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Spotlight on chimeric antigen receptor engineered T cell research and clinical trials in China

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Science China(Life Sciences) 2016年第4期59卷 349-359页

作者： Can Luo jianshu wei weidong Han Institute of Basic Medicine/Bio-therapeutic Department Chinese PLA General Hospital Beijing 100853 China

T cell mediated adoptive immune response has been characterized as the key to anti-tumor immunity. Scientists around the world including in China, have been trying to harness the power of T cells against tumors for decades. Recently, the biosynthetic chimeric antigen receptor engineered T cell(CAR-T) strategy was developed and exhibited encouraging clinical efficacy, especially in hematological malignancies. Chimeric antigen receptor research reports began in 2009 in China according to our Pub Med search results. Clinical trials have been ongoing in China since 2013 according to the trial registrations on ***.. After years of assiduous efforts, research and clinical scientists in China have made their own achievements in the CAR-T therapy field. In this review, we aim to highlight CAR-T research and clinical trials in China, to provide an informative reference for colleagues in the field.

关键词： chimeric antigen receptor tumor associated antigen adoptive cell therapy gene modification combination strategy

Sol-Gel Preparation of LaNiO3 and Its Physical and Chemical Properties

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Journal of Rare Earths 2004年第Z1期22卷 15-17页

作者： Lu jianshu Zhou Caiming wei Gaoyao Collage of chemical Engineering and Materials Zhejiang University of Technology Hangzhou 310014China Zhuji Bafang Battery Factory Zhuji 311801 China Collage of chemical Engineering and Materials Zhejiang University of Technology Hangzhou 310014China

LaNiO3 was synthesized by sol-gel method in which lanthanum nitrate and nickel nitrate were used as start materials and citric acid was used as complex for gel *** precursor was dried and subsequently heated at elevated temperature to form the desired *** analysis shows that pure LaNiO3 was *** conductivity and electrochemical performance of the material were *** electrical conductivity decreases from 34.5that there are current peaks in the curve, which is the evidence of the electrochemical activity of LaNiO3.

关键词： lanthanum nickelate catalysis sol-gel method

Optimized collaboration of the first and third signals endows robust activity to T cells within the immunocompetent tumor microenvironment

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Cellular & Molecular Immunology 2023年第11期20卷 1393-1394页

作者： jianshu wei Xin Lin weidong Han Changping Laboratory Yard 28Science Park RoadChangping District102206BeijingChina Department of Basic Medical Sciences Tsinghua University School of Medicine100084BeijingChina Tsinghua-Peking Center for Life Sciences 100084BeijingChina Department of Biotherapy the First Medical CenterChinese PLA General Hospital100853BeijingChina

CAR T-cell therapy has shown remarkable potential in the treatment of hematologic malignancies,and these successes have greatly motivated research on treatment of solid *** numerous clinical trials have been actively carried out,exciting clinical responses are still sporadic and may be are transient for patients with solid tumors[1].

关键词： clinical treatment transient

Clinical development of CAR T cell therapy in China:2020 update

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Cellular & Molecular Immunology 2021年第4期18卷 792-804页

作者： jianshu wei Yelei Guo Yao Wang Zhiqiang Wu Jian Bo Bin Zhang Jun Zhu weidong Han Department of Bio-Therapeutic The First Medical CenterChinese PLA General HospitalBeijing 100853China Department of Hematology The First Medical CenterChinese PLA General HospitalBeijing 100853China Department of Hematopoietic Stem Cell Transplantation The Fifth Medical CenterChinese PLA General HospitalBeijing 100071China Key Laboratory of Carcinogenesis and Translational Research Departments of LymphomaRadiology and Nuclear MedicinePeking University Cancer Hospital and InstituteBeijing 100036China

Chimeric antigen receptor(CAR)T-cell therapy has achieved significant success in the treatment of hematological *** recent years,fast-growing CAR T clinical trials have actively explored their potential application *** to the data from the *** website,China became the country with the most registered CAR T trials in September *** of June 30,2020,the number of registered CAR T trials in China has reached *** addition,as many as 150 other CAR T trials have been registered on *** CAR T therapy is flourishing in China,there are still some problems that cannot be *** this review,we aim to systematically summarize the clinical practice of CAR T-cell therapy in *** review will provide an informative reference for colleagues in the field,and a better understanding of the history and current situation will help us more reasonably conduct research and promote cooperation.

关键词： chimeric antigen receptor clinical trials China

Inducing immunogenic cell death in immuno-oncological therapies

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Chinese Journal of Cancer Research 2022年第1期34卷 1-10页

作者： Dongdong Ti Xin Yan jianshu wei Zhiqiang Wu Yao Wang weidong Han Department of Bio-therapeutic the First Medical CenterChinese PLA General HospitalBeijing 100853China

Immunotherapy has revolutionized cancer treatment and substantially improved patient outcomes with respect to multiple types of ***,most patients cannot benefit from such therapies,mainly due to the intrinsic low immunogenicity of cancer cells(CCs)that allows them to escape recognition by immune cells of the *** cell death(ICD),which is a form of regulated cell death,engages in a complex dialogue between dying CCs and immune cells in the tumor microenvironment(TME),ultimately evoking the damage-associated molecular pattern(DAMP)signals to activate tumor-specific *** ICD inducers mediate the death of CCs and improve both antigenicity and *** the same time,they reprogram TME with a“cold-warmhot”immune status,ultimately amplifying and sustaining dendritic cell-and T cell-dependent innate sensing as well as the antitumor immune *** this review,we discuss how to stimulate ICD based upon the biological properties of CCs that have evolved under diverse stress ***,we highlight how this dynamic interaction contributes to priming tumor immunogenicity,thereby boosting anticancer immune *** believe that a deep understanding of these ICD processes will provide a framework for evaluating its vital role in cancer immunotherapy.

关键词： Immunogenic cell death damage-associated molecular pattern tumor immunogenicity antitumor immune responses

Adaptive T cell immunotherapy in cancer

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Science China(Life Sciences) 2021年第3期64卷 363-371页

作者： Dongdong Ti Miaomiao Bai Xiaolei Li jianshu wei Deyun Chen Zhiqiang Wu Yao Wang weidong Han Bio-therapeutic Department Chinese PLA General HospitalBeijing 100853China

Impaired tumor-specific effector T cells contribute to tumor progression and unfavorable clinical outcomes. As a compensatoryT cell-dependent cancer immunoediting strategy, adoptive T cell therapy (ACT) has achieved encouraging therapeutic results,and this strategy is now on the center stage of cancer treatment and research. ACT involves the ex vivo stimulation and expansionof tumor-infiltrating lymphocytes (TILs) with inherent tumor reactivity or T cells that have been genetically modified to expressthe cognate chimeric antigen receptor or T cell receptor (CAR/TCR), followed by the passive transfer of these cells into alymphodepleted host. Primed T cells must provide highly efficient and long-lasting immune defense against transformed cellsduring ACT. Anin-depth understanding of the basic mechanisms of these living drugs can help us improve upon currentstrategies and design better next-generation T cell-based immunotherapies. From this perspective, we provide an overview ofcurrent developments in different ACT strategies, with a focus on frontier clinical trials that offer a proof of principle. Meanwhile,insights into the determinants of ACT are discussed, which will lead to more rational, potent and widespread applicationsin the future.

关键词： adoptive T cell therapy tumor-infiltrating lymphocytes chimeric antigen receptor T cell receptor

Identification of NOXA as a pivotal regulator of resistance to CAR T-cell therapy in B-cell malignancies

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Signal Transduction and Targeted Therapy 2022年第5期7卷 1634-1643页

作者： Xin Yan Deyun Chen Yao Wang Yelei Guo Chuan Tong jianshu wei Yajing Zhang Zhiqiang Wu weidong Han School of Medicine Nankai UniversityTianjinChina Department of Bio-therapeutic the First Medical CenterChinese PLA General HospitalBeijingChina National Clinical Research Center for Hematologic Diseases the First Affiliated Hospital of Soochow UniversitySuzhouChina

Despite the remarkable success of chimeric antigen receptor(CAR)T-cell therapy for treating hematologic malignancies,resistance and recurrence still occur,while the markers or mechanisms underlying this resistance remain poorly ***,via an unbiased genome-wide CRISPR/Cas9 screening,we identified loss of NOXA,a B-cell lymphoma 2(BCL2)family protein in B-cell malignancies,as a pivotal regulator of resistance to CAR T-cell therapy by impairing apoptosis of tumor cells both in vitro and in ***,low NOXA expression in tumor samples was correlated with worse survival in a tandem CD19/20 CAR T clinical trial in relapsed/refractory B-cell lymphoma.

关键词： CRISPR/Cas9 NOXA malignancies

Characteristics of premanufacture CD8^(+) T cells determine CAR-T efficacy in patients with diffuse large B-cell lymphoma

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Signal Transduction and Targeted Therapy 2023年第11期8卷 5528-5538页

作者： Yao Wang Chuan Tong Yuting Lu Zhiqiang Wu Yelei Guo Yang Liu jianshu wei Chunmeng Wang Qingming Yang weidong Han Department of Bio-Therapeutic The First Medical CenterChinese PLA General HospitalBeijingChina Changping Laboratory BeijingPR China National Clinical Research Center for Hematologic Diseases The First Affiliated Hospital of Soochow UniversitySuzhouChina

Although chimeric antigen receptor(CAR)T cells have become an important treatment option for patients with relapsed/refractory B-cell malignancies,more than 60%of patients with diffuse large B-cell lymphoma(DLBCL)treated with CAR-T cell therapies fail to achieve a durable *** reveal changes in CAR-T cell therapy and identify response biomarkers,we conducted a retrospective analysis of pre-manufacture source T cells and CAR-T cell products and their association with outcome in 58 patients with r/rDLBCL who received tandem CD19/CD20 CAR-T cell *** performed bulk RNA-Seq,single-cell RNA-Seq,and paired T cell receptor sequencing on CAR-T cell products and pre-manufacture T cells from DLBCL *** note that a CD8+stem cell-like memory T cell population with a higher proportion and enhanced activating capacity of the CAR-T cell products was key to achieving durable clinical *** analysing autologously-derived,pre-manufacture T cells,our data suggest that heterogeneity in the cellular and molecular features of pre-manufacture T cells contribute to the variation in efficacy after CAR-T cell therapy in *** differences in anti-tumour efficacy of CAR-T cells among patients with different clinical outcomes appear to be due to the loss of CCR7 gene expression,coupled with increased expression of activation-and inhibitor-related genes in the CD8+naïve-T cell populations among the apheresis T cells from patients with a poor molecular *** findings significantly advance our understanding of the underlying molecular determinants of pre-manufacture T cell function.

关键词： patients lymphoma manufacture

The model of cytokine release syndrome in CAR T-cell treatment for B-cell non-Hodgkin lymphoma

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Signal Transduction and Targeted Therapy 2020年第1期5卷 1295-1303页

作者： jianshu wei Yang Liu Chunmeng Wang Yajing Zhang Chuan Tong Guanghai Dai wei Wang John E.J.Rasko J.Joseph Melenhorst Wenbin Qian Aibin Liang weidong Han Department of Bio-therapeutic the First Medical CenterChinese PLA General Hospital100853 BeijingChina Department of Oncology the first Medical CenterChinese PLA General Hospital100853 BeijingChina State Key Laboratory of Biotherapy and Cancer Center West China HospitalSichuan UniversityChengdu 610041China Collaborative Innovation Center for Biotherapy Chengdu 610041China Department of Cell and Molecular Therapies Royal Prince Alfred HospitalSydneyNSW 2006Australia Gene and Stem Cell Therapy Program Centenary InstituteUniversity of SydneySydneyNSW 2006Australia Central Clinical School Faculty of Medicine and HealthThe University of SydneyCamperdownNSW 2050Australia Department of Pathology and Laboratory Medicine Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaPA 19104-515USA Department of Hematology The Second Affiliated HospitalCollege of MedicineZhejiang UniversityHangzhou 310009China Department of Hematology Shanghai Tongji HospitalTongji University School of MedicineShanghai 200065China State Key Laboratory of Kidney Diseases National Clinical Research Center for Kidney Diseases100853 BeijingChina

Chimeric antigen receptor T(CAR T)cell therapy has demonstrated efficacy in the treatment of haematologic ***,the accompanying adverse events,the most common of which is cytokine release syndrome(CRS),substantially limit its wide *** to its unique physiological characteristics,CRS in CAR T-cell treatment for B-cell non-Hodgkin lymphoma(BNHL)may exhibit some special *** existing guidelines had greatly promoted the recognition and management of CRS,many recommendations are not fully applicable to ***,it is imperative to identify responses that are specific to CRS observed following CAR T treatment for *** on underlying biological processes and known pathophysiological mechanisms,we tentatively propose a new model to illustrate the occurrence and evolution of CAR T-cell-therapy-related CRS in *** this model,tumour burden and bone marrow suppression are considered determinants of *** phenomena after CAR T-cell infusion(such as local inflammatory response)are further *** proposed model will help us better understand the basic biology of CRS and recognize and manage it more rationally.

关键词： cytokine lymphoma treatment