The highly immunosuppressive microenvironment after surgery has a crucial impact on the recurrence and metastasis in breast cancer patients.Programmable delivery of immunotherapy-involving combinations through a singl...The highly immunosuppressive microenvironment after surgery has a crucial impact on the recurrence and metastasis in breast cancer patients.Programmable delivery of immunotherapy-involving combinations through a single drug delivery system is highly promising,yet greatly challenging,to reverse postoperative immunosuppression.Here,an injectable hierarchical gel matrix,composed of dual lipid gel(DLG)layers with different soybean phosphatidylcholine/glycerol dioleate mass ratios,was developed to achieve the time-programmed sequential delivery of combined cancer immunotherapy.The outer layer of the DLG matrix was thermally responsive and loaded with sorafenib-adsorbed graphene oxide(GO)nanoparticles.GO under manually controlled near-infrared irradiation generated mild heat and provoked the release of sorafenib first to reeducate tumor-associated macrophages(TAMs)and promote an immunogenic tumor microenvironment.The inner layer,loaded with anti-CD47 antibody(aCD47),could maintain the gel state for a much longer time,enabling the sustained release of aCD47 afterward to block the CD47-signal regulatory proteinα(SIRPα)pathway for a long-term antitumor effect.In vivo studies on 4T1 tumor-bearing mouse model demonstrated that the DLG-based strategy efficiently prevented tumor recurrence and metastasis by locally reversing the immunosuppression and synergistically blocking the CD47-dependent immune escape,thereby boosting the systemic immune responses.展开更多
目的探讨使用单克隆抗-CD47(简称抗-CD47单抗)对患者输血前检测干扰的解决策略。方法以抗-CD47单抗类药物临床试验的输血病例为研究对象,检索PUBMED、MEDLINE、web of science、万方数据知识服务平台及中国知网数据库中检索国内外病例报...目的探讨使用单克隆抗-CD47(简称抗-CD47单抗)对患者输血前检测干扰的解决策略。方法以抗-CD47单抗类药物临床试验的输血病例为研究对象,检索PUBMED、MEDLINE、web of science、万方数据知识服务平台及中国知网数据库中检索国内外病例报告,从中提取病例的输血前检测信息,分析抗-CD47单抗干扰输血前检测的主要方面及解决策略。结果共检索到26例使用抗-CD47单抗药后进行输血前检测的病例,排除无效病例,共纳入16例病例(均使用的抗-CD47单抗药均是Hu5F9-G4)。使用Hu5F9-G4治疗后,输血前检测发现ABO血型鉴定正反不符率达69%,抗体筛查全部凝集,血小板抗体筛查也100%被干扰。这些说明Hu5F9-G4严重影响输血前检测。进一步分析病例中采用的排除抗-CD47干扰的方法及其优缺点。结论根据现有临床病例中抗-CD47单抗干扰输血前检测的特点,分析了排除抗-CD47对输血前检测策略的优缺点,为输血的实验室检测提供参考。展开更多
The third-generation epidermal growth factor receptor (EGFR) inhibitor osimertinib (OSI) has been approved as the first-line treatment for EGFR-mutant non-small cell lung cancer (NSCLC). This study aims to explore a r...The third-generation epidermal growth factor receptor (EGFR) inhibitor osimertinib (OSI) has been approved as the first-line treatment for EGFR-mutant non-small cell lung cancer (NSCLC). This study aims to explore a rational combination strategy for enhancing the OSI efficacy. In this study, OSI induced higher CD47 expression, an important anti-phagocytic immune checkpoint, via the NF-κB pathway in EGFR-mutant NSCLC HCC827 and NCI-H1975 cells. The combination treatment of OSI and the anti-CD47 antibody exhibited dramatically increasing phagocytosis in HCC827 and NCI-H1975 cells, which highly relied on the antibody-dependent cellular phagocytosis effect. Consistently, the enhanced phagocytosis index from combination treatment was reversed in CD47 knockout HCC827 cells. Meanwhile, combining the anti-CD47 antibody significantly augmented the anticancer effect of OSI in HCC827 xenograft mice model. Notably, OSI induced the surface exposure of “eat me” signal calreticulin and reduced the expression of immune-inhibitory receptor PD-L1 in cancer cells, which might contribute to the increased phagocytosis on cancer cells pretreated with OSI. In summary, these findings suggest the multidimensional regulation by OSI and encourage the further exploration of combining anti-CD47 antibody with OSI as a new strategy to enhance the anticancer efficacy in EGFR-mutant NSCLC with CD47 activation induced by OSI.展开更多
基金This work was funded by the budgets from the National Basic Research Plan of China(2018YFA0208903)National Natural Science Foundation of China(21877042,22077038,81972894,81673364)+2 种基金the Ministry of Science and Technology of the People’s Republic of China(2017ZX09101001006)the Fundamental Research Funds for the Central Universities(2632018ZD13)the startup fund of Huazhong University of Science and Technology,and the Priority Academic Program Development of Jiangsu Higher Education Institutions.The authors also thank the assistance from the Research Core Facilities for Life Science(HUST).
文摘The highly immunosuppressive microenvironment after surgery has a crucial impact on the recurrence and metastasis in breast cancer patients.Programmable delivery of immunotherapy-involving combinations through a single drug delivery system is highly promising,yet greatly challenging,to reverse postoperative immunosuppression.Here,an injectable hierarchical gel matrix,composed of dual lipid gel(DLG)layers with different soybean phosphatidylcholine/glycerol dioleate mass ratios,was developed to achieve the time-programmed sequential delivery of combined cancer immunotherapy.The outer layer of the DLG matrix was thermally responsive and loaded with sorafenib-adsorbed graphene oxide(GO)nanoparticles.GO under manually controlled near-infrared irradiation generated mild heat and provoked the release of sorafenib first to reeducate tumor-associated macrophages(TAMs)and promote an immunogenic tumor microenvironment.The inner layer,loaded with anti-CD47 antibody(aCD47),could maintain the gel state for a much longer time,enabling the sustained release of aCD47 afterward to block the CD47-signal regulatory proteinα(SIRPα)pathway for a long-term antitumor effect.In vivo studies on 4T1 tumor-bearing mouse model demonstrated that the DLG-based strategy efficiently prevented tumor recurrence and metastasis by locally reversing the immunosuppression and synergistically blocking the CD47-dependent immune escape,thereby boosting the systemic immune responses.
文摘目的探讨使用单克隆抗-CD47(简称抗-CD47单抗)对患者输血前检测干扰的解决策略。方法以抗-CD47单抗类药物临床试验的输血病例为研究对象,检索PUBMED、MEDLINE、web of science、万方数据知识服务平台及中国知网数据库中检索国内外病例报告,从中提取病例的输血前检测信息,分析抗-CD47单抗干扰输血前检测的主要方面及解决策略。结果共检索到26例使用抗-CD47单抗药后进行输血前检测的病例,排除无效病例,共纳入16例病例(均使用的抗-CD47单抗药均是Hu5F9-G4)。使用Hu5F9-G4治疗后,输血前检测发现ABO血型鉴定正反不符率达69%,抗体筛查全部凝集,血小板抗体筛查也100%被干扰。这些说明Hu5F9-G4严重影响输血前检测。进一步分析病例中采用的排除抗-CD47干扰的方法及其优缺点。结论根据现有临床病例中抗-CD47单抗干扰输血前检测的特点,分析了排除抗-CD47对输血前检测策略的优缺点,为输血的实验室检测提供参考。
基金the Science and Technology Development Fund,Macao SAR(File no.0129/2019/A3).
文摘The third-generation epidermal growth factor receptor (EGFR) inhibitor osimertinib (OSI) has been approved as the first-line treatment for EGFR-mutant non-small cell lung cancer (NSCLC). This study aims to explore a rational combination strategy for enhancing the OSI efficacy. In this study, OSI induced higher CD47 expression, an important anti-phagocytic immune checkpoint, via the NF-κB pathway in EGFR-mutant NSCLC HCC827 and NCI-H1975 cells. The combination treatment of OSI and the anti-CD47 antibody exhibited dramatically increasing phagocytosis in HCC827 and NCI-H1975 cells, which highly relied on the antibody-dependent cellular phagocytosis effect. Consistently, the enhanced phagocytosis index from combination treatment was reversed in CD47 knockout HCC827 cells. Meanwhile, combining the anti-CD47 antibody significantly augmented the anticancer effect of OSI in HCC827 xenograft mice model. Notably, OSI induced the surface exposure of “eat me” signal calreticulin and reduced the expression of immune-inhibitory receptor PD-L1 in cancer cells, which might contribute to the increased phagocytosis on cancer cells pretreated with OSI. In summary, these findings suggest the multidimensional regulation by OSI and encourage the further exploration of combining anti-CD47 antibody with OSI as a new strategy to enhance the anticancer efficacy in EGFR-mutant NSCLC with CD47 activation induced by OSI.
