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A DL-4- and TNFα-based culture system to generate high numbers of nonmodified or genetically modified immunotherapeutic human T-lymphoid progenitors

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Cellular & Molecular Immunology 2021年第7期18卷 1662-1676页

作者： Ranjita Devi Moirangthem Kuiying Ma Sabrina Lizot Anne Cordesse Juliette Olivré Corinne de Chappedelaine Akshay Joshi Agata Cieslak John Tchen Nicolas Cagnard Vahid Asnafi Antonio Rausell Laura Simons Julien Zuber Tom Taghon Frank J.T.Staal Françoise Pflumio Emmanuelle Six Marina Cavazzana Chantal Lagresle-Peyrou tayebeh soheili Isabelle André Universitéde Paris Imagine InstituteLaboratory of Human LymphohematopoiesisINSERM UMR 1163ParisFrance Laboratory of Onco-Hematology AP-HPHôpital Necker-Enfants Malades.ParisFrance Universitéde Paris Institut Necker-Enfants Malades(INEM)INSERM UMR 1151ParisFrance Plateforme Bio-informatique UniversitéParis DescartesStructure Fédérative de Recherche NeckerINSERM US24/CNRS UMS 3633ParisFrance Universitéde Paris Imagine InstituteLaboratory of Clinical BioinformaticsINSERM UMR 1163ParisFrance Department of Biotherapy Clinical Investigation Center AP-HPHôpital Necker-Enfants MaladesParisFrance Department of Adult Kidney Transplantation AP-HPHôpital NeckerParisFrance Cancer Research Institute Ghent(CRIG) GhentBelgium Department of Diagnostic Sciences Faculty of Medicine and Health SciencesGhent UniversityGhentBelgium Department of Immunohematology&Blood Transfusion Leiden University Medical CenterLeidenthe Netherlands Team Niche and Cancer in Hematopoiesis Universitéde Paris and UniversitéParis-SaclayINSERMiRCM/IBFJ CEAUMR StabilitéGénétique Cellules Souches et RadiationsFontenay-aux-RosesFrance

Several obstacles to the production,expansion and genetic modification of immunotherapeutic T cells in vitro have restricted the widespread use of T-cell *** the context of HSCT,delayed naïve T-cell recovery contributes to poor outcomes.A novel approach to overcome the major limitations of both T-cell immunotherapy and HSCT would be to transplant human T-lymphoid progenitors(HTLPs),allowing reconstitution of a fully functional naïve T-cell pool in the patient ***,it is challenging to produce HTLPs in the high numbers required to meet clinical ***,we found that adding tumor necrosis factor alpha(TNFα)to a DL-4-based culture system led to the generation of a large number of nonmodified or genetically modified HTLPs possessing highly efficient in vitro and in vivo T-cell potential from either CB HSPCs or mPB HSPCs through accelerated T-cell differentiation and enhanced HTLP cell cycling and *** study provides a clinically suitable cell culture platform to generate high numbers of clinically potent nonmodified or genetically modified HTLPs for accelerating immune recovery after HSCT and for T-cell-based immunotherapy(including CAR T-cell therapy).

关键词： Human T-lymphoid progenitor Tumor necrosis factor alpha Delta-like ligand 4 Hematopoietic stem and progenitor cells Mobilized peripheral blood

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