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

Ranjita 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 Staal; Françoise Pflumio; Emmanuelle Six; Marina Cavazzana; Chantal Lagresle-Peyrou; Tayebeh Soheili; Isabelle Andre

doi:10.1038/s41423-021-00706-8

Journal articles

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

Ranjita Moirangthem ¹ Kuiying Ma ¹ Sabrina Lizot ¹ Anne Cordesse ¹ Juliette Olivré ¹ Corinne de Chappedelaine ¹ Akshay Joshi ¹ Agata Cieslak ^{2, 3} John Tchen ¹ Nicolas Cagnard ⁴ Vahid Asnafi ^{2, 3} Antonio Rausell ⁵ Laura Simons ³ Julien Zuber ^{1, 6} Tom Taghon ^{7, 8} Frank Staal ⁹ Françoise Pflumio ¹⁰ Emmanuelle Six ¹ Marina Cavazzana ^{1, 3} Chantal Lagresle-Peyrou ^{1, 3} Tayebeh Soheili ¹ Isabelle Andre ^{1, *}

* Corresponding author

1 Equipe Inserm U1163 - Human Lymphohematopoiesis Laboratory

Imagine - U1163 - Imagine - Institut des maladies génétiques (IHU)

2 INEM - UM 111 (UMR 8253 / U1151) - Institut Necker Enfants-Malades

3 CHU Necker - Enfants Malades [AP-HP]

4 SFR Necker - UMS 3633 / US24 - Structure Fédérative de Recherche Necker

5 Equipe Inserm U1163 - The Clinical Bioinformatics laboratory

Imagine - U1163 - Imagine - Institut des maladies génétiques (IHU)

6 Service Néphrologie et transplantation rénale Adultes [CHU Necker]

7 CRIG - Cancer Research Institute Ghent [Gand, Belgique]

8 UGENT - Ghent University [Belgium]

9 Leiden University Medical Center (LUMC)

10 SGCSR (U_1274 / UMR_E_008) - Stabilité génétique, cellules souches et radiations

Abstract : 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 Tlymphoid 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).

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

Document type :

Journal articles

Domain :

Life Sciences [q-bio]

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https://www.hal.inserm.fr/inserm-03259822
Contributor : Isabelle Andre <>
Submitted on : Monday, June 14, 2021 - 2:49:06 PM
Last modification on : Wednesday, July 21, 2021 - 4:10:02 PM

Moirangthem_et_al-2021-Cellula...

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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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