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T cell metabolism in graft-versus-host disease

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Blood Science 2020年第1期2卷 16-21页

作者： Yujing Zou Benny J.Chen division of hematologic malignancies and cellular therapy/bmt Duke University Medical CenterDurhamNCUSA

Graft-versus-host disease(GVHD)is a major source of morbidity and mortality following allogeneic hematopoietic stem cell transplant(allo-HSCT),one of the most effective approaches to treat hematopoietic malignancies.1 However,current prophylaxis regimens and treatments that reduce the detrimental effect of acute GVHD can be offset by increased incidence in opportunistic infections and relapse of the primary malignancy.2 In addition,the majority of the approaches that inhibit T cell responses are non-specific,resulting in the inhibition of both alloreactive T cells and protective T cells from the ***,there is an increase in the demand to develop novel approaches that selectively target alloreactive T *** potential means to address this issue is to take advantage of the unique metabolic profile of activated T cells.

关键词： Graft-versus-host-disease Metabolism T cells

Targeting autophagy overcomes cancer-intrinsic resistance to CAR-T immunotherapy in B-cell malignancies

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Cancer Communications 2024年第3期44卷 408-432页

作者： Lu Tang Huan Zhang Fen Zhou Qiuzhe Wei Mengyi Du Jianghua Wu Chenggong Li Wenjing Luo Jie Zhou Xindi Wang Zhaozhao Chen Yinqiang Zhang Zhongpei Huang Zhuolin Wu Yuxi Wen Huiwen Jiang Danying Liao Haiming Kou Wei Xiong Heng Mei Yu Hu Institute of Hematology Union HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanHubeiP.R.China Hubei Clinical Medical Center of Cell therapy For Neoplastic Disease WuhanHubeiP.R.China Key Laboratory of Biological Targeted therapy the Ministry of EducationWuhanHubeiP.R.China Department of Thoracic Surgery Union HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanHubeiP.R.China Department of Pediatrics Union HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanHubeiP.R.China Hubei Key Laboratory of Biological Targeted therapy Union HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanHubeiP.R.China

Background:Chimeric antigen receptor T(CAR-T)therapy has substantially revolutionized the clinical outcomes of patients with hematologic malignan-cies,but the cancer-intrinsic mechanisms underlying resistance to CAR-T cells remain yet to be fully *** study aims to explore the molecular deter-minants of cancer cell sensitivity to CAR-T cell-mediated killing and to provide a better understanding of the underlying mechanisms and potential modulation to improve clinical ***:The human whole-genome CRISPR/Cas9-based knockout screening was conducted to identify key genes that enable cancer cells to evade CD19 CAR-T-cell-mediated *** in vitro cytotoxicity assays and evaluation of tumor tissue and bone marrow specimens were further conducted to confirm the role of the key genes in cancer cell susceptibility to CAR-T *** addition,the specific mechanisms influencing CAR-T cell-mediated cancer clearance were elucidated in mouse and cellular ***:The CRISPR/Cas9-based knockout screening showed that the enrich-ment of autophagy-related genes(ATG3,BECN1,and RB1CC1)provided protec-tion of cancer cells from CD19 CAR-T cell-mediated *** findings were further validated by in vitro cytotoxicity assays in cells with genetic and pharmacological inhibition of ***,higher expression of the three autophagy-related proteins in tumor samples was correlated with poorer respon-siveness and worse survival in patients with relapsed/refractory B-cell lymphoma after CD19 CAR-T *** RNA sequencing analysis of bone marrow samples from B-cell leukemia patients also suggested the clinical relevance of autophagy to the therapeutic response and relapse after CD19 CAR-T cell *** inhibition of autophagy and knockout of RB1CC1 could dramatically sensitize tumor cells to CD19 CAR-T cell-mediated killing in mouse models of both B-cell leukemia and ***,our study revealed that cancer-intrinsic

关键词： CAR-T resistance Autophagy Immune evasion Apoptosis Chemotaxis

Metabolic alterations and the potential for targeting metabolic pathways in the treatment of multiple myeloma

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Journal of Cancer Metastasis and Treatment 2019年第4期4卷 1-16页

作者： Dustin Rizzieri Barry Paul Yubin Kang division of hematological malignancies and cellular therapy Duke University Medical Center Durham NC 27710 USA

Metabolism is defined as the collection of complex biochemical processes that living cells use to generate energy and maintain their growth and survival. Metabolism encompasses the synthesis and breakdown of glucose, fatty acids, and amino acids;the generation of energy (ATP);and oxidative phosphorylation. In cancer cells, metabolism can be commandeered to promote tumor growth and cellular proliferation. These alterations in metabolism have emerged as an additional hallmark of various cancers. In this review we focus on metabolic alterations in multiple myeloma (MM) - a malignancy of plasma cells - including derangements in glycolysis, gluconeogenesis, the tricarboxylic acid cycle, oxidative phosphorylation, and fatty acid/amino acid synthesis and degradation. Particular focus is given to metabolic alterations that contribute to myeloma cell growth, proliferation and drug resistance. Finally, novel approaches that target metabolic pathways for the treatment of MM are discussed.

关键词： Metabolism alterations multiple myeloma treatment

Dynamic immune profiling identifies the stronger graft-versus-leukemia (GVL) effects with haploidentical allografts compared to HLA-matched stem cell transplantation

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cellular & Molecular Immunology 2021年第5期18卷 1172-1185页

作者： Huidong Guo Ying-Jun Chang Yan Hong Lan-Ping Xu Yu Wang Xiao-Hui Zhang Ming Wang Huan Chen Yu-Hong Chen Feng-Rong Wang Wei-Han Yu-Qian Sun Chen-Hua Yan Fei-Fei Tang Xiao-Dong Mo Kai-Yan Liu Xiao-Jun Huang Peking University People’s Hospital&Peking University Institute of Hematology National Clinical Research Center for Hematologic DiseaseBeijing Key Laboratory of Hematopoietic Stem Cell TransplantationNo.11 South Street of XizhimenXicheng District100044BeijingChina Peking-Tsinghua Center for Life Sciences 100871BeijingChina Research Unit of Key Technique for Diagnosis and Treatments of hematologic malignancies Chinese Academy of Medical Sciences2019RU029BeijingChina

Haploidentical stem cell transplantation(haplo-SCT)achieves superior or at least comparable clinical outcomes to HLA-matched sibling donor transplantation(MSDT)in treating hematological *** define the underlying regulatory dynamics,we analyzed time courses of leukemia burden and immune abundance of haplo-SCT or MSDT from multiple ***,we employed two nonirradiated leukemia mouse models which carried human AML-ETO or MLL-AF9 fusion gene to establish haplo-identical and major histocompatibility(MHC)-matched transplantation models and investigated the immune cell dynamic response during leukemia development in *** found that haplo-matching the MHCs of leukemia cells with recipient mouse T cells prolonged leukemic mice survival and reduced leukemia *** stronger graft-versus-leukemia activity in haplo-SCT group mainly induced by decreased apoptosis and increased cytotoxic cytokine secretion including tumor necrosis factor–α,interferon-γ,pore-forming proteins and CD107a secreted by T cells or natural killer ***,we conducted a prospective clinical trial which enrolled 135 patients with t(8;21)acute myeloid leukemia that displayed minimal residual disease before transplantation and underwent either haplo-SCT or *** results showed that the haplo-SCT slowed the kinetics of the leukemia burden in vivo and reduced the cumulative incidence of relapse compared with *** vivo experiments showed that,1 year after transplantation,cytotoxic T lymphocytes from the haplo-SCT group had higher cytotoxicity than those from the MSDT group during the same *** results unraveled the role of immune cells in superior antileukemia effects of haplo-SCT compared with MSDT.

关键词： Graft-versus-leukemia Haplo-SCT MSDT AML MRD

Recalcitrant Cutaneous Mastocytosis Treated With Genetically Informed Targeted therapy:A Case Report

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International Journal of Dermatology and Venereology 2023年第2期6卷 107-109页

作者： Laura Gleason Volkan Tekmen Alexa Cohen Safiyyah Bhatti Burcu Beksac Jisun Cha Pierluigi Porcu Neda Nikbakht Department of Dermatology and Cutaneous Biology Thomas Jefferson UniversityPhiladelphiaPA 19107USA division of hematologic malignancies and Hematopoietic Stem Cell Transplant Department of Medical OncologySidney Kimmel Cancer CenterThomas Jefferson UniversityPhiladelphiaPA 19107USA Department of Dermatopathology Schweiger Dermatology GroupNew YorkNY 10006USA

Introduction:Mastocytosis,a clonal proliferation of mast cells commonly involving the skin and bone marrow,has a varied clinical presentation ranging from cutaneous lesions to systemic *** mastocytosis is managed symptomatically,but systemic mastocytosis is treated with targeted therapy against the mutated receptor tyrosine kinase c-KIT,the pathogenic driver of ***,there are no guidelines for the treatment of cutaneous mastocytosis refractory to symptomatic *** herein report a method to select genetically informed therapy for symptomatic and recalcitrant cutaneous *** presentation:We performed a mutational analysis of dermal mast cells after enrichment by laser capture in a 23-year-old woman with recalcitrant cutaneous *** analysis revealed a aspartic acid to valine substitution at codon 816(D816V)mutation in the protein *** on these results,we initiated treatment with the multi-kinase/KIT inhibitor midostaurin,a treatment effective against the D816V c-KIT *** 3 months of treatment,the patient exhibited a reduction in the number and size of cutaneous lesions and reported resolution of pruritus and decreased severity of other mast cell-related ***:The treatment of mastocytosis relies heavily on whether the disease is limited to the skin or ***,there are no guidelines for cutaneous mastocytosis that does not respond to symptomatic *** the present report describing a patient with recalcitrant cutaneous mastocytosis,we describe a strategy in which skin mutational analysis is used to guide the selection of targeted ***:Performing mast cell mutational analyses in the skin provides a means to select targeted therapy for symptomatic and refractory cutaneous mastocytosis.

关键词： mastocytosis c-KIT molecular genetics targeted therapy midostaurin

Preclinical evaluation of cyclophosphamide and fludarabine combined with CD19 CAR-T in the treatment of B-cell hematologic malignancies in vivo

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Oncology Research 2024年第6期32卷 1109-1118页

作者： ZHIGANG XIA MENGYAO TIAN YUCAI CHENG WENFANG YI ZEFAN DU TIANWEN LI YUCHEN WEN LINDI LI YONG LIU CHUN CHEN Pediatric Hematology Laboratory Division of Hematology/OncologyDepartment of PediatricsThe Seventh Affiliated Hospital of Sun Yat-sen UniversityShenzhen518107China Scientific Research Center The Seventh Affiliated Hospital of Sun Yat-sen UniversityShenzhen518107China

Background:Chimeric antigen receptor T(CAR-T)cell therapy has achieved marked therapeutic success in ameliorating hematological ***,there is an extant void in the clinical guidelines concerning the most effective chemotherapy regimen prior to chimeric antigen receptor T(CAR-T)cell therapy,as well as the optimal timing for CAR-T cell infusion *** and Methods:We employed cell-derived tumor xenograft(CDX)murine models to delineate the optimal pre-conditioning chemotherapy regimen and timing for CAR-T cell ***,transcriptome sequencing was implemented to identify the therapeutic targets and elucidate the underlying mechanisms governing the treatment ***:Our preclinical in vivo evaluation determined that a combination of cyclophosphamide and fludarabine,followed by the infusion of CD19 CAR-T cells five days subsequent to the chemotherapy,exerts the most efficacious therapeutic effect in B-cell hematological ***,RNA-seq data indicated that the therapeutic efficacy predominantly perturbs tumor cell metabolism,primarily through the inhibition of key mitochondrial targets,such as C-Jun Kinase enzyme(C-JUN).Conclusion:In summary,the present study offers critical clinical guidance and serves as an authoritative reference for the deployment of CD19 CAR-T cell therapy in the treatment of B-cell hematological malignancies.

关键词： CD19 CAR-T B-cell hematologic malignancies Metabolism In vivo

脐血间充质干细胞的生物学特征及其对造血干/祖细胞体外扩增的支持作用

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中华血液学杂志 2005年第2期26卷 65-68页

作者：王丽娟张叶萍王金福吴亦凡项盈解纯刚贾冰冰 Jenny Harrington IanK. McNiece 浙江大学生命科学学院浙江大学附属妇产科医院 Johns Hopkins Oncology Center Division of Hematologic MalignanciesBaltimoreMD21231USA

目的探讨脐血间充质干细胞(MSC)的生物学特征及其对造血干/祖细胞体外扩增的支持作用。方法用液体培养法分离脐血贴壁细胞,采用ELISA方法检测贴壁细胞条件培养液中细胞因子的表达;用流式细胞术分析其免疫表型特征;在成软骨细胞诱导培养... 详细信息

目的探讨脐血间充质干细胞(MSC)的生物学特征及其对造血干/祖细胞体外扩增的支持作用。方法用液体培养法分离脐血贴壁细胞,采用ELISA方法检测贴壁细胞条件培养液中细胞因子的表达;用流式细胞术分析其免疫表型特征;在成软骨细胞诱导培养条件下诱导细胞分化,并用RTPCR方法检测分化后细胞原胶原Ⅱ型基因的表达。采用分阶段共培养方法观察脐血贴壁细胞对CD34+细胞体外扩增的支持作用。结果脐血单个核细胞纤维样细胞集落形成率为(3.5±0.7)/106。脐血MSC体外至少可以扩增15代。没有分化的脐血MSC表型为CD13、CD29、CD90、CD105、CD166、SH2、SH3和SH4阳性,CD45、CD34和CD14阴性;脐血MSC培养上清中干细胞因子、IL6和肿瘤坏死因子α检测阳性。在成软骨细胞诱导培养基培养条件下,脐血MSC原胶原Ⅱ型基因mRNA表达阳性。脐血MSC与CD34+细胞共掊养14d,CD34+细胞扩增率高于未共培养组4倍。结论脐血MSC具有类似于成体骨髓MSC的特征,对造血干细胞增殖有明显的支持作用。

关键词：脐血体外扩增 CD34^+细胞造血干/祖细胞阳性间充质干细胞贴壁细胞 SH3 共培养成体

Navigating the complex terrain of hepatitis B virus reactivation in the era of Bruton tyrosine kinase inhibitors

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World Journal of Gastroenterology 2024年第21期30卷 2748-2750页

作者： Wei-Nung Liu Ming-Shen Dai Felicia Lin Gen-Min Lin Department of Medicine Tri-Service General HospitalTaipei 114Taiwan division of Hematology/Oncology Department of Internal MedicineNational Defense Medical CenterTaipei 114Taiwan Community Care Minnesota OncologyMinneapolisMN 55404United States Department of Medicine Hualien Armed Forces General HospitalHualien City 970Taiwan

In this editorial,we offer a summary of the risk associated with hepatitis B reactivation(HBVr)in the setting of both solid and hematologic malignancies treated with Bruton tyrosine kinase(BTK)inhibitors,with insights derived from current ***,we emphasize the critical need for a framework regarding robust risk evaluation in patients undergoing such *** framework is essential for identifying those at increased risk of HBVr,enabling healthcare providers to implement proactive measures to prevent reactivation and ensure the safe administration of BTK inhibitor therapy.

关键词： Hepatitis B virus reactivation Bruton tyrosine kinase inhibitors hematologic malignancies Solid tumors Prophylaxis guidelines

Development of allogeneic hematopoietic stem cell transplantation in 2022:Regenerating“Groot”to heal the world

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The Innovation 2023年第1期4卷 34-35页

作者： Meng Lv Mengzhu Shen Xiaodong Mo Peking University People’s Hospital Peking University Institute of HematologyNational Clinical Research Center for Hematologic DiseaseBeijing Key Laboratory of Hematopoietic Stem Cell TransplantationBeijing 100044China Research Unit of Key Technique for Diagnosis and Treatments of hematologic malignancies Chinese Academy of Medical SciencesBeijing 100044China Research Unit of Key Technique for Diagnosis and Treatments of hematologic malignancies Chinese Academy of Medical Sciences2019RU029Beijing 100044China

Allogeneic hematopoietic stem cell transplantation(allo-HSCT),the pioneer and mainstream form of cellular therapy,represents the only curative or preferred treatment for various malignant and nonmalignant disorders or facilitates organ transplantation by reconstituting the new blood and immune system of a patient with donor’s regenerative HSCs,similar to the comics character“Groot,”who has an incredible regeneration *** annual cases of allo-HSCT in China's Mainland increased from 10042 in 2020 to 12744 in 2021,suggesting that the negative impact of the severe acute respiratory syndrome coronavirus 2 pandemic might be eliminated,while Europe and North American registries reported 18796 and 8326 cases in 2020,respectively.1 In addition,cutting-edge progress in other cellular therapies,including chimeric antigen receptor T(CAR-T)cells,mesenchymal stromal cells,and specific cytotoxic T lymphocyte(CTL)cells,promotes the combination of allo-HSCT with these therapies to compose the new chapter“Strong Together,Guardians of Life”to save more patients worldwide.

关键词： hematopoietic generating mainland