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Relapse after CAR-T cell therapy in b-cell malignancies: challenges and future approaches

Journal of Zhejiang University-Science b(biomedicine & biotechnology) 2022年第10期23卷 793-811页

作者： Tianning GU Meng ZHU He HUANG Yongxian HU bone Marrow Transplantation Center the First Affiliated HospitalZhejiang University School of MedicineHangzhou 310003China Liangzhu Laboratory Zhejiang University Medical CenterHangzhou 311121China Institute of Hematology Zhejiang UniversityHangzhou 310058China Zhejiang Province Engineering Laboratory for Stem cell and Immunity Therapy Hangzhou 310058China

Chimeric antigen receptor-T(CAR-T)cell therapy,as a novel cellular immunotherapy,has dramatically reshaped the landscape of cancer treatment,especially in hematological malignancies.However,relapse is still one of the most troublesome obstacles to achieving broad clinical application.The intrinsic factors and superior adaptability of tumor cells mark a fundamental aspect of relapse.The unique biological function of CAR-T cells governed by their special CAR construction also affects treatment efficacy.Moreover,complex cross-interactions among CAR-T cells,tumor cells,and the tumor microenvironment(TME)profoundly influence clinical outcomes concerning CAR-T cell function and persistence.Therefore,in this review,based on the most recent discoveries,we focus on the challenges of relapse after CAR-T cell therapy in b-cell malignancies from the perspective of tumor cells,CAR-T cells,and the TME.We also discuss the corresponding basic and clinical approaches that may overcome the problem in the future.We aim to provide a comprehensive understanding for scientists and physicians that will help improve research and clinical practice.

关键词： Chimeric antigen receptor-T(CAR-T) b-cell malignancies Mechanisms of relapse Strategy

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SY-1530, a highly selective bTK inhibitor, effectively treats b-cell malignancies by blocking b-cell activation

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Cancer biology & Medicine 2022年第7期19卷 995-1007页

作者： Liao Wang Yinghui Sun Xijie Liu Hongjuan Li Chang Lu Ronghui Yang Chuanzhen Yang binghui Li Department of biochemistry and Molecular biology School of Basic Medical SciencesCapital Medical UniversityBeijing 100069China Advanced Innovation Center for Human brain Protection Capital Medical UniversityBeijing 100069China Shouyao Holdings Co. LtdBeijing 100195China

Objective:b-cell antigen receptor(bCR)signaling is required to maintain the physiological functions of normal b cells and plays an important pathogenic role in b-cell malignancies.bruton tyrosine kinase(bTK),a critical mediator of bCR signaling,is an attractive target for the treatment of b-cell malignancies.This study aimed to identify a highly potent and selective bTK inhibitor.Methods:Homogeneous time-resolved fluorescence assays were used to screen bTK inhibitors.Typhoon fluorescence imaging and Western blot analysis were used to confirm the effects of SY-1530 on the bCR signaling pathway.Additionally,the anti-tumor activities of SY-1530 were evaluated in TMD8 xenografts and spontaneous canine b-cell lymphoma.Results:We found a novel irreversible and non-competitive inhibitor of bTK,SY-1530,which provided dose-dependent and timedependent inhibition.SY-1530 selectively bound to bTK rather than inducible T-cell kinase;consequently,it did not significantly affect T-cell receptor signaling and caused limited off-target effects.SY-1530 blocked the bCR signaling pathway through downregulation of bTK activity,thus leading to impaired phosphorylation of bTK and its downstream kinases.Moreover,SY-1530 induced apoptosis in a caspase-dependent manner and efficaciously inhibited tumor growth in mouse xenograft models of b-cell malignancy(Pb-cell lymphoma.Conclusions:SY-1530 is an irreversible and selective bTK inhibitor that shows inhibitory effects on b-cell malignancies by blocking the bCR signaling pathway.Therefore,it may be a promising therapeutic approach for the treatment of b-cell malignancies.

关键词： SY-1530 bTK irreversible inhibitor bCR signaling b-cell malignancies

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Selective killing of b lymphoma cells by mbAFF-targeted delivery of PinX1

Selective killing of B lymphoma cells by mBAFF-targeted deli...

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中国生物化学与分子生物学会第十届会员代表大会暨全国学术...

作者： Li Zhang Yu Jiang Yingru Zheng Yijun Zeng Gang Huang Dongbo Liu Gengze Wu Min Gao Chaohui Yang Xiaodong Shen Xiaojin Yan Fengtian He Department of biochemistry and Molecular biology College of Basic Medical SciencesThird Military Medical University Department of Obstetrics and Gynecology Research Institute of SurgeryDaping HospitalThird Military Medical University

Increased expression of bAFF(b cell-activating factor belonging to the TNF family) and its receptors has been identified in numerous b-cell malignancies.A bAFF mutant,mbAFF,may function as a competitive inhibitor of bAFF to treat b-cell malignancies and may serve as a novel ligand for targeted anti-cancer therapy.Pin2/TRF1- interacting protein X1(PinX1) is non-toxic to cells but toxic when internalized,translocated from endosomes to cytosol,and located in the nucleolar regions via blockade of telomerase activity.In this study,we generated novel antitumor proteins containing mbAFF,a polyarginine tract, and PinX1/C/N to target lymphoma cells in vitro and in

关键词： PinX1 Mutant bAFF Polyarginine tract b-cell malignancies

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