Despite improvement in outcomes, loss of response(LOR) to tumor necrosis factor-alpha (TNFα) therapies is a big concern in the management of inflammatory bowel disease. LOR is associated with flares of disease, incre...Despite improvement in outcomes, loss of response(LOR) to tumor necrosis factor-alpha (TNFα) therapies is a big concern in the management of inflammatory bowel disease. LOR is associated with flares of disease, increased hospitalisation rates, need for surgical interventions, and decline in quality of life. LOR may be multifactorial, but immunogenicity makes a significant contribution. Traditionally doses of anti-TNFα have been adjusted based on clinical response, using a standard approach. Immunomonitoring involves the measurement of anti-TNFα trough and antibody levels. It takes into account the underlying pharmacokinetics of anti-TNFα therapies. Expanding on this a treat to target approach may be used, where doses are intensified, or tailored to the individual based on the measurement of anti-TNFα trough and antibody levels. This review looks at the history, evolution, and clinical impact that immunomonitoring is having in the treatment of inflammatory bowel disease. It will focus on the role of immunomonitoring in helping to achieve long lasting deep remission and mucosal healing. It will explore the different options in terms of best measuring trough and antibody levels, explore possible advantages of immunomonitoring, and discuss its role in best optimising response, at induction, during the maintenance phase of treatment, as well as a role in withdrawing or switching therapy.展开更多
Multidrug-resistant （MDR） bacterial infection is a common complication of severe acute pancreatitis （SAP）. This study aimed to explore the association between human leukocyte antigen-antigen D-related （HLA-DR） e...Multidrug-resistant （MDR） bacterial infection is a common complication of severe acute pancreatitis （SAP）. This study aimed to explore the association between human leukocyte antigen-antigen D-related （HLA-DR） expression and multidrug-resistant infection in patients with SAP. A total of 24 SAP patients who were admitted to Nanjing Drum Tower Hospital between May 2015 and December 2016 were enrolled in the study. The percentages of CD4^＋, CD8^＋, natural killer （NK）, and HLA-DR （CD14＋） cells and the CD4^＋/CD8^＋ cell ratio on days 1, 7, 14, and 28 after admission were determined by flow cytometry. Eighteen patients presented with the symptoms of infection. Among them, 55.6% patients （10/18） developed MDR infection. The most common causative MDR organisms were Enterobacter cloacae and Acinetobacter baumannii. The CD4＋/CD8＋ cell ratio and the percentage of NK cells were similar between patients with non-MDR and patients with MDR infections. In patients without infection, the HLA-DR percentage was maintained at a high level throughout the 28 days. Compared to the patients without any infection, the HLA-DR percentage in patients with non-MDR infection was reduced on day 1 but increased and reached similar levels on day 28. In patients with MDR infection, the HLA-DR percentage remained below normal levels at all-time points. It was concluded that persistent down-regulation of HLA-DR expression is associated with MDR bacterial infection in patients with SAP.展开更多
Background:Many tumors are refractory to immune checkpoint inhibitors,but their combination with cytotoxics is expected to improve sensitivity.Understanding how and when cytotoxics best re-stimulate tumor immunity cou...Background:Many tumors are refractory to immune checkpoint inhibitors,but their combination with cytotoxics is expected to improve sensitivity.Understanding how and when cytotoxics best re-stimulate tumor immunity could help overcome resistance to immune checkpoint inhibitors.Methods:In vivo studies were performed in C57BL/6 mice grafted with immune-refractory LL/2 lung cancer model.A longitudinal immunomonitoring study on tumor,spleen,and blood after multiple treatments including Cisplatin,Pemetrexed,and anti-VEGF,either alone or in combination,was performed,spanning a period of up to 21 days,to determine the optimal time window during which immune checkpoint inhibitors should be added.Finally,an efficacy study was conducted comparing the antiproliferative performance of various schedules of anti-VEGF,Pemetrexed-Cisplatin doublet,plus anti-PD-1(i.e.,immunomonitoring-guided scheduling,concurrent dosing or a random sequence),as well as single agent anti-PD1.Results:Immunomonitoring showed marked differences between treatments,organs,and time points.However,harnessing tumor immunity(i.e.,promoting CD8 T cells or increasing the T CD8/Treg ratio)started on D7 and peaked on D14 with the anti-VEGF followed by cytotoxics combination.Therefore,a 14-day delay between anti VEGF/cytotoxic and anti-PD1 administration was considered the best sequence to test.Efficacy studies then confirmed that this sequence achieved higher antiproliferative efficacy compared to other treatment modalities(i.e.,-71%in tumor volume compared to control).Conclusions:Anti-VEGF and cytotoxic agents show time-dependent immunomodulatory effects,suggesting that sequencing is a critical feature when combining these agents with immune checkpoint inhibitors.An efficacy study confirmed that sequencing treatments further enhance antiproliferative effects in lung cancer models compared to concurrent dosing and partly reverse the resistance to cytotoxics and anti-PD1.展开更多
基金Supportedby European Crohn’s and Colitis Organisation
文摘Despite improvement in outcomes, loss of response(LOR) to tumor necrosis factor-alpha (TNFα) therapies is a big concern in the management of inflammatory bowel disease. LOR is associated with flares of disease, increased hospitalisation rates, need for surgical interventions, and decline in quality of life. LOR may be multifactorial, but immunogenicity makes a significant contribution. Traditionally doses of anti-TNFα have been adjusted based on clinical response, using a standard approach. Immunomonitoring involves the measurement of anti-TNFα trough and antibody levels. It takes into account the underlying pharmacokinetics of anti-TNFα therapies. Expanding on this a treat to target approach may be used, where doses are intensified, or tailored to the individual based on the measurement of anti-TNFα trough and antibody levels. This review looks at the history, evolution, and clinical impact that immunomonitoring is having in the treatment of inflammatory bowel disease. It will focus on the role of immunomonitoring in helping to achieve long lasting deep remission and mucosal healing. It will explore the different options in terms of best measuring trough and antibody levels, explore possible advantages of immunomonitoring, and discuss its role in best optimising response, at induction, during the maintenance phase of treatment, as well as a role in withdrawing or switching therapy.
基金This work was supported by the National Natural Science Foundation of China （No. 81701953）.
文摘Multidrug-resistant （MDR） bacterial infection is a common complication of severe acute pancreatitis （SAP）. This study aimed to explore the association between human leukocyte antigen-antigen D-related （HLA-DR） expression and multidrug-resistant infection in patients with SAP. A total of 24 SAP patients who were admitted to Nanjing Drum Tower Hospital between May 2015 and December 2016 were enrolled in the study. The percentages of CD4^＋, CD8^＋, natural killer （NK）, and HLA-DR （CD14＋） cells and the CD4^＋/CD8^＋ cell ratio on days 1, 7, 14, and 28 after admission were determined by flow cytometry. Eighteen patients presented with the symptoms of infection. Among them, 55.6% patients （10/18） developed MDR infection. The most common causative MDR organisms were Enterobacter cloacae and Acinetobacter baumannii. The CD4＋/CD8＋ cell ratio and the percentage of NK cells were similar between patients with non-MDR and patients with MDR infections. In patients without infection, the HLA-DR percentage was maintained at a high level throughout the 28 days. Compared to the patients without any infection, the HLA-DR percentage in patients with non-MDR infection was reduced on day 1 but increased and reached similar levels on day 28. In patients with MDR infection, the HLA-DR percentage remained below normal levels at all-time points. It was concluded that persistent down-regulation of HLA-DR expression is associated with MDR bacterial infection in patients with SAP.
基金supported by A^(*)midex Foundation-initiative d’Excellence and the Aix-Marseille Université。
文摘Background:Many tumors are refractory to immune checkpoint inhibitors,but their combination with cytotoxics is expected to improve sensitivity.Understanding how and when cytotoxics best re-stimulate tumor immunity could help overcome resistance to immune checkpoint inhibitors.Methods:In vivo studies were performed in C57BL/6 mice grafted with immune-refractory LL/2 lung cancer model.A longitudinal immunomonitoring study on tumor,spleen,and blood after multiple treatments including Cisplatin,Pemetrexed,and anti-VEGF,either alone or in combination,was performed,spanning a period of up to 21 days,to determine the optimal time window during which immune checkpoint inhibitors should be added.Finally,an efficacy study was conducted comparing the antiproliferative performance of various schedules of anti-VEGF,Pemetrexed-Cisplatin doublet,plus anti-PD-1(i.e.,immunomonitoring-guided scheduling,concurrent dosing or a random sequence),as well as single agent anti-PD1.Results:Immunomonitoring showed marked differences between treatments,organs,and time points.However,harnessing tumor immunity(i.e.,promoting CD8 T cells or increasing the T CD8/Treg ratio)started on D7 and peaked on D14 with the anti-VEGF followed by cytotoxics combination.Therefore,a 14-day delay between anti VEGF/cytotoxic and anti-PD1 administration was considered the best sequence to test.Efficacy studies then confirmed that this sequence achieved higher antiproliferative efficacy compared to other treatment modalities(i.e.,-71%in tumor volume compared to control).Conclusions:Anti-VEGF and cytotoxic agents show time-dependent immunomodulatory effects,suggesting that sequencing is a critical feature when combining these agents with immune checkpoint inhibitors.An efficacy study confirmed that sequencing treatments further enhance antiproliferative effects in lung cancer models compared to concurrent dosing and partly reverse the resistance to cytotoxics and anti-PD1.
