Programmed cell death 1（PD-1）/programmed cell death 1 ligand（PD-L1） blockade has shown promising effects in cancer immunotherapy. Removing the so-called ＂brakes＂ on T cell immune responses by blocking the PD-1/P...Programmed cell death 1（PD-1）/programmed cell death 1 ligand（PD-L1） blockade has shown promising effects in cancer immunotherapy. Removing the so-called ＂brakes＂ on T cell immune responses by blocking the PD-1/PDL1 check point should boost anti-tumor immunity and provide durable tumor regression for cancer patients.However, 30%–60% of patients show no response to PD-1/PD-L1 blockade. Thus, it is urgent to explore the underlying resistance mechanisms to improve sensitivity to anti-PD-1/PD-L1 therapy. We propose that the mechanisms promoting resistance mainly include T cell exclusion or exhaustion at the tumor site,immunosuppressive factors in the tumor microenvironment（TME）, and a range of tumor-intrinsic factors. This review highlights the power of studying the cellular and molecular mechanisms of resistance to improve the rational design of combination therapeutic strategies that can be translated to the clinic. Here, we briefly discuss the development of PD-1/PD-L1 blockade agents and focus on the current issues and future prospects for potential combinatorial therapeutic strategies that include anti-PD-1/PD-L1 therapy, based upon the available preclinical and clinical data.展开更多
During the past decades,the treatment of hepatocellular carcinoma(HCC)has been limited to surgical resection and liver transplantation,but the prognosis is still poor.Recently,tumor immunotherapy,particularly immune c...During the past decades,the treatment of hepatocellular carcinoma(HCC)has been limited to surgical resection and liver transplantation,but the prognosis is still poor.Recently,tumor immunotherapy,particularly immune checkpoints programmed cell death-1/programmed cell death ligand-1(PD-1/PD-L1)blockade,brings a breakthrough for HCC[1,2].However,anti-PD-1/PD-L1 immunotherapy is not satisfactory and the response rates were between 20%and 30%[3].How to improve the efficacy of PD-1/PD-L1blockade is the main issue.展开更多
Objective： The aim of this study was to evaluate the efficacy and safety profile of DeFazio （S-l） combined with oxaliplatin against unresectable advanced or metastatic gastric cancer. Methods： Oxaliplatin was give...Objective： The aim of this study was to evaluate the efficacy and safety profile of DeFazio （S-l） combined with oxaliplatin against unresectable advanced or metastatic gastric cancer. Methods： Oxaliplatin was given intravenously at 130 mg/m2 for 2 h on dl and S-1 was administered bid. at 80 mg/m2/day on d1-14 followed by a 7-day rest during the 3-week schedule. Results： All 62 patients were assessed for efficacy and adverse events. The response and disease control rates were 47.3% and 80.8%, respectively. The median time to progression was 7.8 months, and the median overall survival was 11.6 months. The grade 3/4 adverse events were hematological toxicities, including neutropenia （11.3%）, thrombocytopenia （9.7%） and gastrointestinal reactions （6.5%）. Conclusion： The SOX regimen （oxaliplatin, 130 mg/m2 d l; S-1, 80 mg/m2/day, bid. d1-14, q3w） provide a favorable efficacy and safety profile in patients with advanced gastric cancer.展开更多
目的系统评价PD-1/PD-L1抑制剂单药(I)或联合化疗(I+C)作为晚期非小细胞肺癌一线治疗的疗效和安全性。方法对PubMed、Embase、CNKI等数据库进行检索,纳入符合标准的随机对照试验,采用RevMan 5.3软件和R语言进行统计分析。结果共纳入13...目的系统评价PD-1/PD-L1抑制剂单药(I)或联合化疗(I+C)作为晚期非小细胞肺癌一线治疗的疗效和安全性。方法对PubMed、Embase、CNKI等数据库进行检索,纳入符合标准的随机对照试验,采用RevMan 5.3软件和R语言进行统计分析。结果共纳入13项研究,涉及7281名患者。Meta分析结果显示,PD-1/PD-L1抑制剂单药(I)或联合化疗(I+C)与化疗相比在总生存期OS和无进展生存期PFS方面均明显改善了临床疗效。间接分析(I+C vs I)中,联合治疗(I+C)较单药(I)相比可显著延长PFS,OS没有显著差异。亚组分析显示,“I+C”治疗方案在PD-L1表达阳性(≥1%)和阴性(<1%)人群中均比单药“I”和化疗具有更好的PFS。而3~5级治疗相关不良反应事件发生率在“I+C”联合治疗中更常见。结论在PD-L1表达阴性或阳性情况下,PD-1/PD-L1抑制剂联合化疗在一线治疗晚期NSCLC中均可取得较好的疗效,但不良反应发生率也较高。展开更多
Systemic therapy has become the standard treatment for patients with advanced hepatocellular carcinoma(HCC)whose treatment options are limited.However,the long-term patient response to drugs and the survival outcomes ...Systemic therapy has become the standard treatment for patients with advanced hepatocellular carcinoma(HCC)whose treatment options are limited.However,the long-term patient response to drugs and the survival outcomes remain a concern.With increasing exploration of the HCC microenvironment,particularly in terms of T lymphocyte immunity,a new era of immunomolecular targeted therapy,based on molecular signaling,has arrived for advanced HCC.In the study of immune tolerance of the intrinsic HCC microenvironment,we found that multiple immunosuppressive mechanisms and immune checkpoint inhibitors,such as anti–programmed cell death protein 1/ligand of programmed cell death protein 1 therapy,have improved clinical outcomes in some patients with advanced HCC.Furthermore,various combination therapies have been investigated,and HCC types have been categorized into different types based on anti–programmed cell death protein 1(PD-1)/ligand of programmed cell death protein 1(PD-L1)treatment.In this paper,we first discuss the tumor-infiltrating T lymphocyte immunity and immune tolerance of HCC.We then clarify the basic mechanism of anti–PD-1/PD-L1 therapy and discuss the types of HCC based on anti–PD-1/PD-L1 therapy.Thereafter,we explain the relevant studies and mechanisms of combination therapy of anti–PD-1/PD-L1 with antiangiogenesis drugs or multikinase kinase inhibitors,anti–T lymphocyte–related signaling pathways in HCC,and other anti-CD8+T cell immune checkpoints.In this way,this review offers a deeper understanding of anti–PD-1/PD-L1 immunotherapy for advanced HCC,in order to provide better individualized treatments for patients with advanced HCC.展开更多
Background:Small cell lung cancer(SCLC)is an aggressive malignant tumor with strong immunosuppressive effects,characterized by rapid doubling time and poor prognosis.Currently,effective therapeutic options are urgentl...Background:Small cell lung cancer(SCLC)is an aggressive malignant tumor with strong immunosuppressive effects,characterized by rapid doubling time and poor prognosis.Currently,effective therapeutic options are urgently needed for Extensive-stage small-cell lung Cancer.Case description:In the present case,a combination therapy of anlotinib,envolizumab,and etoposide was administered to treat an 80-year-old female patient with extensive-stage SCLC accompanied by mediastinal lymph node and bone metastasis.After two cycles of treatment,the tumor lesions in the right lungs decreased from 5.04*3.44 cm to 1.65*1.42 cm.As of now,no significant mass is seen there and no serious adverse reactions in this patient.Until September 2023,she has survived for 18 months with no disease progression.Conclusions:Research shows that Alectinib,in combination with evolocumab plus etoposide,could be an original,viable therapeutic option for the treatment option of patients with extensive-stage SCLC.展开更多
Background and aims:Hepatocellular carcinoma(HCC)is a prevalent and deadly disease with limited treatment options.Regorafenib,a tyrosine kinase inhibitor,has shown promise in HCC treatment but faces limitations as a m...Background and aims:Hepatocellular carcinoma(HCC)is a prevalent and deadly disease with limited treatment options.Regorafenib,a tyrosine kinase inhibitor,has shown promise in HCC treatment but faces limitations as a monotherapy.Combining regorafenib with PD-1 inhibitor may improve efficacy and survival outcomes for patients.This retrospective analysis was conducted to explore its efficacy and safety,providing reference experience for better application of this combination therapy.Methods:This retrospective single-center study evaluated the efficacy and safety of combining regorafenib with PD-1 blockade for patients with HCC.Efficacy was evaluated according to the RECIST 1.1 evaluation criteria.Safety was assessed using CTCAE 4.0.Data was analyzed to compare survival status in different subgroups.Results:Generally,there were 76 patients with HCC elected to receive the regorafenib plus PD-1 blockade treatment during the study period.The objective response rate was 21.1%(n?16),and the disease control rate was 56.6%(n?43).Median progression-free survival(PFS)was 6.8 months,and median overall survival had not yet been reached.All patients suffered of at least 1 adverse event.Grade3 adverse events occurred in 31.6%of patients(n?24),with the most common being hand-foot syndrome,decreased appetite,and abdominal distension.Subgroup analyses showed no significant differences in PFS based on cirrhosis status or previous treatment lines.Conclusion:With manageable safety,regorafenib combined PD-1 inhibitor could bring survival benefits for advanced HCC who have received systemic treatment.Further,the Cox analysis showed that HBV infection,metastasis,etc.did not have significant effects on the survival benefits.展开更多
基金supported by grants from the National Natural Science Foundation of China (No. 81171986)the Ministry of Public Health (No. 201501004)
文摘Programmed cell death 1（PD-1）/programmed cell death 1 ligand（PD-L1） blockade has shown promising effects in cancer immunotherapy. Removing the so-called ＂brakes＂ on T cell immune responses by blocking the PD-1/PDL1 check point should boost anti-tumor immunity and provide durable tumor regression for cancer patients.However, 30%–60% of patients show no response to PD-1/PD-L1 blockade. Thus, it is urgent to explore the underlying resistance mechanisms to improve sensitivity to anti-PD-1/PD-L1 therapy. We propose that the mechanisms promoting resistance mainly include T cell exclusion or exhaustion at the tumor site,immunosuppressive factors in the tumor microenvironment（TME）, and a range of tumor-intrinsic factors. This review highlights the power of studying the cellular and molecular mechanisms of resistance to improve the rational design of combination therapeutic strategies that can be translated to the clinic. Here, we briefly discuss the development of PD-1/PD-L1 blockade agents and focus on the current issues and future prospects for potential combinatorial therapeutic strategies that include anti-PD-1/PD-L1 therapy, based upon the available preclinical and clinical data.
基金supported by grants from the CAMS Innovation Fund for Medical Sciences(2016-I2M-1-001)the National High-tech Research and Development Projects(863)(2015AA020303)the National Natural Science Foundation of China(31500818)
文摘During the past decades,the treatment of hepatocellular carcinoma(HCC)has been limited to surgical resection and liver transplantation,but the prognosis is still poor.Recently,tumor immunotherapy,particularly immune checkpoints programmed cell death-1/programmed cell death ligand-1(PD-1/PD-L1)blockade,brings a breakthrough for HCC[1,2].However,anti-PD-1/PD-L1 immunotherapy is not satisfactory and the response rates were between 20%and 30%[3].How to improve the efficacy of PD-1/PD-L1blockade is the main issue.
文摘Objective： The aim of this study was to evaluate the efficacy and safety profile of DeFazio （S-l） combined with oxaliplatin against unresectable advanced or metastatic gastric cancer. Methods： Oxaliplatin was given intravenously at 130 mg/m2 for 2 h on dl and S-1 was administered bid. at 80 mg/m2/day on d1-14 followed by a 7-day rest during the 3-week schedule. Results： All 62 patients were assessed for efficacy and adverse events. The response and disease control rates were 47.3% and 80.8%, respectively. The median time to progression was 7.8 months, and the median overall survival was 11.6 months. The grade 3/4 adverse events were hematological toxicities, including neutropenia （11.3%）, thrombocytopenia （9.7%） and gastrointestinal reactions （6.5%）. Conclusion： The SOX regimen （oxaliplatin, 130 mg/m2 d l; S-1, 80 mg/m2/day, bid. d1-14, q3w） provide a favorable efficacy and safety profile in patients with advanced gastric cancer.
文摘目的系统评价PD-1/PD-L1抑制剂单药(I)或联合化疗(I+C)作为晚期非小细胞肺癌一线治疗的疗效和安全性。方法对PubMed、Embase、CNKI等数据库进行检索,纳入符合标准的随机对照试验,采用RevMan 5.3软件和R语言进行统计分析。结果共纳入13项研究,涉及7281名患者。Meta分析结果显示,PD-1/PD-L1抑制剂单药(I)或联合化疗(I+C)与化疗相比在总生存期OS和无进展生存期PFS方面均明显改善了临床疗效。间接分析(I+C vs I)中,联合治疗(I+C)较单药(I)相比可显著延长PFS,OS没有显著差异。亚组分析显示,“I+C”治疗方案在PD-L1表达阳性(≥1%)和阴性(<1%)人群中均比单药“I”和化疗具有更好的PFS。而3~5级治疗相关不良反应事件发生率在“I+C”联合治疗中更常见。结论在PD-L1表达阴性或阳性情况下,PD-1/PD-L1抑制剂联合化疗在一线治疗晚期NSCLC中均可取得较好的疗效,但不良反应发生率也较高。
文摘Systemic therapy has become the standard treatment for patients with advanced hepatocellular carcinoma(HCC)whose treatment options are limited.However,the long-term patient response to drugs and the survival outcomes remain a concern.With increasing exploration of the HCC microenvironment,particularly in terms of T lymphocyte immunity,a new era of immunomolecular targeted therapy,based on molecular signaling,has arrived for advanced HCC.In the study of immune tolerance of the intrinsic HCC microenvironment,we found that multiple immunosuppressive mechanisms and immune checkpoint inhibitors,such as anti–programmed cell death protein 1/ligand of programmed cell death protein 1 therapy,have improved clinical outcomes in some patients with advanced HCC.Furthermore,various combination therapies have been investigated,and HCC types have been categorized into different types based on anti–programmed cell death protein 1(PD-1)/ligand of programmed cell death protein 1(PD-L1)treatment.In this paper,we first discuss the tumor-infiltrating T lymphocyte immunity and immune tolerance of HCC.We then clarify the basic mechanism of anti–PD-1/PD-L1 therapy and discuss the types of HCC based on anti–PD-1/PD-L1 therapy.Thereafter,we explain the relevant studies and mechanisms of combination therapy of anti–PD-1/PD-L1 with antiangiogenesis drugs or multikinase kinase inhibitors,anti–T lymphocyte–related signaling pathways in HCC,and other anti-CD8+T cell immune checkpoints.In this way,this review offers a deeper understanding of anti–PD-1/PD-L1 immunotherapy for advanced HCC,in order to provide better individualized treatments for patients with advanced HCC.
文摘Background:Small cell lung cancer(SCLC)is an aggressive malignant tumor with strong immunosuppressive effects,characterized by rapid doubling time and poor prognosis.Currently,effective therapeutic options are urgently needed for Extensive-stage small-cell lung Cancer.Case description:In the present case,a combination therapy of anlotinib,envolizumab,and etoposide was administered to treat an 80-year-old female patient with extensive-stage SCLC accompanied by mediastinal lymph node and bone metastasis.After two cycles of treatment,the tumor lesions in the right lungs decreased from 5.04*3.44 cm to 1.65*1.42 cm.As of now,no significant mass is seen there and no serious adverse reactions in this patient.Until September 2023,she has survived for 18 months with no disease progression.Conclusions:Research shows that Alectinib,in combination with evolocumab plus etoposide,could be an original,viable therapeutic option for the treatment option of patients with extensive-stage SCLC.
基金supported by the National Natural Science Foundation of China under contract No.82203000the Shandong Provincial Natural Science Foundation under contract No.ZR202111120102the Taishan Scholars Program of Shandong Province(tsqnz20221164).
文摘Background and aims:Hepatocellular carcinoma(HCC)is a prevalent and deadly disease with limited treatment options.Regorafenib,a tyrosine kinase inhibitor,has shown promise in HCC treatment but faces limitations as a monotherapy.Combining regorafenib with PD-1 inhibitor may improve efficacy and survival outcomes for patients.This retrospective analysis was conducted to explore its efficacy and safety,providing reference experience for better application of this combination therapy.Methods:This retrospective single-center study evaluated the efficacy and safety of combining regorafenib with PD-1 blockade for patients with HCC.Efficacy was evaluated according to the RECIST 1.1 evaluation criteria.Safety was assessed using CTCAE 4.0.Data was analyzed to compare survival status in different subgroups.Results:Generally,there were 76 patients with HCC elected to receive the regorafenib plus PD-1 blockade treatment during the study period.The objective response rate was 21.1%(n?16),and the disease control rate was 56.6%(n?43).Median progression-free survival(PFS)was 6.8 months,and median overall survival had not yet been reached.All patients suffered of at least 1 adverse event.Grade3 adverse events occurred in 31.6%of patients(n?24),with the most common being hand-foot syndrome,decreased appetite,and abdominal distension.Subgroup analyses showed no significant differences in PFS based on cirrhosis status or previous treatment lines.Conclusion:With manageable safety,regorafenib combined PD-1 inhibitor could bring survival benefits for advanced HCC who have received systemic treatment.Further,the Cox analysis showed that HBV infection,metastasis,etc.did not have significant effects on the survival benefits.
