Malignant mesothelioma is a highly aggressive neoplasm.The incidence of malignant mesothelioma is increasing worldwide.Diffuse malignant peritoneal mesothelioma(DMPM) represents one-fourth of all mesotheliomas.Associa...Malignant mesothelioma is a highly aggressive neoplasm.The incidence of malignant mesothelioma is increasing worldwide.Diffuse malignant peritoneal mesothelioma(DMPM) represents one-fourth of all mesotheliomas.Association of asbestos exposure with DMPM has been observed,especially in males.The great majority of patients present with abdominal pain and distension,caused by accumulation of tumors and ascitic ? uid.In the past,DMPM was considered a pre-terminal condition;therefore attracted little attention.Patients invariably died from their disease within a year.Recently,several prospective trials have demonstrated a median survival of 40 to 90 mo and 5-year survival of 30% to 60% after combined treatment using cytoreductive surgery and perioperative intraperitoneal chemotherapy.This remarkable improvement in survival has prompted new search into the medical science related to DMPM,a disease previously ignored as uninteresting.This review article focuses on the key advances in the epidemiology,diagnosis,staging,treatments and prognosis of DMPM that have occurred in the past decade.展开更多
Programmed cell death protein-1(PD-1)-mediated immunosuppression has been proposed to contribute to the limited clinical efficacy of chimeric antigen receptor T(CAR-T)cells in solid tumors.We generated PD-1 and T cell...Programmed cell death protein-1(PD-1)-mediated immunosuppression has been proposed to contribute to the limited clinical efficacy of chimeric antigen receptor T(CAR-T)cells in solid tumors.We generated PD-1 and T cell receptor(TCR)deficient mesothelin-specific CAR-T(MPTK-CAR-T)cells using CRISPR-Cas9 technology and evaluated them in a dose-escalation study.A total of 15 patients received one or more infusions of MPTK-CAR-T cells without prior lymphodepletion.No dose-limiting toxicity or unexpected adverse events were observed in any of the 15 patients.The best overall response was stable disease(2/15 patients).Circulating MPTK-CAR-T cells peaked at days 7–14 and became undetectable beyond 1 month.TCR-positive CAR-T cells rather than TCR-negative CAR-T cells were predominantly detected in effusion or peripheral blood from three patients after infusion.We further confirmed the reduced persistence of TCR-deficient CAR-T cells in animal models.Our results establish the preliminary feasibility and safety of CRISPR-engineered CAR-T cells with PD-1 disruption and suggest that the natural TCR plays an important role in the persistence of CAR-T cells when treating solid tumors.展开更多
Mesothelin,C-ERC/mesothelin is a 40-kD a cell surface glycoprotein that is normally present on normal mesothelial cells lining the pleura,peritoneum,and pericardium.Moreover,mesothelin has been shown to be overexpress...Mesothelin,C-ERC/mesothelin is a 40-kD a cell surface glycoprotein that is normally present on normal mesothelial cells lining the pleura,peritoneum,and pericardium.Moreover,mesothelin has been shown to be overexpressed in several human cancers,including virtually all mesothelioma and pancreatic cancer approximately 70% of ovarian cancer and extra bile duc cancer,and 50% of lung adenocarcinomas and gastric cancer.The full-length human mesothelin gene encodes the primary product,a 71-k Da precursor protein.The71-kD a mesothelin precursor is cleaved into two products40-k Da C-terminal fragment that remains membranebound via glycosylphosphatidylinositol anchor,and a31-kD a N-terminal fragment,megakaryocyte potentiating factor,which is secreted into the blood.The biologica functions of mesothelin remain largely unknown However,results of recent studies have suggested tha the mesothelin may play a role of cell proliferation and migration.In pancreatic cancer,mesothelin expression was immunohistochemically observed in all cases,bu absent in normal pancreas and in chronic pancreatitis Furthermore,the expression of mesothelin was correlated with an poorer patient outcome in severa human cancers.The limited mesothelin expression in normal tissues and high expression in many cancers makes it an attractive candidate for cancer therapy.The present review discusses the expression and function o mesothelin in cancer cells and the utility of mesothelin as a target of cancer therapy.展开更多
文摘Malignant mesothelioma is a highly aggressive neoplasm.The incidence of malignant mesothelioma is increasing worldwide.Diffuse malignant peritoneal mesothelioma(DMPM) represents one-fourth of all mesotheliomas.Association of asbestos exposure with DMPM has been observed,especially in males.The great majority of patients present with abdominal pain and distension,caused by accumulation of tumors and ascitic ? uid.In the past,DMPM was considered a pre-terminal condition;therefore attracted little attention.Patients invariably died from their disease within a year.Recently,several prospective trials have demonstrated a median survival of 40 to 90 mo and 5-year survival of 30% to 60% after combined treatment using cytoreductive surgery and perioperative intraperitoneal chemotherapy.This remarkable improvement in survival has prompted new search into the medical science related to DMPM,a disease previously ignored as uninteresting.This review article focuses on the key advances in the epidemiology,diagnosis,staging,treatments and prognosis of DMPM that have occurred in the past decade.
基金This research was supported by grants from the National Key Research and Development Program of China(No.2019YFC1316205 to J.N.)National Natural Science Foundation of China(Nos.31991171 and 81830002 to W.D.H.,81773269 and 31722036 to H.Y.W.)Strategic Priority Research Program of the Chinese Academy of Sciences(No.XDA16010503 to H.Y.W.).
文摘Programmed cell death protein-1(PD-1)-mediated immunosuppression has been proposed to contribute to the limited clinical efficacy of chimeric antigen receptor T(CAR-T)cells in solid tumors.We generated PD-1 and T cell receptor(TCR)deficient mesothelin-specific CAR-T(MPTK-CAR-T)cells using CRISPR-Cas9 technology and evaluated them in a dose-escalation study.A total of 15 patients received one or more infusions of MPTK-CAR-T cells without prior lymphodepletion.No dose-limiting toxicity or unexpected adverse events were observed in any of the 15 patients.The best overall response was stable disease(2/15 patients).Circulating MPTK-CAR-T cells peaked at days 7–14 and became undetectable beyond 1 month.TCR-positive CAR-T cells rather than TCR-negative CAR-T cells were predominantly detected in effusion or peripheral blood from three patients after infusion.We further confirmed the reduced persistence of TCR-deficient CAR-T cells in animal models.Our results establish the preliminary feasibility and safety of CRISPR-engineered CAR-T cells with PD-1 disruption and suggest that the natural TCR plays an important role in the persistence of CAR-T cells when treating solid tumors.
文摘Mesothelin,C-ERC/mesothelin is a 40-kD a cell surface glycoprotein that is normally present on normal mesothelial cells lining the pleura,peritoneum,and pericardium.Moreover,mesothelin has been shown to be overexpressed in several human cancers,including virtually all mesothelioma and pancreatic cancer approximately 70% of ovarian cancer and extra bile duc cancer,and 50% of lung adenocarcinomas and gastric cancer.The full-length human mesothelin gene encodes the primary product,a 71-k Da precursor protein.The71-kD a mesothelin precursor is cleaved into two products40-k Da C-terminal fragment that remains membranebound via glycosylphosphatidylinositol anchor,and a31-kD a N-terminal fragment,megakaryocyte potentiating factor,which is secreted into the blood.The biologica functions of mesothelin remain largely unknown However,results of recent studies have suggested tha the mesothelin may play a role of cell proliferation and migration.In pancreatic cancer,mesothelin expression was immunohistochemically observed in all cases,bu absent in normal pancreas and in chronic pancreatitis Furthermore,the expression of mesothelin was correlated with an poorer patient outcome in severa human cancers.The limited mesothelin expression in normal tissues and high expression in many cancers makes it an attractive candidate for cancer therapy.The present review discusses the expression and function o mesothelin in cancer cells and the utility of mesothelin as a target of cancer therapy.
