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The cutting-edge progress of immune-checkpoint blockade in lung cancer

Cellular & Molecular Immunology 2021年第2期18卷 279-293页

作者： Fei Zhou Meng Qiao Caicun Zhou Department of Medical Oncology Shanghai Pulmonary HospitalThoracic Cancer InstituteTongji University School of MedicineShanghaiChina

Great advances in immune checkpoint blockade have resulted in a paradigm shift in patients with lung ***-checkpoint inhibitor(ICI)treatment,either as monotherapy or combination therapy,has been established as the standard of care for patients with locally advanced/metastatic non-small cell lung cancer without EGFR/ALK alterations or extensive-stage small cell lung *** increasing number of clinical trials are also ongoing to further investigate the role of ICIs in patients with early-stage lung cancer as neoadjuvant or adjuvant *** PD-L1 expression and tumor mutational burden have been widely studied for patient selection,both of these biomarkers are *** to the complex cancer-immune interactions among tumor cells,the tumor microenvironment and host immunity,collaborative efforts are needed to establish a multidimensional immunogram to integrate complementary predictive biomarkers for personalized ***,as a result of the wide use of ICIs,managing acquired resistance to ICI treatment remains an inevitable challenge.A deeper understanding of the underlying biological mechanisms of acquired resistance to ICIs is helpful to overcome these *** this review,we describe the cutting-edge progress made in patients with lung cancer,the optimal duration of ICI treatment,ICIs in some special populations,the unique response patterns during ICI treatment,the emerging predictive biomarkers,and our understanding of primary and acquired resistance mechanisms to ICI treatment.

关键词： lung cancer immune-checkpoint inhibitor predictive biomarker acquired resistance

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Preclinical and early clinical studies of a novel compound SYHA1813 that efficiently crosses the blood-brain barrier and exhibits potent activity against glioblastoma

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Acta Pharmaceutica Sinica B 2023年第12期13卷 4748-4764页

作者： Yingqiang Liu Zhengsheng Zhan Zhuang Kang Mengyuan Li Yongcong Lv Shenglan Li Linjiang Tong Fang Feng Yan Li Mengge Zhang Yaping Xue Yi Chen Tao Zhang Peiran Song Yi Su Yanyan Shen Yiming Sun Xinying Yang Yi Chen Shanyan Yao Hanyu Yang Caixia Wang Meiyu Geng Wenbin Li Wenhu Duan Hua Xie Jian Ding Division of Antitumor Pharmacology State Key Laboratory of Drug ResearchShanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China Department of Medicinal Chemistry Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China Department of Neuro-oncology Cancer CenterBeijing Tiantan HospitalCapital Medical UniversityBeijing 100070China Shanghai Runshi Pharmaceutical Technology Co. Ltd.Shanghai 201218China Zhongshan Institute for Drug Discovery Shanghai Institute of Materia MedicaChinese Academy of SciencesZhongshan 528400China University of Chinese Academy of Sciences Beijing 100049China Hangzhou Institute for Advanced Study University of Chinese Academy of SciencesHangzhou 310024China

Glioblastoma(GBM)is the most common and aggressive malignant brain tumor in adults and is poorly *** studies have shown that both macrophages and angiogenesis play significant roles in GBM progression,and co-targeting of CSF1R and VEGFR is likely to be an effective strategy for GBM ***,this study developed a novel and selective inhibitor of CSFIR and VEGFR,SYHA1813,possessing potent antitumor activity against ***1813 inhibited VEGFR and CSFIR kinase activities with high potency and selectivity and thus blocked the cell viability of HUVECs and macrophages and exhibited anti-angiogenetic effects both in vitro and in ***1813 also displayed potent in vivo antitumor activity against GBM in immune-competent and immune-deficient mouse models,including temozolomide(TMZ)insensitive ***,SYHA1813 could penetrate the blood-brain barrier(BBB)and prolong the survival time of mice bearing intracranial GBM ***,SYHA1813 treatment resulted in a synergistic antitumor efficacy in combination with the PD-1 *** a clinical proof of concept,SYHA1813 achieved confirmed responses in patients with recurrent GBM in an ongoing first-in-human phase I *** data of this study support the rationale for an ongoing phase I clinical study(ChiCTR2100045380).

关键词： Small molecule inhibitor Glioblastoma VEGFR CSF1R Angiogenesis Macrophage Tumor microenvironment immune-checkpoint inhibitor

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Improving antitumor immunity using antiangiogenic agents:Mechanistic insights,current progress,and clinical challenges

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Cancer Communications 2021年第9期41卷 830-850页

作者： Shu-Jin Li Jia-Xian Chen Zhi-Jun Sun The State Key Laboratory Breeding Base of Basic Science of Stomatology(Hubei-MOST)&Key Laboratory of Oral Biomedicine Ministry of EducationSchool and Hospital of StomatologyWuhan UniversityWuhanHubei 430079P.R.China Department of Oral Maxillofacial-Head Neck Oncology School and Hospital of StomatologyWuhan UniversityWuhanHubei 430079P.R.China

Cancer immunotherapy,especially immune checkpoint blockade(ICB),has revolutionized ***,only a limited number of patients benefit from immunotherapy,and some cancers that initially respond to immunotherapy can ultimately relapse and ***,some studies have investigated combining immunotherapy with other therapies to overcome resistance to ***,multiple preclinical and clinical studies have shown that tumor vasculature is a determinant of whether immunotherapy will elicit an antitumor response;thus,vascular targeting may be a promising strategy to improve cancer immunotherapy outcomes.A successful antitumor immune response requires an intact“Cancer-Immunity Cycle,”including T cell priming and activation,immune cell recruitment,and recognition and killing of cancer *** inducers,especially vascular endothelial growth factor(VEGF),can interfere with activation,infiltration,and function of T cells,thus breaking the“Cancer-Immunity Cycle.”Together with immunostimulation-regulated tumor vessel remodeling,VEGF-mediated immunosuppression provides a solid therapeutic rationale for combining immunotherapy with antiangiogenic agents to treat solid *** the successes of recent landmark phase III clinical trials,therapies combining immune checkpoint inhibitors(ICIs)with antiangiogenic agents have become first-line treatments for multiple solid tumors,whereas the efficacy of such combinations in other solid tumors remains to be validated in ongoing *** this review,we discussed synergies between antiangiogenic agents and cancer immunotherapy based on results from preclinical and translational ***,we discussed recent progress in randomized clinical ***-containing combinations were the focus of this review because of their recent successes,but combinations containing other immunotherapies were also ***,we attempted to define critical challenges in combining ICIs with antiangiogenic agent

关键词： antiangiogenesis bevacizumab cancer combination therapy immune-checkpoint inhibitor immunotherapy vascular endothelial growth factor

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Efficacy and safety of immune checkpoint therapy in hepatocellular carcinoma: meta-analysis

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Hepatoma Research 2019年第6期5卷 7-15页

作者： Weina Tang Long-Teng Ma Yang Deng Wei Wang Hong-Wei Zhang Department of Epidemiology Second Military Medical UniversityShanghai 200433China

Aim:immune checkpoint inhibitors(ICIs)are proven to be an effective way to treat the disease of hematologic *** there is still plenty of uncertainty about the effectiveness of ICIs on hepatocellular *** Meta-analysis was conducted to evaluate the efficacy and safety of ICIs treatment in patients with ***:Four electronic databases,including PubMed,Embase,Cochrane database,and ***,were systematically retrieved for relevant observational studies published before November 1,*** objective response rate(ORR)and adverse events were *** and Metafor Packages in R were utilized to accomplish meta proportion ***:A total of 462 patients from 7 studies were included in this *** pooled estimated ORR of ICIs was 19.8%(95%CI 16.4%to 23.7%).No substantial heterogeneity was observed among studies(Q=2.0427,P=0.92,I 2=0.0%).The common adverse events on any grade were saw in increased AST(22.7%,95%CI 13.8%to 35.2%),fatigue(20.9%,95%CI 10.9%to 36.3%),rash(18.5%,95%CI 8.9%to 34.4%)and pruritus(17.3%,95%CI 13.5%to 21.8%).Increased AST(9.9%,95%CI 4.4%to 21.0%)and increased ALT(5.8%,95%CI 3.7%to 8.9%)were the most common adverse events on grade greater than ***:Although ICIs treatment has a certain efficacy on liver cancer,it also causes some adverse events which should be noticed by clinicians.

关键词： Hepatocellular immune-checkpoint inhibitor CLAT-4 PD1/PD-L1

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PD-1 blockade plus capecitabine as curative-intent treatment for tumor mutational burden-high multi-metastatic pancreatic ductal adenocarcinoma

PD-1 blockade plus capecitabine as curative-intent treatment...

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浙江省免疫学会第十三次学术大会

作者： Yuejun Han Xingxing Yu Huanrong Lan Shiya Yao Mengxiang Yang Jinlin Du Ketao Jin Department of Colorectal Surgery Affiliated Jinhua HosptialZhejiang University School of Medicine Department of Surgical Oncology Affiliated Hangzhou Cancer HosptialZhejiang University School of Medicine

Background:The rising incidence and persistently dismal 5-year overall survival of pancreatic ductal adenocarcinoma（PDAC） highlight the need for effective new systemic *** immunotherapy has increasingly garnered *** methods,such as cell therapy,immune-checkpoint blockers（ICBs）,and cancer vaccines,alone or in combination,have achieved satisfactory results in cancer *** has shown significant benefits in solid organ tumors but has been disappointing in PDAC *** promising preclinical studies,clinical translation has proven challenging,possibly because PDAC has a complex immunosuppressive tumor microenvironment（TME）,which insulates the tumor from an effective cytotoxic immune ***:We aimed to investigate combined approaches to improve ICB ***:Here we present a case of a 69-year-old man diagnosed with multi-metastatic *** analysis revealed a high tumor mutational burden of 9.02 mutations/*** TME was positive for CD4+and CD8+T cells,suggesting potential immunotherapy ***-checkpoint blockade treatment with sintilimab,a programmed cell death protein 1（PD-1） monoclonal antibody,was initiated,leading to disease *** treatment response was confirmed using contrast-enhanced magnetic resonance imaging and computed ***:PDACs possess several intrinsic and extrinsic properties that protect malignant cells from effective adaptive immune *** date,no single immunotherapy strategy has been proven effective,warranting the investigation of combination approaches to improve treatment *** case showed that the use of PD-1 mAb immunotherapy and capecitabine might be a promising treatment option for patients with multi-metastatic PDAC with a high TMB who are positive for CD4and CD8T cells in the *** clinical trials are needed to evaluate combination immunotherapy strategies to demonstrate the role of immunotherapy in PDAC treatm

关键词： anti-PD-L1 immune-checkpoint inhibitor pancreatic ductal adenocarcinoma sintilimab capecitabine

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