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I – Gene & Cell Therapy Trials in Progress -> Gene & Cell Therapy Trials in Progress

Universal Survival and Superior Immune Reconstitution after Lentiviral Gene Therapy with Low Dose Conditioning for X-linked SCID (SCID-X1)

Type: Oral Abstract Session

Presentation Details
Session Title: Late-Breaking Abstracts 1
Location: Room 515 AB
Start Time: 5/19/2023 8:30
End Time: 5/19/2023 8:45

Introduction: Boys with X-linked severe combined immunodeficiency (SCID-X1) lack T and NK cells. B cells fail to function due to lack of IL-2 receptor gamma (IL2RG) signaling. In SCID-X1, corrected progenitors can engraft in the thymus and give rise to mature T cells, without chemotherapy conditioning. After allogeneic transplant (HCT), ~50% of patients achieve optimal T cell recovery at 6 months (PMC6202916, 2018). Trials of gene therapy (GT) using a gammaretroviral (gRV) vector led to T cell development but also insertional oncogenesis. Deletion of gRV LTR enhancers generating a self-inactivating gRV (SIN-gRV) vector led to similar T cell recovery with no leukemias to date (PMC4274995, 2014). Building on this success, we opened a multi-institutional international trial using a lentiviral (LV) vector with codon optimized IL2RG, the same cis-regulatory elements as in the SIN-gRV trial, and busulfan conditioning (NCT03311503/03601286). Our goal was to achieve rapid T and NK cell reconstitution, and B cell function that would be superior to HCT and the previous SIN-gRV trial. Methods: Of 15 enrolled, 13 successfully underwent CD34+ HSC manufacturing at median age 3.5m (1.8-5.6), using mobilized peripheral blood in 12/13 and transduction enhancers in 11/13. Median CD34+ cell dose/kg and vector copy number (VCN) were 9.8 x 10e6 (4.7-17.87) and 1.1 copies/diploid genome (dg) (0.67-3.07). Thawed drug products (DP) were infused after busulfan targeted to AUC 30 mg*h/L given over 2 days at median age 5.2 months (3.2-7.1). Results: All 13 are alive with median follow-up 2.6y (0.2-4.9) with no treatment-related serious adverse events or clonal expansions. All subjects ≥6m post-GT had superior T cell recovery compared to standard HCT (CD3+ T cell >1000 9/9 vs 67/136, p=0.009; CD4+ T cell >500 9/9 vs 72/135, p=0.02). Compared to the SIN-gRV trial, CD3+ and CD4+ T cell numbers were higher at 6m post-GT in conditioned SIN-LV subjects, indicating more rapid recovery (p=0.0002). Sustained multilineage gene marking was seen in B, NK cells and neutrophils. In contrast to SIN-gRV recipients treated without conditioning who remain on IgG replacement therapy (IgRT), 7/8 SIN-LV subjects >1y post-GT are off IgRT; 5/5 responded to vaccines. CD3, CD4 and NK cells were higher at 2y post-GT compared to unconditioned SIN-gRV recipients (p=0.007, 0.002, 0.003). VCN in T, B, NK, and neutrophils was higher in those receiving DP with VCN ≥2 compared to VCN <2 copies/dg (p=0.004, 0.02, 0.02, 0.02). Conclusion: GT using a LV with codon optimized IL2RG and busulfan conditioning resulted in 100% survival and robust T cell recovery more rapid than after standard HCT. Conditioning was associated with sustained multilineage gene marking and B cell function.

Sung-Yun Pai1, Claire Booth2, Donald B. Kohn3, Myriam A. Armant4, Susan E. Prockop4, Karen Buckland2, Sharat Chandra5, Shanmuganathan Chandrakasan6, Kritika Chetty2, Colleen H. Dansereau4, Satiro N. De Oliveira3, John Everett7, Pei-Chi Kao4, Wendy B. London4, Rebecca A. Marsh5, Theodore B. Moore3, Nisha Nagarsheth1, Suhag Parikh6, Dayna R. Terrazas3, Shanna White3, Jinhua Xu-Bayford2, Axel Schambach8, Frederic D. Bushman7, Adrian J. Thrasher2, David A. Williams4

1National Institutes of Health/National Cancer Institute, Bethesda, MD,2UCL Great Ormond Street Institute of Child Health, London, United Kingdom,3University of California, Los Angeles, Los Angeles, CA,4Boston Children's Hospital, Boston, MA,5Cincinnati Children's Hospital Medical Center, Cincinnati, OH,6Children's Hospital of Atlanta, Atlanta, GA,7University of Pennsylvania School of Medicine, Philadelphia, PA,8Hannover Medical School, Hannover, Germany
 S. Pai: None.

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