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A giant step forward: chimeric antigen receptor T-cell therapy for lymphoma

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Frontiers of Medicine 2020年第6期14卷 711-725页

作者： Houli Zhao Yiyun Wang Elaine Tan Su Yin Kui Zhao Yongxian Hu He Huang Bone Marrow Transplantation Center The First Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhou 310000China zhejiang province engineering laboratory for stem cell and immunotherapy Hangzhou 310000China Institute of Hematology Zhejiang UniversityHangzhou 310000China PET-CT Center The First Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhou 310000China

The combination of the immunotherapy(i.e.,the use of monoclonal antibodies)and the conventional chemotherapy increases the long-term survival of patients with ***,for patients with relapsed or treatment-resistant lymphoma,a novel treatment approach is urgently *** antigen receptor T(CAR-T)cells were introduced as a treatment for these *** on recent clinical data,approximately 50%of patients with relapsed or refractory B-cell lymphoma achieved complete remission after receiving the CD19 CAR-T cell ***,clinical data revealed that some patients remained in remission for more than two years after the CAR-T cell *** than the CD19-targeted CAR-T,the novel target antigens,such as CD20,CD22,CD30,and CD37,which were greatly expressed on lymphoma cells,were studied under preclinical and clinical evaluations for use in the treatment of ***,the CAR-T therapy was usually associated with potentially lethal adverse effects,such as the cytokine release syndrome and the ***,optimizing the structure of CAR,creating new drugs,and combining CAR-T cell therapy with stem cell transplantation are potential solutions to increase the effectiveness of treatment and reduce the toxicity in patients with lymphoma after the CAR-T cell therapy.

关键词： chimeric antigen receptor T(CAR-T)cell lymphoma cytokine release syndrome(CRS) immune effector cell-associated neurotoxicity syndrome(ICANS)

RIG-I： a multifunctional protein beyond a pattern recognition receptor

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Protein & cell 2018年第3期9卷 246-253页

作者： Xiao-xiao Xu Han Wan Li Nie Tong Shao Li-xin Xiang Jian-zhong Shao Key laboratory for cell and Gene engineering of zhejiang province College of Life Sciences Zhejiang University Hangzhou 310058 China laboratory for Marine Biology and Biotechnology Qingdao National Laboratory for Marine Science and Technology Qingdao 266235 China

It was widely known that retinoic acid inducible gene I （RIG-I） functions as a cytosolic pattern recognition receptor that initiates innate antiviral immunity by detecting exogenous viral RNAs. However, recent stud- ies showed that RIG-I participates in other various cellular activities by sensing endogenous RNAs under different circumstances. For example, RIG-I facilitates the therapy resistance and expansion of breast cancer cells and promotes T cell-independent B cell activation through interferon signaling activation by recognizing non-coding RNAs and endogenous retroviruses in certain situations. While in hepatocellular carcinoma and acute myeloid leukemia, RIG-I acts as a tumor suppressor through either augmenting STAT1 activation by competitively binding STAT1 against its negative regulator SliP1 or inhibiting AKT-mTOR signaling pathway by directly interacting with Src respectively. These new findings suggest that RIG-I plays more diverse roles in various cellular life activities, such as cell proliferation and differentiation, than previously known. Taken together, the function of RIG-I exceeds far beyond that of a pattern recognition receptor.

关键词： RIG-I viral RNA endogenous RNA immunity cancer

Signaling pathways in the regulation of cytokine release syndrome in human diseases and intervention therapy

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Signal Transduction and Targeted Therapy 2021年第11期6卷 3230-3245页

作者： Xia Li Mi Shao Xiangjun Zeng Pengxu Qian He Huang Bone Marrow Transplantation Center The First Affiliated HospitalZhejiang University School of MedicineHangzhouPeople’s Republic of China Liangzhu laboratory Zhejiang University Medical Center1369 West Wenyi RoadHangzhou311121People’s Republic of China Institute of Hematology Zhejiang UniversityHangzhouZhejiangPeople’s Republic of China zhejiang province engineering laboratory for stem cell and Immunity Therapy HangzhouZhejiangPeople’s Republic of China Center of stem cell and Regenerative Medicine Zhejiang University School of MedicineHangzhouPeople’s Republic of China

Cytokine release syndrome(CRS)embodies a mixture of clinical manifestations,including elevated circulating cytokine levels,acute systemic inflammatory symptoms and secondary organ dysfunction,which was first described in the context of acute graft-versus-host disease after allogeneic hematopoietic stem-cell transplantation and was later observed in pandemics of influenza,SARS-CoV and COVID-19,immunotherapy of tumor,after chimeric antigen receptor T(CAR-T)therapy,and in monogenic disorders and autoimmune ***,severe CRS is a very significant and life-threatening complication,which is clinically characterized by persistent high fever,hyperinflammation,and severe organ ***,CRS is a double-edged sword,which may be both helpful in controlling tumors/viruses/infections and harmful to the *** a high incidence and high levels of cytokines are features of CRS,the detailed kinetics and specific mechanisms of CRS in human diseases and intervention therapy remain *** the present review,we have summarized the most recent advances related to the clinical features and management of CRS as well as cutting-edge technologies to elucidate the mechanisms of *** that CRS is the major adverse event in human diseases and intervention therapy,our review delineates the characteristics,kinetics,signaling pathways,and potential mechanisms of CRS,which shows its clinical relevance for achieving both favorable efficacy and low toxicity.

关键词： cytokine release kinetics

Efficient expansion of rare human circulating hematopoietic stem/progenitor cells in steady-state blood using a polypeptide-forming 3D culture

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Protein & cell 2022年第11期13卷 808-824页

作者： Yulin Xu Xiangjun Zeng Mingming Zhang Binsheng Wang Xin Guo Wei Shan Shuyang Cai Qian Luo Honghu Li Xia Li Xue Li Hao Zhang Limengmeng Wang Yu Lin Lizhen Liu Yanwei Li Meng Zhang Xiaohong Yu Pengxu Qian He Huang Bone Marrow Transplantation Center First Affiliated HospitalZhejiang University School of MedicineHangzhou 310012China Liangzhu laboratory Zhejiang University Medical CenterHangzhou 311121China Institute of Hematology Zhejiang UniversityHangzhou 310012China zhejiang province engineering laboratory for stem cell and Immunity Therapy Hangzhou 310012China Core Facilities Zhejiang University School of MedicineHangzhou 310012China Dr.Li Dak Sum&Yip Yio Chin Center for stem cell and Regenerative Medicine Zhejiang UniversityHangzhou 310012China

Although widely applied in treating hematopoietic malignancies,transplantation of hematopoietic stem/progenitor cells(HSPCs)is impeded by HSPC *** circulating HSPCs(cHSPCs)in steady-state blood could be used as an alternative source remains largely *** we develop a three-dimensional culture system(3DCS)including arginine,glycine,aspartate,and a series of ***-day culture of peripheral blood mononuclear cells(PBMNCs)in 3DCS led to 125-and 70-fold increase of the frequency and number of CD34+***,3DCS-expanded cHSPCs exhibited the similar reconstitution rate com-pared to CD34+HSPCs in bone ***,3DCS fabricated an immunomodulatory niche,secreting cytokines as TNF to support cHSPC survival and ***,3DCS could also promote the expansion of cHSPCs in patients who failed in HSPC *** 3DCS successfully expands rare cHSPCs,providing an alternative source for the HSPC therapy,particularly for the patients/donors who have failed in HSPC mobilization.

关键词： hematopoietic stem/progenitor cell transplantation peripheral blood mononuclear cells expansion mobilization three-dimensional culture selfrenewal and multilineage differentiation

Regenerative treatment of ophthalmic diseases with stem cells:Principles,progress,and challenges

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Advances in Ophthalmology Practice and Research 2024年第2期4卷 52-64页

作者： Yifei Niu Junfeng Ji Ke Yao Qiuli Fu Eye Center of the Second Affiliated Hospital Zhejiang University School of MedicineHangzhouZhejiang ProvinceChina zhejiang Provincial Key Lab of Ophthalmology HangzhouZhejiang ProvinceChina Center of stem cell and Regenerative Medicine School of MedicineZhejiang UniversityHangzhouZhejiang ProvinceChina zhejiang Provincial Key laboratory of Tissue engineering and Regenerative Medicine HangzhouChina

Background:Degenerate eye disorders,such as glaucoma,cataracts and age-related macular degeneration(AMD),are prevalent causes of blindness and visual impairment *** eye disorders,including limbal stem cell deficiency(LSCD),dry eye diseases(DED),and retinitis pigmentosa(RP),result in symptoms such as ocular discomfort and impaired visual function,significantly impacting quality of *** therapies are limited,primarily focus on delaying disease progression,while emerging stem cell therapy directly targets ocular tissues,aiming to restore ocular function by reconstructing ocular *** text:The utilization of stem cells for the treatment of diverse degenerative ocular diseases is becoming increasingly significant,owing to the regenerative and malleable properties of stem cells and their functional ***,stem cell therapy for ophthalmopathy involves various cell types,such as embryonic stem cells(ESCs),induced pluripotent stem cells(iPSCs),mesenchymal stem cells(MSCs),and retinal progenitor cells(RPCs).In the current article,we will review the current progress regarding the utilization of stem cells for the regeneration of ocular tissue covering key eye tissues from the cornea to the *** therapies aim to address the loss of functional cells,restore damaged ocular tissue and or in a paracrine-mediated *** also provide an overview of the ocular disorders that stem cell therapy is targeting,as well as the difficulties and opportunities in this ***:stem cells can not only promote tissue regeneration but also release exosomes to mitigate inflam-mation and provide neuroprotection,making stem cell therapy emerge as a promising approach for treating a wide range of eye disorders through multiple mechanisms.

关键词： stem cell Ocular diseases Induced pluripotent stem cells Mesenchymal stem cells Cataracts Glaucoma Diabetic retinopathy Retinal degenerative diseases

Combination of CRISPR/Cas9 System and CAR-T cell Therapy:A New Era for Refractory and Relapsed Hematological Malignancies

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Current Medical Science 2021年第3期41卷 420-430页

作者： Ke-jia HU Elaine Tan Su YIN Yong-xian HU He HUANG Bone Marrow Transplantation Center the First Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhou 310003China zhejiang province engineering laboratory for stem cell and Immunity Therapy Hangzhou 310003China Institute of Hematology Zhejiang UniversityHangzhou 310003China zhejiang laboratory for Systems&Precision Medicine Zhejiang University Medical CenterHangzhou 310003China Liangzhu laboratory Zhejiang University Medical CenterHangzhou 311121China

Chimeric antigen receptor T(CAR-T)cell therapy is the novel treatment strategy for hematological malignancies such as acute lymphoblastic leukemia(ALL),lymphoma and multiple ***,treatment-related toxicities such as cytokine release syndrome(CRS)and immune effector cell-associated neurotoxicity syndrome(ICANS)have become significant hurdles to CAR-T *** strategies were established to alter the CAR structure on the genomic level to improve efficacy and reduce ***,the innovative gene-editing technology-clustered regularly interspaced short palindromic repeats(CRISPR)/CRISPR-associated nuclease9(Cas9)system,which particularly exhibits preponderance in knock-in and knockout at specific sites,is widely utilized to manufacture CAR-T *** application of CRISPR/Cas9 to CAR-T cell therapy has shown promising clinical results with minimal *** this review,we summarized the past achievements of CRISPR/Cas9 in CAR-T therapy and focused on the potential CAR-T targets.

关键词： chimeric antigen receptor T cell treatment clustered regularly interspaced short palindromic repeats(CRISPR)/CRISPR-associated nuclease9 gene editing immunotherapy hematologic malignancy

Cancer immunotherapy: an evolving paradigm

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Journal of zhejiang University-Science B(Biomedicine & Biotechnology) 2022年第10期23卷 791-792页

作者： Aifu LIN MOE laboratory of Biosystem Homeostasis and Protection College of Life SciencesZhejiang UniversityHangzhou 310058China Cancer Center Zhejiang UniversityHangzhou 310058China Key laboratory for cell and Gene engineering of zhejiang province Hangzhou 310058China

The inhibition of the host’s natural immune response by tumor cells was widely reported in the early phases of the development of oncology therapy,and the concept of employing the host’s immune system to treat cancer,*** immunotherapy,is not ***,as a result of early theoretical constraints,clinical application of immunotherapy did not go smoothly and lagged significantly behind radiation and *** path has been winding,but the future now seems *** research has advanced enormously as a result of the maturing of immuno-editing theory and the creation of numerous technologies,despite a number of unsuccessful endeavors and clinical *** around 1998,the US Food and Drug Administration(FDA)has approved a variety of tumor immunotherapies,including cytokines(interleukin-2,interferons),cancer vaccines(Provenge),immune checkpoint inhibitors(ipilimumab),and cellular therapies(chimeric antigen receptor-T(CAR-T)),signaling a boom in the field.

关键词： immunotherapy clinical chemotherapy

Thread-structural microneedles loaded with engineered exosomes for annulus fibrosus repair by regulating mitophagy recovery and extracellular matrix homeostasis

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Bioactive Materials 2024年第7期37卷 1-13页

作者： Shaojun Hu Meng Zhu Hongyuan Xing Yucheng Xue Jun Li Zhan Wang Zhou Zhu Miaojie Fang Zilong Li Jianbin Xu Yong He Ning Zhang Department of Orthopedic Surgery The Second Affiliated HospitalZhejiang University School of MedicineHangzhou CityZhejiang ProvincePR China Orthopedics Research Institute of zhejiang University Hangzhou CityZhejiang ProvincePR China Key laboratory of Motor System Disease Research and Precision Therapy of zhejiang province Hangzhou CityZhejiang ProvincePR China Clinical Research Center of Motor System Disease of zhejiang province PR China State Key laboratory of Fluid Power and Mechatronic Systems College of Mechanical EngineeringZhejiang UniversityHangzhou310027PR China Department of Orthopaedics The First Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhouZhejiang ProvincePR China

Low back pain is among the most grave public health concerns worldwide and the major clinical manifestation of intervertebral disc degeneration(IVDD).The destruction of annulus fibrosus(AF)is the primary cause of IVDD.A sustainable and stable treatment system for IVDD is lacking because of the special organizational structure and low nutrient supply of *** here found that IVDD results in the impaired mitochondrial function of AF tissue,and mitochondrial autophagy(mitophagy)plays a protective role in this *** therefore reported a thread-structural microneedle(T-MN)matching the ring structure of *** on the adsorption effect of laminin,our T-MN could load with bone marrow mesenchymal stem cell-derived exosomes to envelope the regulating mitophagy microRNA(miRNA 378),named as T-MN@EXO@miR􀀀*** general,we offered in situ locking in the defect site of AF to prevent nucleus pulposus leakage and promoted AF *** design of the thread structure was aimed at bionically matching the layered AF structure,thereby providing stronger *** T-MN@EXO@miR􀀀378 effectively attached to AF and slowly released therapeutic engineered exosomes,and prevented IVDD progression by restoring mitophagy,promoting AF cell proliferation and migration,and inhibiting the pathological remodeling of the extracellular *** functional system can be used as an excellent tool for sustained drug release and has a certain prospect in substituting the conventional treatment of IVDD.

关键词： Intervertebral disc degeneration Microneedle Exosomes Annulus fibrosus Mitophagy

Injectable kartogenin and apocynin loaded micelle enhances the alleviation of intervertebral disc degeneration by adipose-derived stem cell

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Bioactive Materials 2021年第10期6卷 3568-3579页

作者： Chao Yu Dongdong Li Chenggui Wang Kaishun Xia Jingkai Wang Xiaopeng Zhou Liwei Ying Jiawei Shu Xianpeng Huang Haibin Xu Bin Han Qixin Chen Fangcai Li Jianbin Tang Chengzhen Liang Nigel Slater Department of Orthopedics Surgery The Second Affiliated HospitalZhejiang University School of MedicineHangzhou CityZhejiang ProvincePR China Orthopedics Research Institute of zhejiang University Hangzhou CityZhejiang ProvincePR China Key laboratory of Motor System Disease Research and Precision Therapy of zhejiang province Hangzhou CityZhejiang ProvincePR China Key laboratory of Biomass Chemical engineering of Ministry of Education Center for Bionanoengineeringand College of Chemical and Biological EngineeringZhejiang UniversityHangzhouZhejiang310027China Department of Chemical engineering and Biotechnology University of CambridgeCambridgeUnited Kingdom

cell transplantation has been proved the promising therapeutic effects on intervertebral disc degeneration(IVDD).However,the increased levels of reactive oxygen species(ROS)in the degenerated region will impede the efficiency of human adipose-derived stem cells(human ADSCs)transplantation *** inhibits human ADSCs proliferation,and increases human ADSCs ***,we firstly devised a novel amphiphilic copolymer PEG-PAPO,which could self-assemble into a nanosized micelle and load lipophilic kartogenin(KGN),as a single complex(PAKM).It was an injectable esterase-responsive micelle,and showed controlled release ability of KGN and apocynin(APO).Oxidative stimulation promoted the esterase activity in human ADSCs,which accelerate degradation of esterase-responsive *** its monomer,the PAKM micelle possessed better bioactivities,which were attributed to their synergistic *** enhanced the viability,autophagic activation(P62,LC3 II),ECM-related transcription factor(SOX9),and ECM(Collagen II,Aggrecan)maintenance in human ***,it is demonstrated that the injection of PAKM with human ADSCs yielded higher disc height and water content in ***,PAKM micelles perform promoting cell survival and differentiation effects,and may be a potential therapeutic agent for IVDD.

关键词： Intervertebral disc degeneration Polymer-drug conjugates Mesenchymal stem cell Reactive oxygen species stem cell therapy