The doubling potential of T lymphocytes allows clinical-grade production of a bank of genetically modified monoclonal T-cell populations

Autor: Henri Vié, Régine Vivien, Philippe Lemarre, Valérie Chabaud, Soraya Saiagh, Béline Jesson, Patrice Chevallier, Thierry Guillaume, Ulrich Jarry, Catherine Godon, Béatrice Clémenceau
Přispěvatelé: Immunobiology of Human αβ and γδ T Cells and Immunotherapeutic Applications (CRCINA-ÉQUIPE 1), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Unité de Thérapie Cellulaire et Génique [CHU Nantes] (UTCG), Hôtel-Dieu-Centre hospitalier universitaire de Nantes (CHU Nantes), Helixio Biopôle Clermont-Limagne [Saint-Beauzire], Etablissement Français du Sang [Pays de la Loire] (EFS - Site de Nantes), Hôpital Hôtel-Dieu [Nantes] (Centre Hospitalier Universitaire de Nantes), This study was funded by the programme hospitalier de recherche clinique (PHRC) (PHRC-K15-026/020-GUILLAUME) and institutional funding from INSERM., Immunobiology of Human αβ and γδ T cells and Immunotherapeutic Applications ( CRCINA - Département INCIT - Equipe 1 ), Centre de recherche de Cancérologie et d'Immunologie / Nantes - Angers ( CRCINA ), Université d'Angers ( UA ) -Université de Nantes ( UN ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche en Santé de l'Université de Nantes ( IRS-UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ) -Université d'Angers ( UA ) -Université de Nantes ( UN ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche en Santé de l'Université de Nantes ( IRS-UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ), Unité de Thérapie Cellulaire et Génique [CHU Nantes] ( UTCG ), Hôtel-Dieu-Centre hospitalier universitaire de Nantes ( CHU Nantes ), Etablissement Français du Sang [Pays de la Loire] ( EFS - Site de Nantes ), Hôpital Hôtel-Dieu [Nantes] ( Centre Hospitalier Universitaire de Nantes ), Bernardo, Elizabeth, Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)
Rok vydání: 2018
Předmět:
0301 basic medicine
Cancer Research
Adoptive cell transfer
T-Lymphocytes
Transgene
medicine.medical_treatment
T cell
Cytological Techniques
Immunology
Blood Donors
[SDV.CAN]Life Sciences [q-bio]/Cancer
Hematopoietic stem cell transplantation
Biology
T-cell bank
Thymidine Kinase
[ SDV.CAN ] Life Sciences [q-bio]/Cancer
Interferon-gamma
Mice
graft-versus-tumor
03 medical and health sciences
Transduction (genetics)
[SDV.CAN] Life Sciences [q-bio]/Cancer
population doubling
Transduction
Genetic
medicine
Animals
Humans
Immunology and Allergy
HLA-DP beta-Chains
Genetics (clinical)
clone
Transplantation
HLA-DP
Genes
Transgenic
Suicide
Granulocyte-Macrophage Colony-Stimulating Factor
Cell Biology
Suicide gene
Xenograft Model Antitumor Assays
Molecular biology
Clone Cells
Genetically modified organism
030104 developmental biology
medicine.anatomical_structure
Oncology
Monoclonal
Interleukin-2
allogeneic effect
Lymphocyte Culture Test
Mixed
Zdroj: Cytotherapy
Cytotherapy, Elsevier, 2018, 20 (3), pp.436-452. ⟨10.1016/j.jcyt.2017.12.002⟩
Cytotherapy, Elsevier, 2018, 20 (3), pp.436-452. 〈10.1016/j.jcyt.2017.12.002〉
Cytotherapy, 2018, 20 (3), pp.436-452. ⟨10.1016/j.jcyt.2017.12.002⟩
ISSN: 1465-3249
DOI: 10.1016/j.jcyt.2017.12.002
Popis: International audience; Background aims. To produce an anti-leukemic effect after hematopoietic stem cell transplantation we have long considered the theoretical possibility of using banks of HLA-DP specific T-cell clones transduced with a suicide gene. For that application as for any others, a clonal strategy is constrained by the population doubling (PD) potential of T cells, which has been rarely explored or exploited. Methods. We used clinical-grade conditions and two donors who were homozygous and identical for all HLA-alleles except HLA-DP. After mixed lymphocyte culture and transduction, we obtained 14 HLA-DP–specific T-cell clones transduced with the HSV-TK suicide gene. Clones were then selected on the basis of their specificity and functional characteristics and evaluated for their doubling potential. Results. After these steps of selection the clone NAT-DP4[(TK)], specific for HLA-DPB1*04:01/04:02, which produced high levels of interferon-γ (IFNγ), tumor necrosis factor (TNF), interleukin-2 (IL-2) and granulocyte-macrophage colony-stimulating factor (GM-CSF), was fully sequenced. It has two copies of the HSV-TK suicide transgene whose localizations were determined. Four billion NAT-DP4[(TK)] cells were frozen after 50 PDs. Thawed NAT-DP4[(TK)] cells retain the potential to undergo 50 additional PDs, a potential very far beyond that required to produce a biological effect. This PD potential was confirmed on 6/16 additional different T-cell clones. This type of well-defined clone can also support a second genetic modification with CAR constructs. Conclusion. The possibility of choosing rare donors and exploiting the natural proliferative potential of T lymphocytes may dramatically reduce the clinical and immunologic complexity of adoptive transfer protocols that rely on the use of third-party T-cell populations.
Databáze: OpenAIRE
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