After that the era of chemotherapy in the treatment of solid tumors have been overcome by the "translational era", with the innovation introduced by targeted therapies, medical oncology is currently looking ...After that the era of chemotherapy in the treatment of solid tumors have been overcome by the "translational era", with the innovation introduced by targeted therapies, medical oncology is currently looking at the dawn of a new "immunotherapy era" with the advent of immune checkpoint inhibitors(CKI) antibodies.The onset of PD-1/PD-L1 targeted therapy has demonstrated the importance of this axis in the immune escape across almost all human cancers.The new CKI allowed to significantly prolong survival and to generate durable response, demonstrating remarkable efficacy in a wide range of cancer types.The aim of this article is to review the most up to date literature about the clinical effectiveness of CKI antibodies targeting PD-1/PD-L1 axis for the treatment of advanced solid tumors and to explore transversal challenges in the immune checkpoint blockade.展开更多
Pancreatic ductal adenocarcinoma(PDAC) is an almost uniformly lethal disease with less than 5% survival at five years. This is largely due to metastatic disease, which is already present in the majority of patients wh...Pancreatic ductal adenocarcinoma(PDAC) is an almost uniformly lethal disease with less than 5% survival at five years. This is largely due to metastatic disease, which is already present in the majority of patients when diagnosed. Even when the primary cancer can be removed by radical surgery, local recurrence occurs within one year in 50%-80% of cases. Therefore, it is imperative to develop new approaches for the treatment of advanced cancer and the prevention of recurrence after surgery. Tumour-targeted oncolytic viruses(TOVs) have become an attractive therapeutic agent as TOVs can kill cancer cells through multiple mechanisms of action, especially via virus-induced engagement of the immune response specifically against tumour cells. To attack tumour cells effectively, tumour-specific T cells need to overcome negative regulatory signals that suppress their activation or that induce tolerance programmes such as anergy or exhaustion in the tumour microenvironment. In this regard, the recent breakthrough in immunotherapy achieved with immune checkpoint blockade agents, such as anti-cytotoxic T-lymphocyte-associate protein 4, programmed death 1(PD-1) or PD-L1 antibodies, has demonstrated the possibility of relieving immune suppression in PDAC. Therefore, the combination of oncolytic virotherapy and immune checkpoint blockade agents may synergistically function to enhance the antitumour response, lending the opportunity to be the future for treatment of pancreatic cancer.展开更多
程序性死亡受体-1(programmed death receptor-1,PD-1)锚定在抗原特异性细胞毒性T淋巴细胞(cytotoxic T lymphocytes,CTLs)的细胞膜上,其特异性配体程序性死亡–配体1(programmed death-ligand 1,PD-L1)是一种分子量约为40 kDa的I型跨...程序性死亡受体-1(programmed death receptor-1,PD-1)锚定在抗原特异性细胞毒性T淋巴细胞(cytotoxic T lymphocytes,CTLs)的细胞膜上,其特异性配体程序性死亡–配体1(programmed death-ligand 1,PD-L1)是一种分子量约为40 kDa的I型跨膜蛋白,在正常组织中广泛表达。在正常生理条件下,PD-1和PD-L1之间的胞外结合通过抑制CTLs活性从而阻止自身免疫疾病的发生。然而,PD-L1在黑色素瘤、肺癌、肾细胞癌等恶性肿瘤中的异常上调表达通过促进PD-1/PD-L1介导的CTLs失活导致癌细胞逃避免疫监控。近年来,相关研究分别从基因扩增、染色质修饰、转录与转录后修饰、翻译与翻译后修饰等角度阐述了PD-L1表达调控的分子机制。同时,针对PD-1/PD-L1轴的免疫检查点阻断治疗在多种恶性肿瘤的临床治疗中展现出了较好的疗效。该文系统总结了近年来癌细胞中的PD-L1表达调控机制研究领域的重要成果,并在此基础上展望了针对PD-1/PD-L1轴的肿瘤免疫治疗的应用前景。展开更多
文摘After that the era of chemotherapy in the treatment of solid tumors have been overcome by the "translational era", with the innovation introduced by targeted therapies, medical oncology is currently looking at the dawn of a new "immunotherapy era" with the advent of immune checkpoint inhibitors(CKI) antibodies.The onset of PD-1/PD-L1 targeted therapy has demonstrated the importance of this axis in the immune escape across almost all human cancers.The new CKI allowed to significantly prolong survival and to generate durable response, demonstrating remarkable efficacy in a wide range of cancer types.The aim of this article is to review the most up to date literature about the clinical effectiveness of CKI antibodies targeting PD-1/PD-L1 axis for the treatment of advanced solid tumors and to explore transversal challenges in the immune checkpoint blockade.
基金Supported by The United Kingdom Charity pancreatic Cancer Research Fundpancreatic Cancer Research United Kingdom+1 种基金Ministry of Sciences and Technology of ChinaNo.2013DFG32080
文摘Pancreatic ductal adenocarcinoma(PDAC) is an almost uniformly lethal disease with less than 5% survival at five years. This is largely due to metastatic disease, which is already present in the majority of patients when diagnosed. Even when the primary cancer can be removed by radical surgery, local recurrence occurs within one year in 50%-80% of cases. Therefore, it is imperative to develop new approaches for the treatment of advanced cancer and the prevention of recurrence after surgery. Tumour-targeted oncolytic viruses(TOVs) have become an attractive therapeutic agent as TOVs can kill cancer cells through multiple mechanisms of action, especially via virus-induced engagement of the immune response specifically against tumour cells. To attack tumour cells effectively, tumour-specific T cells need to overcome negative regulatory signals that suppress their activation or that induce tolerance programmes such as anergy or exhaustion in the tumour microenvironment. In this regard, the recent breakthrough in immunotherapy achieved with immune checkpoint blockade agents, such as anti-cytotoxic T-lymphocyte-associate protein 4, programmed death 1(PD-1) or PD-L1 antibodies, has demonstrated the possibility of relieving immune suppression in PDAC. Therefore, the combination of oncolytic virotherapy and immune checkpoint blockade agents may synergistically function to enhance the antitumour response, lending the opportunity to be the future for treatment of pancreatic cancer.
文摘程序性死亡受体-1(programmed death receptor-1,PD-1)锚定在抗原特异性细胞毒性T淋巴细胞(cytotoxic T lymphocytes,CTLs)的细胞膜上,其特异性配体程序性死亡–配体1(programmed death-ligand 1,PD-L1)是一种分子量约为40 kDa的I型跨膜蛋白,在正常组织中广泛表达。在正常生理条件下,PD-1和PD-L1之间的胞外结合通过抑制CTLs活性从而阻止自身免疫疾病的发生。然而,PD-L1在黑色素瘤、肺癌、肾细胞癌等恶性肿瘤中的异常上调表达通过促进PD-1/PD-L1介导的CTLs失活导致癌细胞逃避免疫监控。近年来,相关研究分别从基因扩增、染色质修饰、转录与转录后修饰、翻译与翻译后修饰等角度阐述了PD-L1表达调控的分子机制。同时,针对PD-1/PD-L1轴的免疫检查点阻断治疗在多种恶性肿瘤的临床治疗中展现出了较好的疗效。该文系统总结了近年来癌细胞中的PD-L1表达调控机制研究领域的重要成果,并在此基础上展望了针对PD-1/PD-L1轴的肿瘤免疫治疗的应用前景。
