontinuation of the medication is necessary.展开更多
Different approaches for treating lung cancer have been developed over time, including chemotherapy, radiotherapy and targeted therapies against activating mutations. Lately, better understanding of the role of the im...Different approaches for treating lung cancer have been developed over time, including chemotherapy, radiotherapy and targeted therapies against activating mutations. Lately, better understanding of the role of the immunological system in tumor control has opened multiple doors to implement different strategies to enhance immune response against cancer cells. It is known that tumor cells elude immune response by several mechanisms. The development of monoclonal antibodies against the checkpoint inhibitor programmed cell death protein 1 (PD-1) and its ligand (PD-L1), on T cells, has led to high activity in cancer patients with long lasting responses. Nivolumab, an anti PD-1 inhibitor, has been recently approved for the treatment of squamous cell lung cancer patients, given the survival advantage demonstrated in a phase III trial. Pembrolizumab~ another anti PD-1 antibod)5 has received FDA breakthrough therapy designation for treatment of non-small cell lung cancer (NSCLC), supported by data from a phase I trial. Clinical trials with anti PD-1/PD-L1 antibodies in NSCLC have demonstrated very good tolerability and activity, with response rates around 20% and a median duration of response of 18 months.展开更多
Immunotherapy has become a key strategy for cancer treatment, and two immune checkpoints, namely, programmed cell death 1 (PD-1) and its ligand (PD-L1), have recently emerged as important targets. The interaction ...Immunotherapy has become a key strategy for cancer treatment, and two immune checkpoints, namely, programmed cell death 1 (PD-1) and its ligand (PD-L1), have recently emerged as important targets. The interaction blockade of PD-1 and PD-L1 demonstrated promising activity and antitumor efficacy in early phase clinical trials for advanced solid tumors such as non-small cell lung cancer (NSCLC). Many cell types in multiple tissues express PD-L1 as well as several tumor types, thereby suggesting that the ligand may play important roles in inhibiting immune responses throughout the body. Therefore, PD-L1 is a critical immunomodulating component within the lung microenvironment, but the correlation between PD-L1 expression and prognosis is controversial. More evidence is required to support the use of PD-L1 as a potential predictive biomarker. Clinical trials have measured PD-L1 in tumor tissues by immunohistochemistry (IHC) with different antibodies, but the assessment of PD-L1 is not yet standardized. Some commercial antibodies lack specificity and their reproducibility has not been fully evaluated. Further studies are required to clarify the optimal IHC assay as well as to predict and monitor the immune responses of the PD-I/PD-L1 pathway.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
Recent advances in pharmacological immune modulation against tumor cells has dramatically changed the paradigm of cancer treatment.Checkpoint inhibitor therapy is a form of cancer immunotherapy already in clinical set...Recent advances in pharmacological immune modulation against tumor cells has dramatically changed the paradigm of cancer treatment.Checkpoint inhibitor therapy is a form of cancer immunotherapy already in clinical setting but also under active basic and clinical investigation.Nevertheless,some patients are primary unresponsive or develop ulterior resistance to these family of drugs.This review aims to update the basic molecular mechanism of resistance as well as the current strategies for checkpoint inhibitor selection in order to propose new approaches to individualize the use of these novel therapies.展开更多
Radiotherapy(RT)mediated tumor immunogenicity offers an opportunity for simultaneous RT and immunotherapy via immunogenic cell death(ICD),which releases damaged-associated molecular patterns and generates“eat me”sig...Radiotherapy(RT)mediated tumor immunogenicity offers an opportunity for simultaneous RT and immunotherapy via immunogenic cell death(ICD),which releases damaged-associated molecular patterns and generates“eat me”signals for the innate immune system to modulate the immunogenicity.However,tumor hypoxia significantly reduces the therapeutic efficacy of RT and hampers its mediation of ICD induction.Herein,Au@Bi_(2)Te_(3)-polyethylene glycol(PEG)was rationally constructed as theranostic nanozymes for mild photothermal therapy,tumor hypoxia modulation,and RT adjuvant cancer immunotherapy.The tumor-specific production of oxygen could not only augment the effects of RT by enhanced reactive oxygen species(ROS)generation,but also reduce hypoxia-related cytokines and downregulate programmed cell death-ligand 1(PD-L1)to unleash immune-enhancing T cells.Moreover,Au@Bi_(2)Te_(3)-PEG could act as an immune-blocking inhibitor by efficient ICD induction with the combination of mild-photothermal therapy+RT to inhibit the tumor immune escape and improve antitumor immune response.Increased amounts of CD^(4+) and CD^(8+) Tcells and elevated levels of cytokines could be observed that eventually led to effective post-medication inhibition of primary and abscopal tumors.Spectral computed tomography/photoacoustic imaging allowed noninvasive and real-time tracking of nanoparticle(NP)accumulation and oxygenation status at tumor sites.Collectively,Au@Bi_(2)Te_(3)-PEG NPs could serve as effective theranostic nanoregulators with remarkable synergistic mildphotothermal/RT/immunotherapy effects that helped reshape the immune microenvironment and had remarkable molecular imaging properties.展开更多
In China,lung cancer is a primary cancer type with high incidence and mortality.Risk factors for lung cancer include tobacco use,family history,radiation exposure,and the presence of chronic lung diseases.Most early-...In China,lung cancer is a primary cancer type with high incidence and mortality.Risk factors for lung cancer include tobacco use,family history,radiation exposure,and the presence of chronic lung diseases.Most early-stage non-small cell lung cancer(NSCLC)patients miss the optimal timing for treatment due to the lack of clinical presentations.Population-based nationwide screening programs are of significant help in increasing the early detection and survival rates of NSCLC in China.The understanding of molecular carcinogenesis and the identification of oncogenic drivers dramatically facilitate the development of targeted therapy for NSCLC,thus prolonging survival in patients with positive drivers.In the exploration of immune escape mechanisms,programmed cell death protein 1(PD-1)/programmed death-ligand 1(PD-L1)inhibitor monotherapy and PD-1/PD-L1 inhibitor plus chemotherapy have become a standard of care for advanced NSCLC in China.In the Chinese Society of Clinical Oncology’s guidelines for NSCLC,maintenance immunotherapy is recommended for locally advanced NSCLC after chemoradiotherapy.Adjuvant immunotherapy and neoadjuvant chemoimmunotherapy will be approved for resectable NSCLC.In this review,we summarized recent advances in NSCLC in China in terms of epidemiology,biology,molecular pathology,pathogenesis,screening,diagnosis,targeted therapy,and immunotherapy。展开更多
The knowledge that the body possesses natural defenses to combat cancer existed long before the modern period,with multiple anecdotal reports of tumors miraculously disappearing,sometimes spontaneously or after a febr...The knowledge that the body possesses natural defenses to combat cancer existed long before the modern period,with multiple anecdotal reports of tumors miraculously disappearing,sometimes spontaneously or after a febrile or infectious episode.Spontaneous tumor regression of untreated malignant tumors is currently a well-accepted albeit rare phenomenon,and it is recognized that immunosuppression is associated with a higher cancer risk.The treatment of bladder carcinoma by intravesical administration of live attenuated Bacillus Calmette-Guérin bacteria was shown to be very effective in 1976 and is now standard treatment.Effective immunity against cancer involves complex interactions between the tumor,the host,and the environment.Cancer immunotherapy uses various strategies to augment tumor immunity and represents a paradigm shift in treating cancer,since attention has become more focused on the“biologic passport”of the individual tumor rather than the site of origin of the tumor.The different types of cancer immunotherapies discussed here include biologic modifiers,such as cytokines and vaccines,adoptive cell therapies,oncolytic viruses,and antibodies against immune checkpoint inhibitors,such as the co-inhibitory T-cell receptor PD-1 and one of its ligands,programmed death-ligand 1.展开更多
Inhibitory checkpoint molecules include programmed cell death-1(PD-1),programmed cell death ligand-1(PD-L1),cytotoxic T lymphocyte antigen-4(CTLA-4),human endogenous retrovirus-H Long terminal repeat-associating 2(HHL...Inhibitory checkpoint molecules include programmed cell death-1(PD-1),programmed cell death ligand-1(PD-L1),cytotoxic T lymphocyte antigen-4(CTLA-4),human endogenous retrovirus-H Long terminal repeat-associating 2(HHLA2),B7 homolog 4 protein(B7-H4),T cell membrane protein-3(TIM-3)and Lymphocyte-activation gene 3(LAG-3),which are up-regulated during tumorigenesis.These pathways are essential to down-regulate the immune system by blocking the activation of T cells.In recent years,immune checkpoint blockers(ICBs)against PD-1,PD-L1,CTLA-4 or TIM-3 has made remarkable progress in the clinical application,revolutionizing the treatment of malignant tumors and improving patients’overall survival.However,the efficacy of ICBs in some patients does not seem to be good enough,and more immune-related adverse events(irAEs)will inevitably occur.Therefore,biomarkers research provides practical guidance for clinicians to identify patients who are most likely to benefit from or exhibit resistance to particular types of immune checkpoint therapy.There are two points in general.On the one hand,given the spatial and temporal differential expression of immune checkpoint molecules during immunosuppression process,it is essential to understand their mechanisms to design the most effective individualized therapy.On the other hand,due to the lack of potent immune checkpoints,it is necessary to combine them with novel biomarkers(such as exosomes and ctDNA)and other anticancer modalities(such as chemotherapy and radiotherapy).展开更多
Hepatocellular carcinoma(HCC)is the most lethal and common type of liver cancer with limited treatment options at the advanced stage.The use of immune checkpoint inhibitor(ICI)based immunotherapy is exponentially incr...Hepatocellular carcinoma(HCC)is the most lethal and common type of liver cancer with limited treatment options at the advanced stage.The use of immune checkpoint inhibitor(ICI)based immunotherapy is exponentially increasing in the treatment of patients with advanced solid tumors.The expression of immune checkpoints on tumor cells leading to lower activity of T-cells is one of the major mechanisms of immune escape.Checkpoint blockade immunotherapies with antibodies against PD-1,PD-L1 or CTLA-4 are being investigated in clinical trials in HCC patients.ICIs have improved survival in patients with inoperable advanced stage HCC where other curative treatments are not applicable.However,the response rates remain low with only a small subset of patients responding to this therapy.There is an unmet need to identify predictive markers to select those HCC patients who would benefit from ICI therapies.Importantly,epithelial-to-mesenchymal transition(EMT),a major process driving HCC invasion and metastasis by regulating the phenotypic cellular switching from epithelial to mesenchymal state,has been implicated as a resistance mechanism associated with ICI therapies.The role of EMT as a regulator of immune checkpoint molecule in HCC is just emerging.However,the consequence of EMT as a resistance mechanism in HCC patients undergoing ICI treatments remains unexplored.In this review,we summarize the recent clinical studies with ICIs in HCC and highlight the trials underway featuring novel monotherapies and combinatorial approaches based on immune and non-immune therapies.We will discuss the ongoing efforts to discover new immune checkpoint molecules in HCC as potential drug targets.We also highlight the role of EMT in facilitating therapy resistance in HCC treated with ICIs and discuss potential strategies to circumvent resistance in ICI treated HCC patients.展开更多
基金Supported by Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences,No.2021-I2M-1-061 and 2021-I2M-1-003Chinese Society of Clinical Oncology-Hengrui Cancer Research Fund,No.Y-HR2019-0239+1 种基金Chinese Society of Clinical Oncology-MSD Cancer Research Fund,No.Y-MSDZD2021-0213National Ten-thousand Talent Program.
文摘BACKGROUND Programmed death receptor-1(PD-1)inhibitors have been approved as secondline treatment regimen in hepatocellular carcinoma(HCC),but it is still worth studying whether patients can benefit from PD-1 inhibitors as first-line drugs combined with targeted drugs and locoregional therapy.AIM To estimate the clinical outcome of transarterial chemoembolization(TACE)and lenvatinib plus PD-1 inhibitors for patients with unresectable HCC(uHCC).METHODS We carried out retrospective research of 65 patients with uHCC who were treated at Peking Union Medical College Hospital from September 2017 to February 2022.45 patients received the PD-1 inhibitors,lenvatinib,TACE(PD-1-Lenv-T)therapy,and 20 received the lenvatinib,TACE(Lenv-T)therapy.In terms of the dose of lenvatinib,8 mg was given orally for patients weighing less than 60 kg and 12 mg for those weighing more than 60 kg.Of the patients in the PD-1 inhibitor combination group,15 received Toripalimab,14 received Toripalimab,14 received Camrelizumab,4 received Pembrolizumab,9 received Sintilimab,and 2 received Nivolumab,1 with Tislelizumab.According to the investigators’assessment,TACE was performed every 4-6 wk when the patient had good hepatic function(Child-Pugh class A or B)until disease progression occurred.We evaluated the efficacy by the modified Response Evaluation Criteria in Solid Tumors(mRECIST criteria).We accessd the safety by the National Cancer Institute Common Terminology Criteria for Adverse Events,v 5.0.The key adverse events(AEs)after the initiation of combination therapy were observed.RESULTS Patients with uHCC who received PD-1-Lenv-T therapy(n=45)had a clearly longer overall survival than those who underwent Lenv-T therapy(n=20,26.8 vs 14.0 mo;P=0.027).The median progression-free survival time between the two treatment regimens was also measured{11.7 mo[95%confidence interval(CI):7.7-15.7]in the PD-1-Lenv-T group vs 8.5 mo(95%CI:3.0-13.9)in the Lenv-T group(P=0.028)}.The objective response rates of the PD-1-Lenv-T group and Lenv-T group were 44.4%and 20%(P=0.059)according to the mRECIST criteria,meanwhile the disease control rates were 93.3%and 64.0%(P=0.003),respectively.The type and frequency of AEs showed little distinction between patients received the two treatment regimens.CONCLUSION Our results suggest that the early combination of PD-1 inhibitors has manageable toxicity and hopeful efficacy in patients with uHCC.
基金Minhang District University Building Project,No.2017MWDXK03
文摘Immune checkpoints release suppressive signals for T cells,which enable the tumors to escape from immune destruction and provide a new concept that uses the capabilities of the immune system as a therapeutic target for tumors.At present,programmed death receptor 1(PD-1)/programmed death ligand-1(PDL1) has become the most promising therapeutic target.PD-1/PD-L1 blockades exhibit long-lasting antitumor efficacy and safety in patients with various cancers,such as melanoma and non-small-cell lung cancer.Moreover,PD-L1 is highly expressed in the peripheral blood and tumor specimens of patients with cancer,and the expression of PD-L1 is positively correlated with various pathological features and may serve as a predictor of poor prognosis or a diagnostic tool.Clinical trials have verified that PD-1/PD-L1 blockade therapy benefits patients with advanced gastric cancer or gastroesophageal junction cancer.Furthermore,there are many molecules involved in the regulation of PD-1/PD-L1 expression,and the modification of these molecules via drugs and combinations with PD-1/PD-L1 inhibitors may further improve the efficacy of immunotherapy for gastric cancer.In this review,the efficacy,safety,and possible combination treatment options of PD-1/PD-L1 in gastric cancer are reviewed in experimental and clinical settings.
基金supported by the National Natural Science Foundation of China(No.82341038)Natural Science Foundation of Sichuan Province(No.2022NSFSC1491)+2 种基金China Postdoctoral Science Foundation Grant(No.2019M663534,China)Sichuan Veterinary Medicine and Drug Innovation Group of China Agricultural Research System(CARS-SVIDIP)the Fundamental Research Funds for the Central Universities and Sichuan University Postdoctoral Interdisciplinary Innovation Fund.
文摘Although tumor cell membranes with broad-spectrum antigens have been explored for cancer vaccines for decades,their relatively poor capacity to stimulate immune responses,especially cellular immune responses,has limited their application.Here,we presented a novel bacterial and cancerous cell membrane fusogenic liposome for co-delivering cell membrane-derived antigens and adjuvants.Meanwhile,a programmed death-ligand 1(PD-L1)inhibitor,JQ-1,was incorporated into the formulation to tackle the up-regulated PD-L1 expression of antigen-presenting cells(APCs)upon vaccination,thereby augmenting its anti-tumor efficacy.The fusogenic liposomes demonstrated significantly improved cellular uptake by APCs and effectively suppressed PD-L1 expression in bone marrow-derived dendritic cells(BMDCs)in vitro.Following subcutaneous vaccination,the nano-vaccines efficiently drained to the tumor-draining lymph nodes(TDLNs),and significantly inhibited PD-L1 expression of both dendritic cells(DCs)and macrophages within the TDLNs and tumors.As a result,the liposomal vaccine induced robust innate and cellular immune responses and inhibited tumor growth in a colorectal carcinoma-burden mouse model.In summary,the fabricated cell membrane-based fusogenic liposomes offer a safe,effective,and easily applicable strategy for tumor immunotherapy and hold potential for personalized cancer immunotherapy.
基金National Natural Science Foundation of China(No.82073479)
文摘Background:To address the need for immunotherapy in patients with advanced primary hepatocellular carcinoma(HCC),combination with radiotherapy(RT)has emerged as a promising strategy.In preclinical studies,irradiated tumors released tumor antigens to synergistically increase the antitumor effect of immunotherapy.Hence,we investigated whether RT enhances the efficacy of anti-programmed death receptor-1(PD-1)inhibitors in advanced HCC in real-world practice.Methods:Between August 2018 and June 2021,172 patients with advanced primary HCC were enrolled in the tertiary center(Zhongshan Hospital of Fudan University);95 were treated with a combination of RT and the inhibitor of PD-1(RT-PD1 cohort),and 77 were administered anti-PD-1 therapy(PD1 cohort).The first cycle of PD-1 inhibitors was administered within 60 days or concurrently with RT.Propensity score matching for bias reduction was used to evaluate the clinical outcomes.Results:Among 71 propensity-matched pairs,median progression-free survival was 5.7 months in the RT-PD1 cohort vs.2.9 months in the PD1 cohort(P<0.001).Median overall survival was 20.9 months in the RT-PD1 cohort vs.11.2 months in the PD1 cohort(P=0.018).Compared with patients in the PD1 cohort,patients in the RT-PD1 cohort had significantly higher objective response rates(40.8%,29/71 vs.19.7%,14/71,P=0.006)and disease control rates(62.0%,44/71 vs.31.0%,22/71,P<0.001).The incidences of toxic effects were not significantly different between the two cohorts.Conclusions:RT plus anti-PD-1 therapy is well tolerated.RT enhances the efficacy of anti-PD-1 therapy in patients with advanced primary HCC by improving survival outcomes without increased toxic effects.
基金supported in part by NIH/NCI 1R01CA264102-01(D.Z.)Wake Forest Comprehensive Cancer Center P30 CA01219740.A.A.H.is supported by funding from the Department of Veteran’s Affairs(No.2I01BX002559-07)from the National Institutes of Health(No.1R01CA244212-01A1).
文摘Despite therapeutic advancements,the prognosis of locally advanced non-small cell lung cancer(LANSCLC),which has invaded multiple lobes or the other lung and intrapulmonary lymph nodes,remains poor.The emergence of immunotherapy with immune checkpoint blockade(ICB)is transforming cancer treatment.However,only a fraction of lung cancer patients benefit from ICB.Significant clinical evidence suggests that the proinflammatory tumor microenvironment(TME)and programmed death-ligand 1(PD-L1)expression correlate positively with response to the PD-1/PD-L1 blockade.We report here a liposomal nanoparticle loaded with cyclic dinucleotide and aerosolized(AeroNP-CDN)for inhalation delivery to deep-seated lung tumors and target CDN to activate stimulators of interferon(IFN)genes in macrophages and dendritic cells(DCs).Using a mouse model that recapitulates the clinical LANSCLC,we show that AeroNP-CDN efficiently mitigates the immunosuppressive TME by reprogramming tumor-associated macrophage from the M2 to M1 phenotype,activating DCs for effective tumor antigen presentation and increasing tumor-infiltrating CD8+T cells for adaptive anticancer immunity.Intriguingly,activation of interferons by AeroNP-CDN also led to increased PD-L1 expression in lung tumors,which,however,set a stage for response to anti-PD-L1 treatment.Indeed,anti-PD-L1 antibody-mediated blockade of IFNs-induced immune inhibitory PD-1/PD-L1 signaling further prolonged the survival of the LANSCLC-bearing mice.Importantly,AeroNP-CDN alone or combination immunotherapy was safe without local or systemic immunotoxicity.In conclusion,this study demonstrates a potential nano-immunotherapy strategy for LANSCLC,and mechanistic insights into the evolution of adaptive immune resistance provide a rational combination immunotherapy to overcome it.
文摘In recent years,with the extensive application of immunotherapy in clinical practice,it has achieved encouraging therapeutic effects.While enhancing clinical efficacy,however,it can also cause autoimmune damage,triggering immunerelated adverse events(irAEs).Reports of immunotherapy-induced gastritis have been increasing annually,but due to its atypical clinical symptoms,early diagnosis poses a certain challenge.Furthermore,it can lead to severe complications such as gastric bleeding,elevating the risk of adverse outcomes for solid tumor patients if immunotherapy is interrupted.Therefore,gaining a thorough understanding of the pathogenesis,clinical manifestations,diagnostic criteria,and treatment of immune-related gastritis is of utmost importance for early identification,diagnosis,and treatment.Additionally,the treatment of immune-related gastritis should be personalized according to the specific condition of each patient.For patients with grade 2-3 irAEs,restarting immune checkpoint inhibitors(ICIs)therapy may be considered when symptoms subside to grade 0-1.When restarting ICIs therapy,it is often recommended to use different types of ICIs.For grade 4 irAEs,permanent discontinuation of the medication is necessary.
文摘Different approaches for treating lung cancer have been developed over time, including chemotherapy, radiotherapy and targeted therapies against activating mutations. Lately, better understanding of the role of the immunological system in tumor control has opened multiple doors to implement different strategies to enhance immune response against cancer cells. It is known that tumor cells elude immune response by several mechanisms. The development of monoclonal antibodies against the checkpoint inhibitor programmed cell death protein 1 (PD-1) and its ligand (PD-L1), on T cells, has led to high activity in cancer patients with long lasting responses. Nivolumab, an anti PD-1 inhibitor, has been recently approved for the treatment of squamous cell lung cancer patients, given the survival advantage demonstrated in a phase III trial. Pembrolizumab~ another anti PD-1 antibod)5 has received FDA breakthrough therapy designation for treatment of non-small cell lung cancer (NSCLC), supported by data from a phase I trial. Clinical trials with anti PD-1/PD-L1 antibodies in NSCLC have demonstrated very good tolerability and activity, with response rates around 20% and a median duration of response of 18 months.
文摘Immunotherapy has become a key strategy for cancer treatment, and two immune checkpoints, namely, programmed cell death 1 (PD-1) and its ligand (PD-L1), have recently emerged as important targets. The interaction blockade of PD-1 and PD-L1 demonstrated promising activity and antitumor efficacy in early phase clinical trials for advanced solid tumors such as non-small cell lung cancer (NSCLC). Many cell types in multiple tissues express PD-L1 as well as several tumor types, thereby suggesting that the ligand may play important roles in inhibiting immune responses throughout the body. Therefore, PD-L1 is a critical immunomodulating component within the lung microenvironment, but the correlation between PD-L1 expression and prognosis is controversial. More evidence is required to support the use of PD-L1 as a potential predictive biomarker. Clinical trials have measured PD-L1 in tumor tissues by immunohistochemistry (IHC) with different antibodies, but the assessment of PD-L1 is not yet standardized. Some commercial antibodies lack specificity and their reproducibility has not been fully evaluated. Further studies are required to clarify the optimal IHC assay as well as to predict and monitor the immune responses of the PD-I/PD-L1 pathway.
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We are grateful for the financial support from the“Fondo de Investigaciones Sanitarias”(PI17/01489)the Miguel Servet Program(CPII16/00056)del Instituto de Salud Carlos IIIthe Ministerio de Economía y Competitividad-FEDERER(RTC-2016-4990-1,RTC-2015-3846-1).
文摘Recent advances in pharmacological immune modulation against tumor cells has dramatically changed the paradigm of cancer treatment.Checkpoint inhibitor therapy is a form of cancer immunotherapy already in clinical setting but also under active basic and clinical investigation.Nevertheless,some patients are primary unresponsive or develop ulterior resistance to these family of drugs.This review aims to update the basic molecular mechanism of resistance as well as the current strategies for checkpoint inhibitor selection in order to propose new approaches to individualize the use of these novel therapies.
基金This work was supported by the National Natural Science Foundation of China(Nos.81871334,81801764,82072056,and 51937010)the Guangdong Basic and Applied Basic Research Foundation(Nos.2017A050506011,2018030310343,2020B1515020008,2021A1515012542,and 2021A1515011882)+1 种基金the Medical Scientific Research Foundation of Guangdong Province(No.A2018014)the Pearl River Talented Young Scholar Program(No.2017GC010282).
文摘Radiotherapy(RT)mediated tumor immunogenicity offers an opportunity for simultaneous RT and immunotherapy via immunogenic cell death(ICD),which releases damaged-associated molecular patterns and generates“eat me”signals for the innate immune system to modulate the immunogenicity.However,tumor hypoxia significantly reduces the therapeutic efficacy of RT and hampers its mediation of ICD induction.Herein,Au@Bi_(2)Te_(3)-polyethylene glycol(PEG)was rationally constructed as theranostic nanozymes for mild photothermal therapy,tumor hypoxia modulation,and RT adjuvant cancer immunotherapy.The tumor-specific production of oxygen could not only augment the effects of RT by enhanced reactive oxygen species(ROS)generation,but also reduce hypoxia-related cytokines and downregulate programmed cell death-ligand 1(PD-L1)to unleash immune-enhancing T cells.Moreover,Au@Bi_(2)Te_(3)-PEG could act as an immune-blocking inhibitor by efficient ICD induction with the combination of mild-photothermal therapy+RT to inhibit the tumor immune escape and improve antitumor immune response.Increased amounts of CD^(4+) and CD^(8+) Tcells and elevated levels of cytokines could be observed that eventually led to effective post-medication inhibition of primary and abscopal tumors.Spectral computed tomography/photoacoustic imaging allowed noninvasive and real-time tracking of nanoparticle(NP)accumulation and oxygenation status at tumor sites.Collectively,Au@Bi_(2)Te_(3)-PEG NPs could serve as effective theranostic nanoregulators with remarkable synergistic mildphotothermal/RT/immunotherapy effects that helped reshape the immune microenvironment and had remarkable molecular imaging properties.
基金National Natural Science Foundation of China,Grant/Award Number:81871865Collaborative Innovation Program of Shanghai Municipal Health Commission,Grant/Award Number:2020CXJQ02Science and Technology Innovation Action Plan Project of Shanghai Municipal Science and Technology Commission,Grant/Award Numbers:19411950300,19411950301。
文摘In China,lung cancer is a primary cancer type with high incidence and mortality.Risk factors for lung cancer include tobacco use,family history,radiation exposure,and the presence of chronic lung diseases.Most early-stage non-small cell lung cancer(NSCLC)patients miss the optimal timing for treatment due to the lack of clinical presentations.Population-based nationwide screening programs are of significant help in increasing the early detection and survival rates of NSCLC in China.The understanding of molecular carcinogenesis and the identification of oncogenic drivers dramatically facilitate the development of targeted therapy for NSCLC,thus prolonging survival in patients with positive drivers.In the exploration of immune escape mechanisms,programmed cell death protein 1(PD-1)/programmed death-ligand 1(PD-L1)inhibitor monotherapy and PD-1/PD-L1 inhibitor plus chemotherapy have become a standard of care for advanced NSCLC in China.In the Chinese Society of Clinical Oncology’s guidelines for NSCLC,maintenance immunotherapy is recommended for locally advanced NSCLC after chemoradiotherapy.Adjuvant immunotherapy and neoadjuvant chemoimmunotherapy will be approved for resectable NSCLC.In this review,we summarized recent advances in NSCLC in China in terms of epidemiology,biology,molecular pathology,pathogenesis,screening,diagnosis,targeted therapy,and immunotherapy。
文摘The knowledge that the body possesses natural defenses to combat cancer existed long before the modern period,with multiple anecdotal reports of tumors miraculously disappearing,sometimes spontaneously or after a febrile or infectious episode.Spontaneous tumor regression of untreated malignant tumors is currently a well-accepted albeit rare phenomenon,and it is recognized that immunosuppression is associated with a higher cancer risk.The treatment of bladder carcinoma by intravesical administration of live attenuated Bacillus Calmette-Guérin bacteria was shown to be very effective in 1976 and is now standard treatment.Effective immunity against cancer involves complex interactions between the tumor,the host,and the environment.Cancer immunotherapy uses various strategies to augment tumor immunity and represents a paradigm shift in treating cancer,since attention has become more focused on the“biologic passport”of the individual tumor rather than the site of origin of the tumor.The different types of cancer immunotherapies discussed here include biologic modifiers,such as cytokines and vaccines,adoptive cell therapies,oncolytic viruses,and antibodies against immune checkpoint inhibitors,such as the co-inhibitory T-cell receptor PD-1 and one of its ligands,programmed death-ligand 1.
基金the National Natural Science Foundation of China(81872200,31900558)the Natural Science Foundation of Hubei Province(2018CFB510)+1 种基金the Zhongnan Hospital of Wuhan University Science,Technology and Innovation Seed Fund(CXPY2017029)the Fundamental Research Funds for the Central Universities(2042018kf0091).
文摘Inhibitory checkpoint molecules include programmed cell death-1(PD-1),programmed cell death ligand-1(PD-L1),cytotoxic T lymphocyte antigen-4(CTLA-4),human endogenous retrovirus-H Long terminal repeat-associating 2(HHLA2),B7 homolog 4 protein(B7-H4),T cell membrane protein-3(TIM-3)and Lymphocyte-activation gene 3(LAG-3),which are up-regulated during tumorigenesis.These pathways are essential to down-regulate the immune system by blocking the activation of T cells.In recent years,immune checkpoint blockers(ICBs)against PD-1,PD-L1,CTLA-4 or TIM-3 has made remarkable progress in the clinical application,revolutionizing the treatment of malignant tumors and improving patients’overall survival.However,the efficacy of ICBs in some patients does not seem to be good enough,and more immune-related adverse events(irAEs)will inevitably occur.Therefore,biomarkers research provides practical guidance for clinicians to identify patients who are most likely to benefit from or exhibit resistance to particular types of immune checkpoint therapy.There are two points in general.On the one hand,given the spatial and temporal differential expression of immune checkpoint molecules during immunosuppression process,it is essential to understand their mechanisms to design the most effective individualized therapy.On the other hand,due to the lack of potent immune checkpoints,it is necessary to combine them with novel biomarkers(such as exosomes and ctDNA)and other anticancer modalities(such as chemotherapy and radiotherapy).
基金This manuscript publication is funded by Gallipoli Medical Research Foundation.
文摘Hepatocellular carcinoma(HCC)is the most lethal and common type of liver cancer with limited treatment options at the advanced stage.The use of immune checkpoint inhibitor(ICI)based immunotherapy is exponentially increasing in the treatment of patients with advanced solid tumors.The expression of immune checkpoints on tumor cells leading to lower activity of T-cells is one of the major mechanisms of immune escape.Checkpoint blockade immunotherapies with antibodies against PD-1,PD-L1 or CTLA-4 are being investigated in clinical trials in HCC patients.ICIs have improved survival in patients with inoperable advanced stage HCC where other curative treatments are not applicable.However,the response rates remain low with only a small subset of patients responding to this therapy.There is an unmet need to identify predictive markers to select those HCC patients who would benefit from ICI therapies.Importantly,epithelial-to-mesenchymal transition(EMT),a major process driving HCC invasion and metastasis by regulating the phenotypic cellular switching from epithelial to mesenchymal state,has been implicated as a resistance mechanism associated with ICI therapies.The role of EMT as a regulator of immune checkpoint molecule in HCC is just emerging.However,the consequence of EMT as a resistance mechanism in HCC patients undergoing ICI treatments remains unexplored.In this review,we summarize the recent clinical studies with ICIs in HCC and highlight the trials underway featuring novel monotherapies and combinatorial approaches based on immune and non-immune therapies.We will discuss the ongoing efforts to discover new immune checkpoint molecules in HCC as potential drug targets.We also highlight the role of EMT in facilitating therapy resistance in HCC treated with ICIs and discuss potential strategies to circumvent resistance in ICI treated HCC patients.