Efficacy and predictive factors of transarterial chemoembolization combined with lenvatinib plus programmed cell death protein-1 inhibition for unresectable hepatocellular carcinoma

BACKGROUND The efficacy and safety of transarterial chemoembolization(TACE)combined with lenvatinib plus programmed cell death protein-1(PD-1)for unresectable hepato-cellular carcinoma(HCC)have rarely been evaluated and it is unknown which factors are related to efficacy.AIM To evaluate the efficacy and independent predictive factors of TACE combined with lenvatinib plus PD-1 inhibitors for unresectable HCC.METHODS This study retrospectively enrolled patients with unresectable HCC who received TACE/lenvatinib/PD-1 treatment between March 2019 and April 2022.Overall survival(OS)and progression-free survival(PFS)were determined.The objective response rate(ORR)and disease control rate(DCR)were evaluated in accordance with the modified Response Evaluation Criteria in Solid Tumors.Additionally,the prognostic factors affecting the clinical outcome were assessed.RESULTS One hundred and two patients were enrolled with a median follow-up duration of 12.63 months.The median OS was 26.43 months(95%CI:17.00-35.87),and the median PFS was 10.07 months(95%CI:8.50-11.65).The ORR and DCR were 61.76%and 81.37%,respectively.The patients with Barcelona Clinic Liver Cancer Classification(BCLC)B stage,early neutrophil-to-lymphocyte ratio(NLR)response(decrease),or early alpha-fetoprotein(AFP)response(decrease>20%)had superior OS and PFS than their counterparts.CONCLUSION This study showed that TACE/lenvatinib/PD-1 treatment was well tolerated with encouraging efficacy in patients with unresectable HCC.The patients with BCLC B-stage disease with early NLR response(decrease)and early AFP response(decrease>20%)may achieve better clinical outcomes with this triple therapy.

Roles of the tumor microenvironment in the resistance to programmed cell death protein 1 inhibitors in patients with gastric cancer

Despite the continuous developments and advancements in the treatment of gastric cancer(GC),which is one of the most prevalent types of cancer in China,the overall survival is still poor for most patients with advanced GC.In recent years,with the progress in tumor immunology research,attention has shifted toward immunotherapy as a therapeutic approach for GC.Programmed cell death protein 1(PD-1)inhibitors,as novel immunosuppressive medications,have been widely utilized in the treatment of GC.However,many patients are still resistant to PD-1 inhibitors and experience recurrence in the advanced stages of PD-1 immunotherapy.To reduce the occurrence of drug resistance and recurrence in GC patients receiving PD-1 immunotherapy,to maximize the clinical activity of immunosuppressive drugs,and to elicit a lasting immune response,it is essential to research the tumor microenvironment mechanisms leading to PD-1 inhibitor resistance in GC patients.This article reviews the progress in studying the factors influencing the resistance to PD-1 inhibitors in the GC tumor microenvironment,aiming to provide insights and a basis for reducing resistance to PD-1 inhibitors for GC patients in the future.

C-reactive protein to albumin ratio predict responses to programmed cell death-1 inhibitors in hepatocellular carcinoma patients

BACKGROUND Over the years,programmed cell death-1(PD-1)inhibitors have been routinely used for hepatocellular carcinoma(HCC)treatment and yielded improved survival outcomes.Nonetheless,significant heterogeneity surrounds the outcomes of most studies.Therefore,it is critical to search for biomarkers that predict the efficacy of PD-1 inhibitors in patients with HCC.AIM To investigate the role of the C-reactive protein to albumin ratio(CAR)in evaluating the efficacy of PD-1 inhibitors for HCC.METHODS The clinical data of 160 patients with HCC treated with PD-1 inhibitors from January 2018 to November 2022 at the First Affiliated Hospital of Guangxi Medical University were retrospectively analyzed.RESULTS The optimal cut-off value for CAR based on progression-free survival(PFS)was determined to be 1.20 using x-tile software.Cox proportional risk model was used to determine the factors affecting prognosis.Eastern Cooperative Oncology Group performance status[hazard ratio(HR)=1.754,95%confidence interval(95%CI)=1.045-2.944,P=0.033],CAR(HR=2.118,95%CI=1.057-4.243,P=0.034)and tumor number(HR=2.932,95%CI=1.246-6.897,P=0.014)were independent prognostic factors for overall survival.CAR(HR=2.730,95%CI=1.502-4.961,P=0.001),tumor number(HR=1.584,95%CI=1.003-2.500,P=0.048)and neutrophil to lymphocyte ratio(HR=1.120,95%CI=1.022-1.228,P=0.015)were independent prognostic factors for PFS.Two nomograms were constructed based on independent prognostic factors.The C-index index and calibration plots confirmed that the nomogram is a reliable risk prediction tool.The ROC curve and decision curve analysis confirmed that the nomogram has a good predictive effect as well as a net clinical benefit.CONCLUSION Overall,we reveal that the CAR is a potential predictor of short-and long-term prognosis in patients with HCC treated with PD-1 inhibitors.If further verified,CAR-based nomogram may increase the number of markers that predict individualized prognosis.

Efficacy of chemotherapy containing bevacizumab in patients with metastatic colorectal cancer according to programmed cell death ligand 1

BACKGROUND Bevacizumab,an anti-vascular endothelial growth factor(VEGF)monoclonal antibody,inhibits angiogenesis and reduces tumor growth.Serum VEGF-C,lactate dehydrogenase,and inflammatory markers have been reported as predictive markers related to bevacizumab treatment.Programmed cell death ligand 1(PD-L1)could act upon VEGF receptor 2 to induce cancer cell angiogenesis and metastasis.AIM To investigate the efficacy of bevacizumab-containing chemotherapy in patients with metastatic colorectal cancer(CRC)according to the expression of PD-L1.METHODS This analysis included CRC patients who received bevacizumab plus FOLFOX or FOLFIRI as first-line therapy between June 24,2014 and February 28,2022,at Samsung Medical Center(Seoul,South Korea).Analysis of patient data included evaluation of PD-L1 expression by the combined positive score(CPS).We analyzed the efficacy of bevacizumab according to PD-L1 expression status in patients with CRC.RESULTS A total of 124 patients was included in this analysis.Almost all patients were treated with bevacizumab plus FOLFIRI or FOLFOX as the first-line chemotherapy.While 77%of patients received FOLFOX,23%received FOLFIRI as backbone first-line chemotherapy.The numbers of patients with a PD-L1 CPS of 1 or more,5 or more,or 10 or more were 105(85%),64(52%),and 32(26%),respectively.The results showed no significant difference in progression-free survival(PFS)and overall survival(OS)with bevacizumab treatment between patients with PDL1 CPS less than 1 and those with PD-L1 CPS of 1 or more(PD-L1<1%vs PD-L1≥1%;PFS:P=0.93,OS:P=0.33),between patients with PD-L1 CPS less than 5 and of 5 or more(PD-L1<5%vs PD-L1≥5%;PFS:P=0.409,OS:P=0.746),and between patients with PD-L1 CPS less than 10 and of 10 or more(PD-L1<10%vs PD-L1≥10%;PFS:P=0.529,OS:P=0.568).CONCLUSION Chemotherapy containing bevacizumab can be considered as first-line therapy in metastatic CRC irrespective of PD-L1 expression.

Effectiveness and tolerability of programmed cell death protein-1 inhibitor+chemotherapy compared to chemotherapy for upper gastrointestinal tract cancers

BACKGROUND The combination of programmed cell death protein-1(PD-1)inhibitor and che-motherapy is approved as a standard first-or second-line treatment in patients with advanced oesophageal or gastric cancer.However,it is unclear whether this combination is superior to chemotherapy alone.AIM To assess the comparative effectiveness and tolerability of combining PD-1 inhibitors with chemotherapy vs chemotherapy alone in patients with advanced gastric cancer,gastroesophageal junction(GEJ)cancer,or oesophageal carcinoma.METHODS We searched the PubMed and Embase databases for studies that compared the efficacy and tolerance of PD-1 inhibitors in combination with chemotherapy vs chemotherapy alone in patients with advanced oesophageal or gastric cancer.We employed either random or fixed models to analyze the outcomes of each clinical trial,en-compassing data on overall survival(OS),progression-free survival(PFS),objective response rate,and adverse events(AEs).RESULTS Nine phase 3 clinical trials(7016 advanced oesophageal and gastric cancer patients)met the inclusion criteria.Our meta-analysis demonstrated that the pooled PD-1 inhibitor+chemotherapy group had a significantly longer OS than the chemotherapy-alone group[hazard ratio(HR)=0.76,95%confidence interval(CI):0.71-0.81];the pooled PFS result was consistent with that of OS(HR=0.67,95%CI:0.61-0.74).The count of patients achieving an objective response in the PD-1 inhibitor+chemotherapy group surpassed that of the chemotherapy-alone group[odds ratio(OR)=1.86,95%CI:1.59-2.18].AE incidence was also higher in the combination-therapy group than in the chemotherapy-alone group,regardless of whether≥grade 3 only(OR=1.30,95%CI:1.07-1.57)or all AE grades(OR=1.88,95%CI:1.39-2.54)were examined.We performed a subgroup analysis based on the programmed death-ligand 1(PD-L1)combined positive score(CPS)and noted extended OS and PFS durations within the CPS≥1,CPS≥5,and CPS≥10 subgroups of the PD-1 inhibitor+chemotherapy group.CONCLUSION In contrast to chemotherapy alone,the combination of PD-1 inhibitor and chemotherapy appears to present a more favorable option for initial or subsequent treatment in patients with gastric cancer,GEJ tumor,or oesophageal cancer.This holds true particularly for individuals with PD-L1 CPS scores of≥5 and≥10.

Programmed cell death 1 inhibitor sintilimab plus concurrent chemoradiotherapy for locally advanced pancreatic adenocarcinoma

BACKGROUND Pancreatic adenocarcinoma,a malignancy that arises in the cells of the pancreas,is a devastating disease with unclear etiology and often poor prognosis.Locally advanced pancreatic cancer,a stage where the tumor has grown significantly but has not yet spread to distant organs,presents unique challenges in treatment.This article aims to discuss the current strategies,challenges,and future directions in the management of locally advanced pancreatic adenocarcinoma(LAPC).AIM To investigate the feasibility and efficacy of programmed cell death 1(PD-1)inhibitor sintilimab plus concurrent chemoradiotherapy for LAPC.METHODS Eligible patients had LAPC,an Eastern cooperative oncology group performance status of 0 or 1,adequate organ and marrow functions,and no prior anticancer therapy.In the observation group,participants received intravenous sintilimab 200 mg once every 3 wk,and received concurrent chemoradiotherapy(concurrent conventional fractionated radiotherapy with doses planning target volume 50.4 Gy and gross tumor volume 60 Gy in 28 fractions and oral S-140 mg/m2 twice daily on days 1-14 of a 21-d cycle and intravenous gemcitabine 1000 mg/m2 on days 1 and 8 of a 21-d cycle for eight cycles until disease progression,death,or unacceptable toxicity).In the control group,participants only received concurrent chemoradiotherapy.From April 2020 to November 2021,64 participants were finally enrolled with 34 in the observation group and 30 in the control group.RESULTS Thirty-four patients completed the scheduled course of chemoradiotherapy,while 32(94.1%)received sintilimab plus concurrent chemoradiotherapy with 2 patients discontinuing sintilimab in the observation group.Thirty patients completed the scheduled course of chemoradiotherapy in the control group.Based on the Response Evaluation Criteria in Solid Tumors guidelines,the analysis of the observation group revealed that a partial response was observed in 11 patients(32.4%),stable disease was evident in 19 patients(55.9%),and 4 patients(11.8%)experienced progressive disease;a partial response was observed in 6(20.0%)patients,stable disease in 18(60%),and progressive disease in 6(20%)in the control group.The major toxic effects were leukopenia and nausea.The incidence of severe adverse events(AEs)(grade 3 or 4)was 26.5%(9/34)in the observation group and 23.3%(7/30)in the control group.There were no treatment-related deaths.The observation group demonstrated a significantly longer median overall survival(22.1 mo compared to 15.8 mo)(P<0.05)and progression-free survival(12.2 mo vs 10.1 mo)(P<0.05)in comparison to the control group.The occurrence of severe AEs did not exhibit a statistically significant difference between the observation group and the control group(P>0.05).CONCLUSION Sintilimab plus concurrent chemoradiotherapy was effective and safe for LAPC patients,and warrants further investigation.

Over-expression of programmed death-ligand 1 and programmed death-1 on antigen-presenting cells as a predictor of organ dysfunction and mortality during early sepsis: a prospective cohort study

BACKGROUND:This study aimed to explore the changes of programmed death-ligand 1(PDL1)and programmed death-1(PD-1)expression on antigen-presenting cells(APCs)and evaluate their association with organ failure and mortality during early sepsis.METHODS:In total,40 healthy controls and 198 patients with sepsis were included in this study.Peripheral blood was collected within the first 24 h after the diagnosis of sepsis.The expression of PDL1 and PD-1 was determined on APCs,such as B cells,monocytes,and dendritic cells(DCs),by flow cytometry.Cytokines in plasma,such as interferon-γ(IFN-γ),tumor necrosis factor-α(TNF-α),interleukin-4(IL-4),IL-6,IL-10,and IL-17A were determined by Luminex assay.RESULTS:PD-1 expression decreased significantly on B cells,monocytes,myeloid DCs(mDCs),and plasmacytoid DCs(pDCs)as the severity of sepsis increased.PD-1 expression was also markedly decreased in non-survivors compared with survivors.In contrast,PD-L1 expression was markedly higher on mDCs,pDCs,and monocytes in patients with sepsis than in healthy controls and in non-survivors than in survivors.The PD-L1 expression on APCs(monocytes and DCs)was weakly related to organ dysfunction and infl ammation.The area under the receiver operating characteristic curve(AUC)of the PD-1 percentage of monocytes(monocyte PD-1%)+APACHE II model(0.823)and monocyte PD-1%+SOFA model(0.816)had higher prognostic value than other parameters alone.Monocyte PD-1%was an independent risk factor for 28-day mortality.CONCLUSION:The severity of sepsis was correlated with PD-L1 or PD-1 over-expression on APCs.PD-L1 in monocytes and DCs was weakly correlated with infl ammation and organ dysfunction during early sepsis.The combination of SOFA or APACHE II scores with monocyte PD-1%could improve the prediction ability for mortality.

Clinical significance of programmed cell death-ligand expression in small bowel adenocarcinoma is determined by the tumor microenvironment

BACKGROUND Comprehensive genomic analysis has shown that small bowel adenocarcinoma(SBA)has different genomic profiles from gastric and colorectal cancers.Hence,it is essential to establish chemotherapeutic regimens based on SBA characteristics.The expression of programmed cell death-ligand 1(PD-L1)and programmed cell death-ligand 2(PD-L2)in SBA is not fully understood.Anti-PD-L1/PD-1 therapy uses tumor-infiltrating lymphocytes(TILs);therefore,the status of TILs in the tumor microenvironment(TME)may influence their efficacy.The ratio of FoxP3+to CD8+T cells has been reported to be useful in predicting the prognosis of digestive system cancers.AIM To investigate the clinicopathological significance of PD-L1/2 expression according to the status of TILs in SBA tissues.METHODS We performed immunohistochemical analysis for PD-L1,PD-L2,CD8,FoxP3,and DNA mismatch repair(MMR)proteins using formalin-fixed,paraffin-embedded tissues from 50 patients diagnosed with primary SBA.The immunoreactivities of PD-L1 and PD-L2 were determined separately in tumor cells and tumor-infiltrating immune cells throughout the tumor center and invasive margins,and finally evaluated using the combined positive score(CPS).We assessed CD8+and FoxP3+T cells in the intratumoral and tumor-surrounding stroma.Subsequently,we calculated and summed the ratio of FoxP3 to CD8+T cell counts.Immune-related cell densities were graded as low or high.Immunohistochemical results were compared with clinicopathological factors and patient prognosis.The distribution of cancer-specific survival(CSS)was estimated using the Kaplan–Meier method,and the log-rank test was used to test for significant differences in CSS.A Cox proportional hazard model was also used to assess the effect of tumor variables on CSS.RESULTS PD-L1 expression was positive in 34%in tumor cells(T-PD-L1)and 54%in tumor-infiltrating immune cells(I-PDL1)of the cases examined.T-PD-L2 was positive in 34%and I-PD-L2 was positive in 42%of the cases.PD-L1 CPS≥10 and PD-L2 CPS≥10 were observed in 50%and 56%of the cases,respectively.Deficient MMR(dMMR)was 14%of the cases.T-PD-L1,I-PD-L1 and PD-L1 CPS≥10 were all significantly associated with dMMR(P=0.037,P=0.009,and P=0.005,respectively).T-PD-L1,I-PD-L1,and PD-L1 CPS≥10 were all associated with deeper depth of invasion(P=0.001,P=0.024,and P=0.002,respectively).I-PD-L2 expression and PD-L2 CPS≥10 were significantly higher in the differentiated histological type(P=0.015 and P=0.030,respectively).The I-PD-L1 and IPD-L2 levels were significantly associated with better CSS(P=0.037 and P=0.015,respectively).CD8-high was significantly associated with less lymph node metastasis(P=0.047),less distant metastasis(P=0.024),less peritoneal dissemination(P=0.034),and earlier TNM stage(P=0.047).The CD8-high group had better prognosis than the CD8-low group(P=0.018).FoxP3 expression was not associated with any clinicopathological factors or prognosis.We found that patients with PD-L2 CPS≥10 tended to have worse prognosis in the FoxP3/CD8-low group(P=0.088).CONCLUSION The clinicopathological significance of PD-L1/2 expression may differ depending on the TME status.Immune checkpoint inhibitors may improve the prognosis of SBA patients with low FoxP3/CD8 ratio and PD-L2 expression.

Advances on biological evaluation methods of programmed cell death protein-1/ligand-1 inhibitors

Immuno-oncology represents a groundbreaking and well-established field within cancer treatment.Among the various immuno-oncology targets,the exploration of programmed cell death-1/ligand-1 for drug discovery has proven to be one of the most successful endeavors.Remarkably,it took nearly 30 years from the initial target identification to the clinical approval of monoclonal antibodies.Providing suitable and reliable bioassays for drug candidate evaluation is of paramount importance throughout the early stages of drug discovery,from lead compound identification to in vivo efficacy testing.This assay review aims to shed light on diverse assays reported in the literature for testing antagonism activity and efficacy of programmed cell death-1/ligand-1 inhibitors.Each of these assays possesses inherent advantages and can be applied in different research scenarios.The insights presented in this summary can serve as a valuable resource for scientists in this field,aiding in the selection of appropriate assays for their specific investigations.

Prognostic value of programmed death.1, programmed death-ligand 1, programmed death-ligand 2 expression, and CD8(+) T cell density in primary tumors and metastatic lymph nodes from patients with stage T1.4N+M0 gastric adenocarcinoma

Background: Anti-programmed death-1/programmed death-ligand 1(PD-1/PD-L1) immunotherapy has been proved to be effective on gastric cancer in ongoing clinical trials. However, the value of PD-L1 in predicting responses of patients with gastric cancer to anti-PD-1/PD-L1 immunotherapy is controversial. Some studies suggested that intra-and inter-tumoral heterogeneity of PD-L1 expression might explain the controversy.This study aimed to analyze the expression of PD-L1, PD-L2, and PD-1 as well as CD8(+) T-cell density in primary tumors and lymph nodes from patients with stage T1-4 N+M0 gastric adenocarcinoma to explore the heterogeneity of PD-1 signaling pathway molecules.Methods: In primary tumors and metastatic as well as non-metastatic lymph nodes from patients with stage T1-4 N+M0 gastric adenocarcinoma, we detected PD-L1 and PD-L2 expression with immunohistochemistry. CD8(+)T-cell density in primary tumors and PD-1 expression on CD8(+)T cells were detected with immunofluorescence. Univariate analysis was used to determine the prognostic values of them. Cox proportional hazard regression model was used to identify independent risk factors that affect patients' overall survival and disease-free survival.Results: Among 119 eligible patients who had undergone surgical resection, the positive rate of PD-L1 was higher in metastatic lymph nodes than in primary tumors(45.4% vs. 38.7%, P = 0.005); the positive rate of PD-1 on CD8(+)T cells was significantly higher in primary tumors and metastatic lymph nodes than in tumor-free lymph nodes(both P < 0.001). The intensity of PD-1 expression on CD8(+) T cells in primary tumors and in metastatic lymph nodes were stronger than that in tumor-free lymph nodes from the same patient. Beside, the positive rate of PD-L2 did not show any differences between primary tumors and metastatic lymph nodes. In multivariate analysis, PD-L1 expression,PD-L2 expression, a low density of CD8(+) T cells in primary tumors, and PD-1 expression on CD8(+) T cells in primary tumors were associated with poor prognosis.Conclusion: The expression of PD-L1 is heterogeneous in primary tumors and in metastatic lymph nodes from patients with stageT1-4 N+M0 gastric adenocarcinoma, which might explain the inconsistent results in assessing the prognostic value of PD-L1 expression in previous studies.

Expression and clinical value of programmed cell death-ligand 1(PD-L1)in diffuse large B cell lymphoma:a retrospective study

Background: The programmed cell death-1(PD-1)/programmed cell death-ligand 1(PD-L1) pathway inhibits the activation of T cells and plays a crucial role in the negative regulation of cellular and humoral immune responses.Diffuse large B-cell lymphoma(DLBCL) is the most common lymphoid malignancy in adults. In the present study, we aimed to detect the expression of PD-L1 in DLBCL and to analyze its relationship with prognosis.Methods: We reviewed medical records of 204 newly diagnosed DLBCL patients in Sun Yat-sen University Cancer Center between October 2005 and August 2012. The expression of PD-L1 in tumor tissues from these 204 patients was detected using immunohistochemical(IHC) assay. The expression of anaplastic lymphoma kinase(ALK), CD5,CD30, and C-Myc in tumor specimens from 109 patients was detected using IHC, and Epstein-Barr virus(EBV)-encoded RNAs(EBERs) were detected using fluorescence in situ hybridization. The Spearman method was used for correlation analysis. The Kaplan-Meier method with log-rank test was used for univariate analysis. Cox proportional hazards model was used for multivariate analysis.Results: Of the 204 patients, 100(49.0%) were PD-L1-positive in tumor cells and 44(21.6%) were PD-L1-positive in tumor microenvironment. PD-L1 expression in tumor cells and tumor microenvironment were more common in the non-germinal center B-cell-like(GCB) subtype than in the GCB subtype(P = 0.02 and P= 0.04). Patients with PD-L1 expression in tumor microenvironment were more likely to be resistant to first-line chemotherapy when compared with the patients without PD-L1 expression in tumor microenvironment(P = 0.03). PD-L1 expression in tumor microenvironment was negatively correlated with C-Myc expression(r =-0.20, P = 0.04). No correlations were detected between PD-L1 expression and the expression of ALK, CD5, and CD30 as well as EBERs. The 5-year overall survival(OS)rates were 50.0% and 67.3% in patients with and without PD-L1 expression in tumor cells(P = 0.02). PD-L1 expression in tumor cells was an independent risk predictor for OS(P < 0.01).Conclusions: PD-L1 expression is more common in the non-GCB subtype than in the GCB subtype. PD-L1 expression in tumor microenvironment has a negative correlation with C-Myc. PD-L1 positivity predicts short survival in DLBCL patients. For patients with PD-L1 expression, more strategy such as anti-PD-L1 antibody treatment should be recommended.

Relationship Between Programmed Death-ligand 1 and Clinicopathological Characteristics in Non-small Cell Lung Cancer Patients

Objective To evaluate the correlation between programmed death-ligand 1 （PD-L1） expression in primary lung cancer cells, tumor associated macrophages （TAM） and patients＇ clinicopathological characteristics. Methods From 2008 to 2010, 208 non-small cell lung cancer patients who underwent surgery or CT-guided biopsy were recruited from Huadong Hospital, Fudan University. Immunohistochemistry staining was performed to evaluate the PD-L1 expression in both primary lung cancer cells and CD68 positive TAM.

IMpower210:A phase Ⅲ study of second-line atezolizumab vs. docetaxel in East Asian patients with non-small cell lung cancer

Objective: IMpower210(NCT02813785) explored the efficacy and safety of single-agent atezolizumab vs.docetaxel as second-line treatment for advanced non-small cell lung cancer(NSCLC) in East Asian patients.Methods: Key eligibility criteria for this phase Ⅲ, open-label, randomized study included age ≥18 years;histologically documented advanced NSCLC per the Union for International Cancer Control/American Joint Committee on Cancer staging system(7th edition);Eastern Cooperative Oncology Group performance status of 0 or 1;and disease progression following platinum-based chemotherapy for advanced or metastatic NSCLC. Patients were randomized 2:1 to receive either atezolizumab(1,200 mg) or docetaxel(75 mg/m^(2)). The primary study endpoint was overall survival(OS) in the intention-to-treat(ITT) population with wild-type epidermal growth factor receptor expression(ITT EGFR-WT) and in the overall ITT population.Results: Median OS in the ITT EGFR-WT population(n=467) was 12.3 [95% confidence interval(95% CI),10.3-13.8] months in the atezolizumab arm(n=312) and 9.9(95% CI, 7.8-13.9) months in the docetaxel arm[n=155;stratified hazard ratio(HR), 0.82;95% CI, 0.66-1.03]. Median OS in the overall ITT population was 12.5(95% CI, 10.8-13.8) months with atezolizumab treatment and 11.1(95% CI, 8.4-14.2) months(n=377) with docetaxel treatment(n=188;stratified HR, 0.87;95% CI, 0.71-1.08). Grade 3/4 treatment-related adverse events(TRAEs) occurred in 18.4% of patients in the atezolizumab arm and 50.0% of patients in the docetaxel arm.Conclusions: IMpower210 did not meet its primary efficacy endpoint of OS in the ITT EGFR-WT or overall ITT populations. Atezolizumab was comparatively more tolerable than docetaxel, with a lower incidence of grade3/4 TRAEs.

Expression characteristics of peripheral lymphocyte programmed death 1 and FoxP3+ Tregs in gastric cancer during surgery and chemotherapy

BACKGROUND Programmed death 1(PD-1)and CD4^(+)CD25^(+)FoxP3^(+)expression in peripheral blood T-cells has been previously reported in various types of cancer.However,the specific variation tendency during surgery and chemotherapy,as well as their relationship in gastric cancer patients,still remain unclear.Understanding this aspect may provide some novel insights for future studies on tumor recurrence and tumor immune escape,and also serve as a reference for determining the optimal timing and dose of clinical anti-PD-1 antibodies.AIM To observe and analyze the expression characteristics of peripheral lymphocyte PD-1 and FoxP3^(+)regulatory T cells(FoxP3^(+)Tregs)before and after surgery or chemotherapy in gastric cancer patients.METHODS Twenty-nine stomach cancer patients undergoing chemotherapy after a D2 gastrectomy provided 10 mL peripheral blood samples at each phase of the perioperative period and during chemotherapy.This study also included 29 agematched healthy donors as a control group.PD-1 expression was detected on lymphocytes,including CD4^(+)CD8^(+)CD45RO^(+),CD4^(+)CD45RO^(+),and CD8^(+)CD45RO^(+)lymphocytes as well as regulatory T cells.RESULTS We observed a significant increase of PD-1 expression on immune subsets and a larger number of FoxP3^(+)Tregs in gastric cancer patients(P<0.05).Following D2 gastrectomy,peripheral lymphocytes PD-1 expression and the number of FoxP3^(+)Tregs notably decrease(P<0.05).However,during postoperative chemotherapy,we only observed a decrease in PD-1 expression on lymphocytes in the CD8^(+)CD45RO^(+)and CD8^(+)CD45RO^(+)populations.Additionally,linear correlation analysis indicated a positive correlation between PD-1 expression and the number of CD4^(+)CD45RO^(+)FoxP3high activated Tregs(aTregs)on the total peripheral lymphocytes(r=0.5622,P<0.0001).CONCLUSION The observed alterations in PD-1 expression and the activation of regulatory T cells during gastric cancer treatment may offer novel insights for future investigations into tumor immune evasion and the clinical application of anti-PD-1 antibodies in gastric cancer.

Immune-related adverse events induced by programmed death protein-1 inhibitors from the perspective of lymphoma immunotherapy

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.

Natural course of chronic hepatitis B is characterized by changing patterns of programmed death type-1 of CD8-positive T cells

AIM:To investigate if and how programmed death type-1(PD-1)expression affects the natural course of hepatitis B virus(HBV)infection. METHODS:Sixty-four patients in different natural stages of chronic HBV infection were enrolled in this study.PD-1 expression in total T cells was detected by flow cytometry.Levels of total CD8+T cell responses and proliferation in relation to PD-1 expression levels were analyzed with intracellular staining and PD-1/ PD-L1 blockage. RESULTS:The PD-1 expression in T cells was dynamically changed during the natural course of chronic HBV infection,did not significantly increase in the immune tolerance phase,and returned to normal in the inactive virus carrier stage.Blockage of the PD-1/PD-L1 pathway could not affect the T-cell response in the immune tolerance and inactive virus carrier stages of chronic HBV infection.However,it could significantly restore the T-cell response in the immune clearance stage of chronic HBV infection.Furthermore,the PD-1 expression level in T cells was associated with the alanine aminotransferase level during the immune clearance stage of chronic HBV infection. CONCLUSION:The PD-l/PD-L1 pathway plays a different role in T-cell response during the natural course of chronic HBV infection.

Use of programmed cell death protein ligand 1 assay to predict the outcomes of non-small cell lung cancer patients treated with immune checkpoint inhibitors

The recent discovery of immune checkpoints inhibitors, especially anti-programmed cell death protein 1(PD-1)and anti-programmed cell death protein ligand 1(PD-L1) monoclonal antibodies, has opened new scenarios in the management of non-small cell lung cancer(NSCLC) and this new class of drugs has achieved a rapid development in the treatment of this disease. However, considering the costs of these drugs and the fact that only a subset of patients experience long-term disease control, the identification of predictive biomarkers for the selection of candidates suitable for treatment has become a priority. The research focused mainly on the expression of the PD-L1 receptor on both tumor cells and/or immune infiltrates determined by immunohistochemistry(IHC). However, different checkpoint inhibitors were tested, different IHC assays were used, different targets were considered(tumor cells, immune infiltrates or both) and different expression thresholds were employed in clinical trials. In some trials the assay was used prospectively to select the patients, while in other trials it was evaluated retrospectively. Some confusion emerges, which makes it difficult to easily compare the literature data and to translate them in practice management. This mini-review shows the possibilities and pitfalls of the PD-L1 expression to predict the activity and efficacy of anti PD1/PD-L1 monoclonal antibodies in the treatment of NSCLC.

Programmed cell death-1 inhibitor-related sclerosing cholangitis:A systematic review

BACKGROUND Programmed cell death-1(PD-1)inhibitor has been indicated for many types of malignancies.However,these inhibitors also cause immune-related adverse events.Hepatobiliary disorder is a phenotype of immune-related adverse event affecting 0%–4.5%of patients treated with PD-1 inhibitors.Recent studies have reported PD-1 inhibitor-related sclerosing cholangitis(SC);however,the associated clinical and pathological features are unclear.AIM To evaluate the clinical and pathological features of PD-1 inhibitor-related SC through a systematic review of the literature.METHODS The review,conducted using electronic databases in PubMed,was restricted to the period from January 2014 to September 2019 and focused on case reports/series on PD-1 inhibitor-related SC published in English.We scanned the references of the selected literature to identify any further relevant studies.Six cases previously studied by us,including three that have not yet been published,were included in this review.RESULTS Thirty-one PD-1 inhibitor-related SC cases were evaluated.Median age of patients was 67 years(range,43–89),with a male to female ratio of 21:10.The main disease requiring PD-1 inhibitor treatment was non-small cell lung cancer.Agents that caused PD-1 inhibitor-related SC were nivolumab(19 cases),pembrolizumab(10 cases),avelumab(1 case),and durvalumab(1 case).The median number of cycles until PD-1 inhibitor-related SC onset was 5.5(range,1–27).Abdominal pain or discomfort(35.5%,11/31)was the most frequent symptom.Blood serum tests identified liver dysfunction with a notable increase in biliary tract enzymes relative to hepatic enzymes,and a normal level of serum immunoglobulin G4.Biliary dilation without obstruction(76.9%,20/26),diffuse hypertrophy of the extrahepatic biliary tract(90.5%,19/21),and multiple strictures of the intrahepatic biliary tract(30.4%,7/23)were noted.In 11/23(47.8%)cases,pathological examination indicated that CD8+T cells were the dominant inflammatory cells in the bile duct or peribiliary tract.Although corticosteroids were mainly used for PD inhibitor-related SC treatment,the response rate was 11.5%(3/26).CONCLUSION Some clinical and pathological features of PD-1 inhibitor-related SC were revealed.To establish diagnostic criteria for PD-1 inhibitor-related SC,more cases need to be evaluated.

Programmed cell death, antioxidant response and oxidative stress in wheat f lag leaves induced by chemical hybridization agent SQ-1

Male sterility induced by a chemical hybridization agent （CHA） is an important tool for utilizing crop heterosis. Leaves, especially the flag leaves, as CHA initial recipients play a decisive role in inducing male sterility. To investigate effects of different treatment times of CHA-SQ-1 used, morphological, biochemical and physiological responses of wheat flag leaves were detected in thistudy. CHA induced programmed cell death （PCD） as shown in terminal deoxynucleotidyl transferase-mediated dUTP nick end-labelling （TUNEL） and DNA laddering analysis. In the early phase, CHA-SQ-1 trig- gered organelle changes arid PCD in wheat leaves accompanied by excess production of reactive oxygen species （O2- and H202） and down-regulation of the activities of superoxide dismutase （SOD）, catalase （CAT） and guaiacol peroxidase （POD）. Meanwhile, leaf cell DNAs showed ladder-like patterns on agarose gel, indicating that CHA-SQ-1 led to the activation of the responsible endonuclease. The oxidative stress assays showed that lipid peroxidation was strongly activated and photosynthesis was obviously inhibited in SQ-l-induced leaves. However, CHA contents in wheat leaves gradually reduced along with the time CHA-SQ-1 applied. Young flags returned to an oxidative/antioxidative balance and ultimately developed into mature green leaves. These results provide explanation of the relations between PCD and anther abortion and practical application of CHA for hybrid breeding.

Comprehensive insights into the effects and regulatory mechanisms of immune cells expressing programmed death-1/programmed death ligand 1 in solid tumors

The programmed cell death-1(PD-1)/programmed cell death ligand 1(PD-L1)signaling pathway is an important mechanism in tumor immune escape,and expression of PD-L1 on tumor cells has been reported more frequently.However,accumulating evidence suggests that PD-1/PD-L1 is also widely expressed on immune cells,and that regulation is also critical for tumor immune responses.In this review,we emphasized that under solid tumor conditions,the immunoregulatory effects of immune cells expressing PD-1 or PD-L1,affected the prognoses of cancer patients.Therefore,a better understanding of the mechanisms that regulate PD-1 or PD-L1 expression on immune cells would provide clear insights into the increased efficacy of anti-PD antibodies and the development of novel tumor immunotherapy strategies.