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Safety of CD34+ Hematopoietic Stem Cells and CD4+ T Lymphocytes Transduced with LVsh5/C46 in HIV-1 Infected Patients with High-Risk Lymphoma

Marianne Delville 1, 2, 3, * Fabien Touzot 1, 3 Chloé Couzin 1, 3 Isabelle Hmitou 1, 3 Lounes Djerroudi 1, 3 Amani Ouedrani 1, 3 François Lefrère 3, 1 Caroline Tuchman-Durand 1, 3 Chloe Mollet 1, 3 Jean-Roch Fabreguettes 4, 5 Nicolas Ferry 6 Laurent Laganier 1, 3 Alessandra Magnani 3, 1 Elisa Magrin 3, 1 Valerie Jolaine 7 Asier Sáez-Cirión 8 Orit Wolstein 9 Geoffrey Symonds 9 Pierre Frange 10, 11 Hélène Moins-Teisserenc 12, 13 Marie-Laure Chaix-Baudier 14 Antoine Toubert 13, 12 Jérome Larghero 15 Nathalie Parquet 16 Anne Brignier 16 Françoise Barré-Sinoussi 17 Eric Oksenhendler 16 Marina Cavazzana 3, 2, 1
* Corresponding author
1 Unité de recherche clinique / Centre d'investigation clinique [CHU Necker]
2 Equipe Inserm U1163 - Human Lymphohematopoiesis Laboratory
IMAGINE - U1163 - Imagine - Institut des maladies génétiques
3 Département de Biothérapie [CHU Necker]
4 AGEPS - Agence Générale des Equipements et Produits de Santé [Paris]
5 AP-HP - Assistance publique - Hôpitaux de Paris (AP-HP)
6 Hôpital Saint-Louis
7 CIC 1419 - CIC - Mère Enfant Necker Cochin Paris Centre
8 HIV, Inflammation et persistance
9 CSL Behring
10 CHU Necker - Enfants Malades [AP-HP]
11 IMAGINE - U1163 - Imagine - Institut des maladies génétiques
12 A2T - Alloimmunité-Autoimmunité-Transplantation
13 Service d'Immunologie et d'Histocompatibilité
14 Pathologie cellulaire : aspects moléculaires et viraux / Pathologie et Virologie Moléculaire
15 (CIC-BT 301) - CIC - Biotherapie - Saint Louis
16 Hôpital Saint-Louis
17 Direction Internationale de l'Institut Pasteur
Abstract : Although the risk of developing lymphoma has decreased in the highly active antiretroviral therapy era, this cancer remains the major cause of mortality in HIV-infected patients. Autologous hematopoietic stem cell transplantation (ASCT) outcome does not differ for HIV-infected versus HIV-uninfected patients. We propose to develop a new treatment for HIV-associated high-risk lymphoma based on autologous transplantation of two genetically modified products: CD4+ T lymphocytes and CD34+ hematopoietic stem cells (HSPCs). The cells will be transduced ex vivo with the Cal-1 lentiviral vector encoding for both a short hairpin RNA (shRNA) against CCR5 (sh5) and the HIV-1 fusion inhibitor C46. The transduced cells will be resistant to HIV infection by two complementary mechanisms: impaired binding of the virus to the cellular CCR5 co-receptor and decreased fusion of the virus as C46 interacts with gp41 and inhibits HIV infection. This phase I/II pilot study, also entitled GENHIV, will involve two French participating centers: Saint Louis Hospital and Necker Hospital in Paris. We plan to enroll five HIV-1-infected patients presenting with high-risk lymphoma and require a treatment with ASCT. The primary objective of this study is to evaluate the safety, feasibility, and success of engraftment of Cal-1 gene-transduced CD4+ T lymphocytes and CD34+ HSPCs.
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Marianne Delville, Fabien Touzot, Chloé Couzin, Isabelle Hmitou, Lounes Djerroudi, et al.. Safety of CD34+ Hematopoietic Stem Cells and CD4+ T Lymphocytes Transduced with LVsh5/C46 in HIV-1 Infected Patients with High-Risk Lymphoma. Molecular Therapy - Methods and Clinical Development, Nature Publishing Group, 2019, 13, pp.303-309. ⟨10.1016/j.omtm.2019.02.006⟩. ⟨pasteur-02549969⟩

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