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; Fabien Touzot; Chloé Couzin; Isabelle Hmitou; Lounes Djerroudi; Amani Ouedrani; François Lefrère; Caroline Tuchman-Durand; Chloé Mollet; Jean-Roch Fabreguettes; Nicolas Ferry; Laurent Laganier; Alessandra Magnani; Elisa Magrin; Valérie Jolaine; Asier Saez-Cirion; Orit Wolstein; Geoffrey Symonds; Pierre Frange; Hélène Moins-Teisserenc; Marie-Laure Chaix-Baudier; Antoine Toubert; Jérôme Larghero; Nathalie Parquet; Anne C Brignier; Françoise Barré-Sinoussi; Eric Oksenhendler; Marina Cavazzana

doi:10.1016/j.omtm.2019.02.006

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

Mol Ther Methods Clin Dev. 2019 Feb 26:13:303-309. doi: 10.1016/j.omtm.2019.02.006. eCollection 2019 Jun 14.

Authors

Marianne Delville^{1

2

3}, Fabien Touzot^{1

2}, Chloé Couzin^{1

2}, Isabelle Hmitou², Lounes Djerroudi², Amani Ouedrani², François Lefrère², Caroline Tuchman-Durand², Chloé Mollet², Jean-Roch Fabreguettes⁴, Nicolas Ferry⁵, Laurent Laganier², Alessandra Magnani², Elisa Magrin², Valérie Jolaine⁶, Asier Saez-Cirion⁷, Orit Wolstein⁸, Geoffrey Symonds⁸, Pierre Frange^{9

10}, Hélène Moins-Teisserenc¹¹, Marie-Laure Chaix-Baudier¹², Antoine Toubert¹¹, Jérôme Larghero¹³, Nathalie Parquet¹⁴, Anne C Brignier¹⁴, Françoise Barré-Sinoussi¹⁵, Eric Oksenhendler¹⁶, Marina Cavazzana^{1

2

3}

Affiliations

¹ Paris Descartes, Sorbonne Paris Cité, France.
² Clinical Investigation Center CIC1416 and Département de Biothérapie, Hôpital Necker, Assistance Publique des Hôpitaux de Paris, Paris, France.
³ Laboratoire de Lymphohématopoïèse Humaine, INSERM U1163, Paris Descartes, Sorbonne Paris Cité, France.
⁴ Département Essais Cliniques, AGEPS, Assistance Publique des Hôpitaux de Paris, Paris, France.
⁵ Hôpital Saint Louis, Assistance Publique des Hôpitaux de Paris, Paris, France.
⁶ Paris Descartes Necker - Cochin Clinical Research Unit, Assistance Publique-Hôpitaux de Paris, Paris, France.
⁷ Unité HIV Inflammation et Persistance, Institut Pasteur, Paris, France.
⁸ CSL Behring, LLC (formerly Calimmune, Inc.), Darlinghurst, NSW, Australia.
⁹ EHU 7328, Institut Imagine, Université Paris Descartes, Sorbonne Paris Cité, France.
¹⁰ Unité d'Immunologie, d'Hématologie et de Rhumatologie Pédiatriques, Hôpital Necker, Assistance Publique des Hôpitaux de Paris, Paris, France.
¹¹ INSERM U1160, Université Paris Diderot and Département d'Immunologie, Hôpital Saint Louis, Assistance Publique des Hôpitaux de Paris, Paris, France.
¹² INSERM U944, Université Paris Diderot and Laboratoire de Virology Hôpital Saint-Louis, Paris, France.
¹³ CIC de Biothérapie CBT501, Université Paris Diderot and Hôpital Saint Louis, Assistance Publique des Hôpitaux de Paris, Paris, France.
¹⁴ Département d'Aphérèse Thérapeutique, Hôpital Saint Louis, Assistance Publique des Hôpitaux de Paris, Paris, France.
¹⁵ Département des Affaires Internationales, Institut Pasteur, Paris, France.
¹⁶ Université Paris Diderot and Service d'Immunopathologie Clinique, Hôpital Saint Louis, Assistance Publique des Hôpitaux de Paris, Paris, France.

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.