Generation of adult human T-cell progenitors for immunotherapeutic applications

Simons, Laura; Ma, Kuiying; Chappedelaine, Corinne de; Moiranghtem, Ranjita Devi; Elkaim, Élodie; Olivré, Juliette; Susini, Sandrine; Appourchaux, Kevin; Reimann, Christian; Sadek, Hanem; Pellé, Olivier; Cagnard, Nicolas; Magrin, Elisa; Lagresle-Peyrou, Chantal; Taghon, Tom; Rausell, Antonio; Cavazzana, Marina; André-Schmutz, Isabelle

doi:10.1016/j.jaci.2017.10.034

Cited by 16 publications

(21 citation statements)

References 10 publications

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“…This approach will be tested in a phase I/II clinical trial at Necker Children's Hospital, Paris, France, in 2019. These T precursor cells can be obtained from any source of CD34 + HSPCs (mobilized peripheral blood or cord blood) in a 1-week in vitro stromal cell-free culture system that uses the Delta-like protein 4 (DLL4)-Notch signalling pathway and pro-T cell cytokines 38,39 . Furthermore, the T precursor cells can be genetically modified using a lentiviral vector (I.A.-S., unpublished results).…”

Section: Xlinked Severe Combined Immunodeficiencymentioning

confidence: 99%

“…In addition to the standard nonmanipulated graft, each patient will receive a single dose of T cell precursors generated from donor HSPCs. If the preclinical results in murine models of SCIDs 39 are confirmed in the clinic, this procedure should solve the problem of the delayed immune reconstitution for both partially HLA-compatible HSCT and the autologous transplantation of genetically modified cells. The treatment algorithm in SCID-X1 is less clear than that described in ADA deficiency, where the toxic effects of the accumulated metabolites and the need for intracellular detoxification limit the long-term benefit of ERT and are responsible for high mortality and morbidity in recipients of non-genoidentical transplants.…”

Section: Xlinked Severe Combined Immunodeficiencymentioning

confidence: 99%

See 1 more Smart Citation

Gene therapy targeting haematopoietic stem cells for inherited diseases: progress and challenges

Cavazzana

Bushman

Miccio

et al. 2019

Nat Rev Drug Discov

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156

108

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Pioneering gene therapy trials have shown that the genetic engineering of haematopoietic stem and progenitor cells can be an alternative to allogeneic transplantation in the treatment of primary immunodeficiencies. Early trials also highlighted the risk of insertional mutagenesis and oncogene transactivation associated with the first generation of gammaretroviral vectors. These events prompted the development of safer, self-inactivating lentiviral or gammaretroviral vectors. These lentiviral vectors have been successfully used to treat over 200 patients with 10 different haematological disorders (including primary immunodeficiencies, haemoglobinopathies and metabolic disorders) and for the generation of chimeric antigen receptor-T cells for cancer therapy. However, several challenges, such as effective reconstitution during inflammation, remain if gene therapy is to be extended to more complex diseases in which haematopoietic stem and progenitor cells can be altered by the disease environment. We discuss the progress made and future challenges for gene therapy and contrast gene therapy with gene-editing strategies.

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Section: Xlinked Severe Combined Immunodeficiencymentioning

confidence: 99%

Section: Xlinked Severe Combined Immunodeficiencymentioning

confidence: 99%

Gene therapy targeting haematopoietic stem cells for inherited diseases: progress and challenges

Cavazzana

Bushman

Miccio

et al. 2019

Nat Rev Drug Discov

Self Cite

156

108

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“…19 We previously implemented a stromal cell-free culture system based on immobilized DL-4 (Notch ligand) to generate CD7 + HTLPs from either cord blood (CB) HSPCs or mobilized peripheral blood (mPB) HSPCs during a 7-day period of culture. 20,21 These progenitors displayed the phenotype and molecular signature of very immature thymic progenitors and expressed T-lineage transcriptional regulators (TCF7, IL7Rα, BCL11B, GATA3, and CD3ε). Upon transplantation into irradiated adult or nonirradiated neonate NOD/SCID/γC −/− (NSG) recipients, HTLPs seeded the thymus and generated mature, polyclonal and functional T cells.…”

Section: Introductionmentioning

confidence: 99%

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

Moirangthem

Lizot

et al. 2021

Cell Mol Immunol

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Several obstacles to the production, expansion and genetic modification of immunotherapeutic T cells in vitro have restricted the widespread use of T-cell immunotherapy. In 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 thymus. However, it is challenging to produce HTLPs in the high numbers required to meet clinical needs. Here, 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 survival. This 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).

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“…Human thymic engraftment was greatly accelerated occurring at only 4 weeks in the mice injected with day 7 adult HTLPs and persisting thereafter (as compared with 12 weeks after injection of uncultured CD34 + selected HSCs). Active human thymopoiesis was further demonstrated by the presence of human CD4+ CD8+ DP cells and enlarged thymic lobes as compared with recipients of uncultured adult HSPCs . This data provided further evidence of the ability of in vitro‐generated HTLP to accelerate T‐cell reconstitution in vivo.…”

Section: Ex Vivo Generated T‐cell Progenitors To Accelerate Reconstitmentioning

confidence: 68%

“…This system allows for the in vitro generation of large amounts of HTLPs from different CD34+ hematopoietic stem cell sources. In recent years, we have extended and improved this protocol to differentiate and expand not only neonatal cord blood (CB) but also adult CD34+ cells from granulocyte‐colony stimulation factor (G‐CSF)‐mobilized peripheral blood (mPB) . mPB is currently the main source of HSPCs in allogeneic HSCT, as adult HSPCs are available in large quantity and exhibit several advantages over CB grafts in the clinical setting.…”

Section: Ex Vivo Generated T‐cell Progenitors To Accelerate Reconstitmentioning

confidence: 99%

Concise Review: Boosting T-Cell Reconstitution Following Allogeneic Transplantation—Current Concepts and Future Perspectives

Simons

Cavazzana

André-Schmutz

2019

Stem Cells Translational Medicine

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Allogeneic hematopoietic stem cell transplantation (HSCT) is the treatment of choice for a large number of malignant and nonmalignant (inherited) diseases of the hematopoietic system. Nevertheless, non‐HLA identical transplantations are complicated by a severe T‐cell immunodeficiency associated with a high rate of infection, relapse and graft‐versus‐host disease. Initial recovery of T‐cell immunity following HSCT relies on peripheral expansion of memory T cells mostly driven by cytokines. The reconstitution of a diverse, self‐tolerant, and naive T‐cell repertoire, however, may take up to 2 years and crucially relies on the interaction of T‐cell progenitors with the host thymic epithelium, which may be altered by GvHD, age or transplant‐related toxicities. In this review, we summarize current concepts to stimulate reconstitution of a peripheral and polyclonal T‐cell compartment following allogeneic transplantation such as graft manipulation (i.e., T‐cell depletion), transfusion of ex vivo manipulated donor T cells or the exogenous administration of cytokines and growth factors to stimulate host‐thymopoiesis with emphasis on approaches which have led to clinical trials. Particular attention will be given to the development of cellular therapies such as the ex vivo generation of T‐cell precursors to fasten generation of a polyclonal and functional host‐derived T‐cell repertoire. Having been tested so far only in preclinical mouse models, clinical studies are now on the way to validate the efficacy of such T‐cell progenitors in enhancing immune reconstitution following HSCT in various clinical settings. stem cells translational medicine 2019;00:1–8

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Generation of adult human T-cell progenitors for immunotherapeutic applications

Cited by 16 publications

References 10 publications

Gene therapy targeting haematopoietic stem cells for inherited diseases: progress and challenges

Gene therapy targeting haematopoietic stem cells for inherited diseases: progress and challenges

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

Concise Review: Boosting T-Cell Reconstitution Following Allogeneic Transplantation—Current Concepts and Future Perspectives

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