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

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.

PMID: 30911587
PMCID: PMC6416524
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

Marianne Delville et al. Mol Ther Methods Clin Dev. 2019.

. 2019 Feb 26:13:303-309.

doi: 10.1016/j.omtm.2019.02.006. eCollection 2019 Jun 14.

Authors

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.

PMID: 30911587
PMCID: PMC6416524
DOI: 10.1016/j.omtm.2019.02.006

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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References

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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

Affiliations

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

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Affiliations

Abstract

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