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2201 Gene Therapy for Artemis-SCID and Artemis-Leaky-SCID Patients: Preliminary Results of the French Artegene Phase I/II Clinical Trial

Program: Oral and Poster Abstracts
Session: 801. Gene Therapies: Poster I
Hematology Disease Topics & Pathways:
Research, Translational Research, Pediatric, Diseases, Immune Disorders, Immunodeficiency, Gene Therapy, Treatment Considerations, Biological therapies, Study Population, Human, Transplantation (Allogeneic and Autologous)
Saturday, December 7, 2024, 5:30 PM-7:30 PM

Jean-Sebastien Diana, MD1*, Despina Moshous, MD, PhD2*, Martin Castelle, MD2*, Boris Bessot, B.S.3*, Elisa Magrin, PhD, PharmaD4*, Marwa Chbihi, MD5*, Paul Bastard, MD, Ph.D6*, Alice Girardot4*, Cecile Roudaut, B.S.7*, Chloe Mollet, Ph.D2*, Clotilde Aussel, PhD, PharmD8*, Caroline Tuchmann-Durand4*, Eden Schwartz, PharmD4*, Olaf Neth, MD, Ph.D9*, Peter Olbrich, MD, Ph.D10*, Irene d'Alba, MD11*, Jacques Riviere, MD12*, Medhi Oualha, MD, Ph.D8*, Laure Joseph, MD13*, Benedicte Neven, MD, Ph.D14*, Jean-Pierre De Villartay, Ph.D3*, Anne Galy, PharmD, PhD15*, Chantal Lagresle-Peyrou, PhD3* and Marina Cavazzana, MD, PhD4

1Necker Hospital, Biotherapy Department, PARIS, PARIS, France
2Necker Hospital (APHP), Paris, France
3Institut Imagine, Inserm, Paris, France
4Necker Hospital, Biotherapy Department, Paris, France
5APHP, Hopital Necker, Paris, FRA
6Hopital Necker, APHP, Paris, France
7Hopital Necker (APHP), Paris, France
8Hopital Necker (APHP), Paris, France
9Pediatric Infectious Diseases, Rheumatology and Immunology Unit, Hospital Universitario Virgen del Rocío, Institute of Biomedicine of Seville (IBIS)/ Universidad de Sevilla/CSIC, Red de Investigación Traslacional en Infectología Pediátrica RITIP, Sevilla, Spain
10Hospital Infantil Virgen Del Rocio, Sevilla, ESP
11Maternal Infant Hospital "G. Salesi", Ancona, Italy
12Hospital Vall D´Hebron, Barcelona, Spain
13Biotherapy Department, French National Sickle Cell Referral Center, Hopital Necker, AP-HP, Paris, France
14BMT unit, Hopital Necker (APHP), Paris, France
15Genethon, Evry, France

Introduction: Genetic deficiency of the endonuclease DCLRE1C/Artemis, a key factor for the Non-Homologous End-Joining (NHEJ) mechanism, causes Severe Combined Immunodeficiency (SCID) or leaky-SCID characterized by a lack of T and B-cells associated with hypersensitivity to ionizing radiations. Allogeneic Hematopoietic Stem and progenitor Cells (HSPCs) transplantation is the gold standard for treating Artemis deficiency. However, graft-versus-host disease and graft rejection, which can lead to post-transplant complications and mortality, are increased in case of HLA incompatibility between the donor and recipient. In this context, gene addition for autologous HSPCs was presented as an alternative therapeutic strategy, and a clinical trial of gene therapy is already ongoing in the United States. Using a different Lentiviral Vector (LV) containing a short intron-less EF1α promoter regulating the expression of human DCLRE1C cDNA, we recently opened a European phase I/II clinical trial (NCT05071222) at the Necker hospital in Paris.

Methods: Two SCID phenotypes (P1, P3) and one leaky-SCID form (P2) have been included in this trial with 6 to 18 months follow-up. P1 had a severe and heavily treated maternal GvHD (steroids, ciclosporin, Ruxolitinib, Thymoglobulin) with a pretransplant history of infection due to immune deficiency, including treatment for pneumocystis, post-rotavirus vaccination gastroenteritis, and undocumented hepatitis. At the same time, P3 was asymptomatic and diagnosed after newborn screening. P2, aged 41 months, was diagnosed in the context of IBD, CMV disease, and hepatitis. We processed and transduced autologous CD34+ HSPCs from bone marrow and mobilized peripheral blood to increase the quantity of gene-corrected HSPCs. Each patient received between 1.8 to 3.7 10e6 CD34/kg corrected HSPC after a BU-based conditioning regimen with an AUC of 10000 microM.min.

Results: For all patients, we could detect the engraftment of gene-corrected HSPC at the hematological recovery by quantifying the transgene integration in CD15+ circulating cells. Both SCID patients had progressively increased VCN in the PBMC and restored T-cell and B-cell compartments after transplant. By testing the corrected HSPCs' functionality, we also demonstrated that transduced HSPCs initiate T-cell rearrangements in vitro and acquire the capacity to restore T-cell differentiation with polyclonal repertoires in vivo. P1 rapidly controlled his pretransplant maternal GvHD and post-rotavirus vaccination gastroenteritis. However, for the leaky phenotype (P2), despite sufficient HSPC-corrected cells in the drug product and the engraftment of 20% corrected CD34+ cells in bone marrow, the VCN in the PBMC never exceeded 0.2 copies/cells. This was insufficient to initiate the T-cells and B-cell reconstitution after seven months of follow-up.

Conclusion/discussion: Our data confirme the success of the ARTEGENE gene transfer protocol, which has restored a functional T- and B-cell compartment in Artemis-deficient SCID phenotypes with low toxicity. However, the reason why gene therapy failed in the patient with the leaky phenotype requires further analysis. The detailed clinical outcomes of all patients will be presented at the upcoming congress. These results need to be confirmed by including more patients.

Disclosures: Joseph: Vertex: Honoraria; GBT: Honoraria; Addmedica: Honoraria; Novartis: Honoraria.

*signifies non-member of ASH