This editorial discusses Christodoulidis et al's article,which appeared in the most recent edition.The clinical trials have demonstrated the programmed cell death receptor 1(PD-1)inhibitor Pembrolizumab involved c...This editorial discusses Christodoulidis et al's article,which appeared in the most recent edition.The clinical trials have demonstrated the programmed cell death receptor 1(PD-1)inhibitor Pembrolizumab involved combination therapy can improve the efficacy of advanced gastric cancer(AGC).Pembrolizumab combined with chemotherapy can enhance its sensitivity,and further eliminate tumor cells that develop resistance to chemotherapy.The combination of Pembrolizumab and Trastuzumab targeting human epidermal growth factor receptor 2 showed improved prognosis.The overall toxic effects of Pembrolizumab are significantly lower than traditional chemotherapy,and the safety is controllable.PD-1 inhibitor Pembrolizumab sheds a light on the treatment of AGC and brings new hope to the clinical practice.展开更多
BACKGROUND: The role of programmed death 1 (PD-1) and programmed death ligand 1 (PD-L1) in persistent HBV infection is controversial. Increasing PD-1 and PD-L1 expression has been found in hepatitis B patients during ...BACKGROUND: The role of programmed death 1 (PD-1) and programmed death ligand 1 (PD-L1) in persistent HBV infection is controversial. Increasing PD-1 and PD-L1 expression has been found in hepatitis B patients during immune clearance phase, but not in HBV-tolerant patients. We investigated PD-1 and PD-L1 expression and inflammation in chronic hepatitis B. METHODS: Twenty patients with chronic hepatitis B participated in this study. Fifteen patients were in the immune clearance phase, and 5 were in the immune inactive phase. Circulating HBV-specific T cells were analyzed by flow cytometric detection of major histocompatibility complex (MHC) class I peptide complexes, known as pentamers. Intra-hepatic PD-1 and PD-L1 expressions were analyzed by immunostaining. RESULTS: The frequency of pentamers, including core 18-27 (1.88%±0.36%), env 335-343 (1.85%±0.37%), and pol 575-583 (1.56%±0.29%) was 8.30-, 7.71- and 8.48-fold greater during immune clearance phase than those during the immune inactive phase. In addition, more than 70% of circulating pentamers were PD-1 positive. During immune clearance phase, the numbers of intra-hepatic PD-1 and PD-L1 positive cells were 108±23/HPF and 97±20/HPF respectively, in contrast, there was a paucity of PD-1 and PD-L1 positive cells in the immune inactive phase. The numbers of intra-hepatic PD-1 and PD-L1 positive cells were positively correlated with serum alanine aminotransferase and the number of intra-hepatic CD8 + T cells. Immunofluorescence showed that almost all of the intra- hepatic CD8 + T cells were PD-1 and CCR6 positive. These cells aggregated around macrophage inflammatory protein-3 alpha (MIP3α) positive cells and mixed with PD-L1 positive cells.CONCLUSIONS: PD-1 and PD-L1 expressions were significantly correlated with inflammation. CCR6 and PD-1 co-expressed in the same cells; these cells were increased both in circulation and the inflamed liver and aggregated around MIP3α positive cells. The mixture of CCR6 and PD-1, MIP3α and PD-L1 positive cells created immune response compartments which played an important role in specific immune response in HBV immune clearance.展开更多
OBJECTIVE:To investigate the effect of Ganoderma Lucidum Spore Oil(GLSO)on the tumor growth and survival of H22 tumor-bearing mice treated with cyclophosphamide(CTX),and explore the underlying mechanism.METHODS:Allogr...OBJECTIVE:To investigate the effect of Ganoderma Lucidum Spore Oil(GLSO)on the tumor growth and survival of H22 tumor-bearing mice treated with cyclophosphamide(CTX),and explore the underlying mechanism.METHODS:Allograft H22 hepatocellular carcinoma mouse model was applied to investigate the effect of GLSO on the tumor growth and survival of animals,and Kaplan-Meier survival analysis was used to analyze the life span.Plasma biochemical examination was used to determine the levels of alanine aminotransferase(ALT),aspartate aminotransferase(AST),urea(UREA)and creatinine(CRE).Western blot analysis was performed to detect Programmed Death-1(PD-1),Programmed Death Ligand 1(PD-L1),Janus Kinase 2(JAK2),phosphorylated Signal Transducer and Activator of Transcription 3(p-STAT3),and Signal Transducer and Activator of Transcription 3(STAT3)expression.RESULTS:GLSO increased the anti-tumor effect of CTX and prolonged the survival of H22 tumor-bearing mice treated with CTX.Meanwhile,GLSO increased the thymus index and showed no obvious toxicity to liver functions of animals.GLSO also decreased the level of UREA in H22 tumor-bearing mice treated with CTX.Furthermore,GLSO could inhibit the expression of PD-1 in spleen,which was independent of JAK2 expression and STAT3 phosphorylation.However,GLSO did not affect the expression of PD-L1,JAK2,and p-STAT3 in tumor tissue.CONCLUSION:GLSO could strengthen the anti-tumor effect of CTX and prolong the life span of H22 tumorbearing mice,while the underlying mechanism might be relevant to the amelioration effect of thymus function and inhibition of PD-1 expression in spleen.Furthermore,these findings implied the promising role of GLSO in combination with CTX to extend the survival of patients in clinical chemotherapy of hepatocellular carcinoma.展开更多
OBJECTIVE:To explore the effects of Weitiao No.3(微调3号方,WD-3)on anti-programmed cell death protein-1(PD-1)immunotherapy in gastric cancer(GC).METHODS:The intestinal microbiota was analyzed by 16S rDNA sequencing of...OBJECTIVE:To explore the effects of Weitiao No.3(微调3号方,WD-3)on anti-programmed cell death protein-1(PD-1)immunotherapy in gastric cancer(GC).METHODS:The intestinal microbiota was analyzed by 16S rDNA sequencing of fecal samples from three groups:healthy people(Health),GC patients(GC),and WD-3-treated GC patients(WD-3).Next,we established an orthotopic model of GC mice,which were treated with anti-PD-1,WD-3,or an inoculation of intestinal bacteria.Immune markers CD3,CD4,CD8,and forkhead box protein P3(FOXP3),and the cell proliferation marker Ki67,were evaluated by immunohistochemistry.Cell apoptosis in GC tumors was assessed by terminaldeoxynucleotidyl-transferase-mediated deoxyuridine triphosphate nick end labeling staining.Enzyme-linked immunosorbent assays(ELISAs)were performed to analyze the serum levels of the following cytokines in GC mice:tumor necrosis factor(TNF)-α,interleukin(IL)-2,IL-6,IL-10,interferon(IFN)-γ,and transforming growth factor(TGF)-β.RESULTS:Sequencing data showed that there were significant differences in the composition of the gut microbial community among the three human groups.The gut bacteria in the three groups mainly comprised the phyla Firmicutes,Proteobacteria,Bacteroidetes,and Actinobacteria.At the genus level,the relative abundances of Bifidobacterium and Coprococcus showed significant decreases in the GC group,and an obvious increase in the WD-3 group,compared with the Health group.Interestingly,the relative abundance of Saccharopolyspora was only detected in the WD-3 group.The results of in vivo experiments in GC mice showed that WD-3 or anti-PD-1 treatment increased the levels of CD3+,CD4+,and CD8+T cells,but decreased the levels of FOXP3+regulatory T cells.Furthermore,WD-3 or PD-1 antibody treatment inhibited proliferation and promoted apoptosis of GC tumor cells.ELISA analysis showed that WD-3 or PD-1 antibody treatment facilitated TNF-α,IL-2,and IFN-γexpression,while suppressing IL-6,IL-10,and TGF-βexpression.Combination therapy with WD-3 and anti-PD-1 intensified all of these effects.CONCLUSION:WD-3 enhanced the immunotherapeutic efficacy of anti-PD-1 by modulating the intestinal microbiota in an orthotopic model of GC mice.展开更多
Lymphoma,which is highly malignant,stems from lymph nodes and lymphoid tissue.Lymphoma cells express programmed death-ligand 1/2(PD-L1/PD-L2),which binds with programmed cell death 1 protein(PD-1)to establish inhibito...Lymphoma,which is highly malignant,stems from lymph nodes and lymphoid tissue.Lymphoma cells express programmed death-ligand 1/2(PD-L1/PD-L2),which binds with programmed cell death 1 protein(PD-1)to establish inhibitory signaling that impedes the normal function of T cells and allows tumor cells to escape immune system surveillance.Recently,immune checkpoint inhibitor immunotherapies such as PD-1 inhibitors(nivolumab and pembrolizumab)have been introduced into the lymphoma treatment algorithm and have shown remarkable clinical efficacy and greatly improve prognosis in lymphoma patients.Accordingly,the number of lymphoma patients who are seeking treatment with PD-1 inhibitors is growing annually,which results in an increasing number of patients developing immune-related adverse events(irAEs).The occurrence of irAEs inevitably affects the benefits provided by immunotherapy,particularly when PD-1 inhibitors are applied.However,the mechanisms and characteristics of irAEs induced by PD-1 inhibitors in lymphoma need further investigation.This review article summarizes the latest research advances in irAEs during treatment of lymphoma with PD-1 inhibitors.A comprehensive understanding of irAEs incurred in immunotherapy can help to achieve better efficacy with PD-1 inhibitors in lymphoma.展开更多
Objective Antibodies targeting programmed cell death protein 1(PD-1)have become the mainstay of treatment for chemotherapy-refractory gastric cancer,characterized by high levels of programmed cell death ligand-1(PDL-1...Objective Antibodies targeting programmed cell death protein 1(PD-1)have become the mainstay of treatment for chemotherapy-refractory gastric cancer,characterized by high levels of programmed cell death ligand-1(PDL-1)expression.However,the routine clinical implementation of PDL-1 testing is currently limited by the lack of robust detection methods.In this regard,the role of plasmaγ-glutamyl transpeptidase(GGT),an N-terminal nucleophilic hydrolase,as an independent predictor of the efficacy of anti-PD-1 therapy remains unknown.In this study,we aimed to assessed the prognostic role of changes in plasma GGT levels(6 weeks vs.baseline)in patients with advanced gastric cancer treated with anti-PD-1 immunotherapy.Methods We retrospectively analyzed data from 57 patients with gastric cancer treated with anti-PD-1 antibodies(camrelizumab,sintilimab,nivolumab,tislelizumab,and toripalimab)at the Union Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan,China,from July 2018 to February 2021.Results We found that after 6 weeks of treatment,there were significant differences between responders and non-responders with respect to plasma GGT levels(P<0.001).Multivariate logistic regression analysis revealed that the continuous value of the 6-week difference in GGT levels(OR=1.437,95%CI=1.116-1.849,P=0.005)and 6-week difference in GGT≥0 or<0(OR=53.675,95%CI=6.379-451.669,P<0.001)were independent predictors of disease control.Survival analysis indicated that a reduction in plasma GGT6 levels during treatment was significantly associated with a favorable progression-free survival(PFS)and overall survival(P<0.001).Consistently,univariate and multivariate Cox regression analyses revealed that a reduction in plasma GGT6 levels during treatment was an independent predictor of PFS(HR=1.033,95%CI=1.013-1.053,P=0.001).Conclusion Alterations in plasma GGT levels during treatment can be used as a predictor of disease progression and survival in patients with advanced gastric cancer undergoing treatment with anti-PD-1 antibodies.展开更多
Primary liver cancer,mainly hepatocellular carcinoma(HCC),is the sixth most diagnosed cancer and third leading cause of cancer-related death globally.Recently,immunotherapies such as immune checkpoint inhibitors(ICIs)...Primary liver cancer,mainly hepatocellular carcinoma(HCC),is the sixth most diagnosed cancer and third leading cause of cancer-related death globally.Recently,immunotherapies such as immune checkpoint inhibitors(ICIs)have made great progress in the systemic treatment of HCC.However,anti-PD-1 therapy with pembrolizumab or nivolumab as a single agent did not meet their predefined end points of overall survival in the KEYNOTE-240 and Check Mate 459 trials.It is urgent to understand the immunological rationale and explore novel ways to improve the efflcacy of immunotherapy.The combination of ICIs with other therapies,such as tyrosine kinase inhibitors(TKIs),monoclonal antibodies,or local therapy,has been demonstrated to improve overall response rate and survival.In addition,modulating tumor microenvironment is a potential way to overcome the primary and secondary resistance to immunotherapies.In this review,we summarized the latest findings in the immune microenvironment,the mechanisms of their synergistic effects when combined with anti-VEGF agents or TKIs,as well as other kinds of immune treatment.展开更多
Objective:The open-label,phase II RATIONALE-209 study evaluated tislelizumab(anti-programmed cell death protein 1 antibody)as a tissue-agnostic monotherapy for microsatellite instability-high(MSI-H)/mismatch repair-de...Objective:The open-label,phase II RATIONALE-209 study evaluated tislelizumab(anti-programmed cell death protein 1 antibody)as a tissue-agnostic monotherapy for microsatellite instability-high(MSI-H)/mismatch repair-deficient(dMMR)tumors.Methods:Adults with previously treated,locally advanced unresectable or metastatic MSI-H/dMMR solid tumors were enrolled.Patients received tislelizumab 200 mg intravenously every 3 weeks.Objective response rate(ORR;primary endpoint),duration of response(DoR),and progression-free survival(PFS)were assessed by independent review committee(Response Evaluation Criteria in Solid Tumors v1.1).Results:Eighty patients were enrolled and treated;75(93.8%)patients had measurable disease at baseline.Most had metastatic disease and received at least one prior therapy for advanced/metastatic disease(n=79;98.8%).At primary analysis(data cutoff July 8,2021;median follow-up 15.2 months),overall ORR[46.7%;95%confidence interval(95%CI),35.1−58.6;one-sided P<0.0001]and ORR across tumor-specific subgroups[colorectal(n=46):39.1%(95%CI,25.1–54.6);gastric/gastroesophageal junction(n=9):55.6%(95%CI,21.2−86.3);others(n=20):60.0%(95%CI,36.1−80.9)]were significantly greater with tislelizumab vs.a prespecified historical control ORR of 10%;five(6.7%)patients had complete responses.Median DoR,PFS,and overall survival were not reached with long-term follow-up(data cutoff December 5,2022;median follow-up 28.9 months).Tislelizumab was well tolerated with no unexpected safety signals.Treatment-related adverse events(TRAEs)of grade≥3 occurred in 53.8%of patients;7.5%of patients discontinued treatment due to TRAEs.Conclusions:Tislelizumab demonstrated a significant ORR improvement in patients with previously treated,locally advanced unresectable or metastatic MSI-H/dMMR tumors and was generally well tolerated.展开更多
Renal cell cancer(RCC)represents 2%-3% of all adulthood cancers and is the most common malignant neoplasm of the kidney(90%).In the mid-nineties of the last century,the standard of treatment for patients with metastat...Renal cell cancer(RCC)represents 2%-3% of all adulthood cancers and is the most common malignant neoplasm of the kidney(90%).In the mid-nineties of the last century,the standard of treatment for patients with metastatic RCC was cytokines.Sunititib and pazopanib were registered in 2007 and 2009,respectively,and have since been the standard first-line treatment for metastatic clear cell RCC(mccRCC).Renal cell cancer is a highly immunogenic tumor with tumor infiltrating cells,including CD8+T lymphocytes,dendritic cells,natural killer cells(NK)and macrophages.This observation led to the design of new clinical trials in which patients were treated with immunotherapy.With the growing evidence that proangiogenic factors can have immunomodulatory effects on the host’s immune system,the idea of combining angiogenic drugs with immunotherapy has emerged,and new clinical trials have been designed.In the last few years,several therapeutic options have been approved[immunotherapy and immunotherapy/tyrosine kinase inhibitors(TKI)]for the first-line treatment of mccRCC.Nivolumab/ipilimumab is approved for the treatment of patients with intermediate and poor prognoses.Several checkpoint inhibitors(pembrolizumab,nivolumab,avelumab)in combination with TKI(axitinib,lenvatinib,cabozantinib)are approved for the treatment of patients regardless of their International mRCC Database Consortium prognostic group and PD-L1 expression.There is no specific and ideal biomarker that could help in selecting the ideal patient for the appropriate first-line treatment.展开更多
Neuroendocrine neoplasm of the pancreas is a rare tumor with limited treatment options.Among such tumors,treatment for pancreatic neuroendocrine tumor(PanNET)G3 is the most difficult.Temozolomide(TMZ)is commonly used ...Neuroendocrine neoplasm of the pancreas is a rare tumor with limited treatment options.Among such tumors,treatment for pancreatic neuroendocrine tumor(PanNET)G3 is the most difficult.Temozolomide(TMZ)is commonly used to treat PanNET.However,TMZ may cause tumor gene alkylation,which induces drug resistance and rapid disease progression.Herein,we present a case of a female who was diagnosed with PanNET G3 and achieved a partial response to toripalimab,an anti-programmed cell death-ligand 1(anti-PD-L1)monoclonal antibody,after multiple cycles of TMZ treatment.Genomic profiling revealed that compared with the patient’s samples collected at baseline,the postTMZ-treatment samples had markedly higher levels of tumor mutational burden(TMB)associated with characteristic alkylating mutational signature representing a positive correlation with favorable response to anti-PD-1 treatment.In addition,we observed a germline truncating mutation of MUTYH(W156*)that was considered to be pathogenic and potentially conferred to genomic instability.This case suggests that anti-PD-1 therapy could be a treatment option for PanNET patients with increased TMB after TMZ-based treatment.展开更多
基金Supported by Jilin Provincial Natural Science Foundation,No.YDZJ202401650ZYTS。
文摘This editorial discusses Christodoulidis et al's article,which appeared in the most recent edition.The clinical trials have demonstrated the programmed cell death receptor 1(PD-1)inhibitor Pembrolizumab involved combination therapy can improve the efficacy of advanced gastric cancer(AGC).Pembrolizumab combined with chemotherapy can enhance its sensitivity,and further eliminate tumor cells that develop resistance to chemotherapy.The combination of Pembrolizumab and Trastuzumab targeting human epidermal growth factor receptor 2 showed improved prognosis.The overall toxic effects of Pembrolizumab are significantly lower than traditional chemotherapy,and the safety is controllable.PD-1 inhibitor Pembrolizumab sheds a light on the treatment of AGC and brings new hope to the clinical practice.
基金supported by agrant from the Zhejiang Provincial Natural Science Foundation(Y2110169)
文摘BACKGROUND: The role of programmed death 1 (PD-1) and programmed death ligand 1 (PD-L1) in persistent HBV infection is controversial. Increasing PD-1 and PD-L1 expression has been found in hepatitis B patients during immune clearance phase, but not in HBV-tolerant patients. We investigated PD-1 and PD-L1 expression and inflammation in chronic hepatitis B. METHODS: Twenty patients with chronic hepatitis B participated in this study. Fifteen patients were in the immune clearance phase, and 5 were in the immune inactive phase. Circulating HBV-specific T cells were analyzed by flow cytometric detection of major histocompatibility complex (MHC) class I peptide complexes, known as pentamers. Intra-hepatic PD-1 and PD-L1 expressions were analyzed by immunostaining. RESULTS: The frequency of pentamers, including core 18-27 (1.88%±0.36%), env 335-343 (1.85%±0.37%), and pol 575-583 (1.56%±0.29%) was 8.30-, 7.71- and 8.48-fold greater during immune clearance phase than those during the immune inactive phase. In addition, more than 70% of circulating pentamers were PD-1 positive. During immune clearance phase, the numbers of intra-hepatic PD-1 and PD-L1 positive cells were 108±23/HPF and 97±20/HPF respectively, in contrast, there was a paucity of PD-1 and PD-L1 positive cells in the immune inactive phase. The numbers of intra-hepatic PD-1 and PD-L1 positive cells were positively correlated with serum alanine aminotransferase and the number of intra-hepatic CD8 + T cells. Immunofluorescence showed that almost all of the intra- hepatic CD8 + T cells were PD-1 and CCR6 positive. These cells aggregated around macrophage inflammatory protein-3 alpha (MIP3α) positive cells and mixed with PD-L1 positive cells.CONCLUSIONS: PD-1 and PD-L1 expressions were significantly correlated with inflammation. CCR6 and PD-1 co-expressed in the same cells; these cells were increased both in circulation and the inflamed liver and aggregated around MIP3α positive cells. The mixture of CCR6 and PD-1, MIP3α and PD-L1 positive cells created immune response compartments which played an important role in specific immune response in HBV immune clearance.
基金the Ministry of Science and Technology of China:Evaluation,Re-examination,Promotion and Demonstration of Complete Sets of Technical Equipment for Efficient and Energy-Saving Extraction and Separation of Traditional Chinese Medicine(No.2017YFC1703104)the Key Laboratory Project of Pharmaceutical Lipids in Guangdong Province:Assessment of Enterprise-Class Key Laboratory of Guangdong Province(No.2020B1212070024)the Guangdong Province Key Areas Research and Development Program Project:Research and Development on Innovative Key Technologies and Intelligent Production Equipment about Processing,Decoction,Extraction and Separation of Traditional Chinese Medicine(No.2020B1111120002)。
文摘OBJECTIVE:To investigate the effect of Ganoderma Lucidum Spore Oil(GLSO)on the tumor growth and survival of H22 tumor-bearing mice treated with cyclophosphamide(CTX),and explore the underlying mechanism.METHODS:Allograft H22 hepatocellular carcinoma mouse model was applied to investigate the effect of GLSO on the tumor growth and survival of animals,and Kaplan-Meier survival analysis was used to analyze the life span.Plasma biochemical examination was used to determine the levels of alanine aminotransferase(ALT),aspartate aminotransferase(AST),urea(UREA)and creatinine(CRE).Western blot analysis was performed to detect Programmed Death-1(PD-1),Programmed Death Ligand 1(PD-L1),Janus Kinase 2(JAK2),phosphorylated Signal Transducer and Activator of Transcription 3(p-STAT3),and Signal Transducer and Activator of Transcription 3(STAT3)expression.RESULTS:GLSO increased the anti-tumor effect of CTX and prolonged the survival of H22 tumor-bearing mice treated with CTX.Meanwhile,GLSO increased the thymus index and showed no obvious toxicity to liver functions of animals.GLSO also decreased the level of UREA in H22 tumor-bearing mice treated with CTX.Furthermore,GLSO could inhibit the expression of PD-1 in spleen,which was independent of JAK2 expression and STAT3 phosphorylation.However,GLSO did not affect the expression of PD-L1,JAK2,and p-STAT3 in tumor tissue.CONCLUSION:GLSO could strengthen the anti-tumor effect of CTX and prolong the life span of H22 tumorbearing mice,while the underlying mechanism might be relevant to the amelioration effect of thymus function and inhibition of PD-1 expression in spleen.Furthermore,these findings implied the promising role of GLSO in combination with CTX to extend the survival of patients in clinical chemotherapy of hepatocellular carcinoma.
基金the National Natural Science Foundation of China:to Explore the Role and Mechanism of Weitiao No.3 in Promoting Immunotherapy of Gastric Cancer by Activating Peroxisome Proliferator-activated Receptor-γ/AMP-activated Protein Kinase Signaling Pathway through Short Chain Fatty Acid based on Intestinal Flora(No.82274269)the Nature Foundation of Nanjing University of Chinese Medicine:to Investigate the Effect and Mechanism of Weitiao No.3 on Immunotherapy of Gastric Cancer based on Peroxisome Proliferator-activated Receptor-γ/AMP-activated Protein Kinase Signaling Pathway(No.XZR2020079)the Wuxi Administration of Traditional Chinese Medicine Scientific Research Project:Clinical and Basic Study on the Effect of Weitiao No.3 Mixture on Immunotherapy of Gastric Cancer by Regulating Intestinal Microecology(No.ZYKJ201906)。
文摘OBJECTIVE:To explore the effects of Weitiao No.3(微调3号方,WD-3)on anti-programmed cell death protein-1(PD-1)immunotherapy in gastric cancer(GC).METHODS:The intestinal microbiota was analyzed by 16S rDNA sequencing of fecal samples from three groups:healthy people(Health),GC patients(GC),and WD-3-treated GC patients(WD-3).Next,we established an orthotopic model of GC mice,which were treated with anti-PD-1,WD-3,or an inoculation of intestinal bacteria.Immune markers CD3,CD4,CD8,and forkhead box protein P3(FOXP3),and the cell proliferation marker Ki67,were evaluated by immunohistochemistry.Cell apoptosis in GC tumors was assessed by terminaldeoxynucleotidyl-transferase-mediated deoxyuridine triphosphate nick end labeling staining.Enzyme-linked immunosorbent assays(ELISAs)were performed to analyze the serum levels of the following cytokines in GC mice:tumor necrosis factor(TNF)-α,interleukin(IL)-2,IL-6,IL-10,interferon(IFN)-γ,and transforming growth factor(TGF)-β.RESULTS:Sequencing data showed that there were significant differences in the composition of the gut microbial community among the three human groups.The gut bacteria in the three groups mainly comprised the phyla Firmicutes,Proteobacteria,Bacteroidetes,and Actinobacteria.At the genus level,the relative abundances of Bifidobacterium and Coprococcus showed significant decreases in the GC group,and an obvious increase in the WD-3 group,compared with the Health group.Interestingly,the relative abundance of Saccharopolyspora was only detected in the WD-3 group.The results of in vivo experiments in GC mice showed that WD-3 or anti-PD-1 treatment increased the levels of CD3+,CD4+,and CD8+T cells,but decreased the levels of FOXP3+regulatory T cells.Furthermore,WD-3 or PD-1 antibody treatment inhibited proliferation and promoted apoptosis of GC tumor cells.ELISA analysis showed that WD-3 or PD-1 antibody treatment facilitated TNF-α,IL-2,and IFN-γexpression,while suppressing IL-6,IL-10,and TGF-βexpression.Combination therapy with WD-3 and anti-PD-1 intensified all of these effects.CONCLUSION:WD-3 enhanced the immunotherapeutic efficacy of anti-PD-1 by modulating the intestinal microbiota in an orthotopic model of GC mice.
基金the 2022 Project of Innovation Foundation of Outstanding Graduate Students of Gansu Provincethe Graduate Innovation Foundation of Major Project of Education Department of Gansu Province,No.lccx2021001+2 种基金the Gansu Provincial Science and Technology Plan Project Assignment(Innovation Base and Talent Plan),No.21JR7RA013the Gansu Province Innovation Base and Talent Plan(Gansu Province Leukemia Clinical Research Center),No.21JR7RA015the 2022 Hospital Project of The 940th Hospital of Joint Logistics Support Force of Chinese People's Liberation Army,No.2022yxky015.
文摘Lymphoma,which is highly malignant,stems from lymph nodes and lymphoid tissue.Lymphoma cells express programmed death-ligand 1/2(PD-L1/PD-L2),which binds with programmed cell death 1 protein(PD-1)to establish inhibitory signaling that impedes the normal function of T cells and allows tumor cells to escape immune system surveillance.Recently,immune checkpoint inhibitor immunotherapies such as PD-1 inhibitors(nivolumab and pembrolizumab)have been introduced into the lymphoma treatment algorithm and have shown remarkable clinical efficacy and greatly improve prognosis in lymphoma patients.Accordingly,the number of lymphoma patients who are seeking treatment with PD-1 inhibitors is growing annually,which results in an increasing number of patients developing immune-related adverse events(irAEs).The occurrence of irAEs inevitably affects the benefits provided by immunotherapy,particularly when PD-1 inhibitors are applied.However,the mechanisms and characteristics of irAEs induced by PD-1 inhibitors in lymphoma need further investigation.This review article summarizes the latest research advances in irAEs during treatment of lymphoma with PD-1 inhibitors.A comprehensive understanding of irAEs incurred in immunotherapy can help to achieve better efficacy with PD-1 inhibitors in lymphoma.
基金Supported by a grant from the Hubei and the Huazhong University of Science and Technology Undergraduate Innovation and Entrepreneurship Training Program(No.S202110487427,DYLC2021072).
文摘Objective Antibodies targeting programmed cell death protein 1(PD-1)have become the mainstay of treatment for chemotherapy-refractory gastric cancer,characterized by high levels of programmed cell death ligand-1(PDL-1)expression.However,the routine clinical implementation of PDL-1 testing is currently limited by the lack of robust detection methods.In this regard,the role of plasmaγ-glutamyl transpeptidase(GGT),an N-terminal nucleophilic hydrolase,as an independent predictor of the efficacy of anti-PD-1 therapy remains unknown.In this study,we aimed to assessed the prognostic role of changes in plasma GGT levels(6 weeks vs.baseline)in patients with advanced gastric cancer treated with anti-PD-1 immunotherapy.Methods We retrospectively analyzed data from 57 patients with gastric cancer treated with anti-PD-1 antibodies(camrelizumab,sintilimab,nivolumab,tislelizumab,and toripalimab)at the Union Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan,China,from July 2018 to February 2021.Results We found that after 6 weeks of treatment,there were significant differences between responders and non-responders with respect to plasma GGT levels(P<0.001).Multivariate logistic regression analysis revealed that the continuous value of the 6-week difference in GGT levels(OR=1.437,95%CI=1.116-1.849,P=0.005)and 6-week difference in GGT≥0 or<0(OR=53.675,95%CI=6.379-451.669,P<0.001)were independent predictors of disease control.Survival analysis indicated that a reduction in plasma GGT6 levels during treatment was significantly associated with a favorable progression-free survival(PFS)and overall survival(P<0.001).Consistently,univariate and multivariate Cox regression analyses revealed that a reduction in plasma GGT6 levels during treatment was an independent predictor of PFS(HR=1.033,95%CI=1.013-1.053,P=0.001).Conclusion Alterations in plasma GGT levels during treatment can be used as a predictor of disease progression and survival in patients with advanced gastric cancer undergoing treatment with anti-PD-1 antibodies.
基金supported by grants from the National Natural Science Foundation of China(81902390)the Major Program of National Natural Science Foundation of China(91959203)the Key Program of the National Natural Science Foundation of China(81930074)。
文摘Primary liver cancer,mainly hepatocellular carcinoma(HCC),is the sixth most diagnosed cancer and third leading cause of cancer-related death globally.Recently,immunotherapies such as immune checkpoint inhibitors(ICIs)have made great progress in the systemic treatment of HCC.However,anti-PD-1 therapy with pembrolizumab or nivolumab as a single agent did not meet their predefined end points of overall survival in the KEYNOTE-240 and Check Mate 459 trials.It is urgent to understand the immunological rationale and explore novel ways to improve the efflcacy of immunotherapy.The combination of ICIs with other therapies,such as tyrosine kinase inhibitors(TKIs),monoclonal antibodies,or local therapy,has been demonstrated to improve overall response rate and survival.In addition,modulating tumor microenvironment is a potential way to overcome the primary and secondary resistance to immunotherapies.In this review,we summarized the latest findings in the immune microenvironment,the mechanisms of their synergistic effects when combined with anti-VEGF agents or TKIs,as well as other kinds of immune treatment.
基金sponsored by BeiGene.Third-party medical writing assistance was provided by Ghina Yaacoub,MSc,of Ashfield MedComms,an Inizio Company,and funded by BeiGene.
文摘Objective:The open-label,phase II RATIONALE-209 study evaluated tislelizumab(anti-programmed cell death protein 1 antibody)as a tissue-agnostic monotherapy for microsatellite instability-high(MSI-H)/mismatch repair-deficient(dMMR)tumors.Methods:Adults with previously treated,locally advanced unresectable or metastatic MSI-H/dMMR solid tumors were enrolled.Patients received tislelizumab 200 mg intravenously every 3 weeks.Objective response rate(ORR;primary endpoint),duration of response(DoR),and progression-free survival(PFS)were assessed by independent review committee(Response Evaluation Criteria in Solid Tumors v1.1).Results:Eighty patients were enrolled and treated;75(93.8%)patients had measurable disease at baseline.Most had metastatic disease and received at least one prior therapy for advanced/metastatic disease(n=79;98.8%).At primary analysis(data cutoff July 8,2021;median follow-up 15.2 months),overall ORR[46.7%;95%confidence interval(95%CI),35.1−58.6;one-sided P<0.0001]and ORR across tumor-specific subgroups[colorectal(n=46):39.1%(95%CI,25.1–54.6);gastric/gastroesophageal junction(n=9):55.6%(95%CI,21.2−86.3);others(n=20):60.0%(95%CI,36.1−80.9)]were significantly greater with tislelizumab vs.a prespecified historical control ORR of 10%;five(6.7%)patients had complete responses.Median DoR,PFS,and overall survival were not reached with long-term follow-up(data cutoff December 5,2022;median follow-up 28.9 months).Tislelizumab was well tolerated with no unexpected safety signals.Treatment-related adverse events(TRAEs)of grade≥3 occurred in 53.8%of patients;7.5%of patients discontinued treatment due to TRAEs.Conclusions:Tislelizumab demonstrated a significant ORR improvement in patients with previously treated,locally advanced unresectable or metastatic MSI-H/dMMR tumors and was generally well tolerated.
文摘Renal cell cancer(RCC)represents 2%-3% of all adulthood cancers and is the most common malignant neoplasm of the kidney(90%).In the mid-nineties of the last century,the standard of treatment for patients with metastatic RCC was cytokines.Sunititib and pazopanib were registered in 2007 and 2009,respectively,and have since been the standard first-line treatment for metastatic clear cell RCC(mccRCC).Renal cell cancer is a highly immunogenic tumor with tumor infiltrating cells,including CD8+T lymphocytes,dendritic cells,natural killer cells(NK)and macrophages.This observation led to the design of new clinical trials in which patients were treated with immunotherapy.With the growing evidence that proangiogenic factors can have immunomodulatory effects on the host’s immune system,the idea of combining angiogenic drugs with immunotherapy has emerged,and new clinical trials have been designed.In the last few years,several therapeutic options have been approved[immunotherapy and immunotherapy/tyrosine kinase inhibitors(TKI)]for the first-line treatment of mccRCC.Nivolumab/ipilimumab is approved for the treatment of patients with intermediate and poor prognoses.Several checkpoint inhibitors(pembrolizumab,nivolumab,avelumab)in combination with TKI(axitinib,lenvatinib,cabozantinib)are approved for the treatment of patients regardless of their International mRCC Database Consortium prognostic group and PD-L1 expression.There is no specific and ideal biomarker that could help in selecting the ideal patient for the appropriate first-line treatment.
文摘Neuroendocrine neoplasm of the pancreas is a rare tumor with limited treatment options.Among such tumors,treatment for pancreatic neuroendocrine tumor(PanNET)G3 is the most difficult.Temozolomide(TMZ)is commonly used to treat PanNET.However,TMZ may cause tumor gene alkylation,which induces drug resistance and rapid disease progression.Herein,we present a case of a female who was diagnosed with PanNET G3 and achieved a partial response to toripalimab,an anti-programmed cell death-ligand 1(anti-PD-L1)monoclonal antibody,after multiple cycles of TMZ treatment.Genomic profiling revealed that compared with the patient’s samples collected at baseline,the postTMZ-treatment samples had markedly higher levels of tumor mutational burden(TMB)associated with characteristic alkylating mutational signature representing a positive correlation with favorable response to anti-PD-1 treatment.In addition,we observed a germline truncating mutation of MUTYH(W156*)that was considered to be pathogenic and potentially conferred to genomic instability.This case suggests that anti-PD-1 therapy could be a treatment option for PanNET patients with increased TMB after TMZ-based treatment.
