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E - Disease Models and Clinical Applications -> Hematologic and Immunologic Diseases

1188: Interim Results from an Ongoing Phase 1/2 Study of Lentiviral-Mediated Ex-Vivo Gene Therapy for Pediatric Patients with Severe Leukocyte Adhesion Deficiency-I (LAD-I)

Type: Oral Abstract Session

Presentation Details
Session Title: Clinical Trials Spotlight Symposium
Location: Ballroom C
Start Time: 5/19/2022 8:00
End Time: 5/19/2022 8:15

Background: Leukocyte Adhesion Deficiency-I (LAD-I) is a rare monogenic disorder of neutrophil adhesion resulting from mutations in the ITGB2 gene that encodes for the β2-integrin component CD18. Severe LAD-I (CD18 on <2% of polymorphonucleocytes [PMNs]) is characterized by severe infections, impaired wound healing, and childhood mortality. Allogeneic hematopoietic stem cell transplant (alloHSCT) is potentially curative; however, efficacy is limited by donor availability and risk of graft-versus-host disease (GVHD) and graft failure. RP-L201-0318 (NCT03812263), a phase 1/2 open-label trial currently underway, employs autologous CD34+ cells transduced with a lentiviral vector (LV) carrying the ITGB2 gene (cDNA). Methods: Pediatric patients ≥ 3 months old with severe LAD-I are eligible. HSCs are collected via apheresis after mobilization with granulocyte-colony stimulating factor (G-CSF) and plerixafor and transduced with Chim-CD18-WPRE-LV. Myeloablative therapeutic drug monitoring (TDM) busulfan conditioning precedes RP-L201 infusion. Patients are followed for safety and efficacy (i.e., survival to age 2 and at least 1-year post-infusion, increase in peripheral blood [PB] PMN leukocyte CD18 expression to at least 10%, PB vector copy number [VCN] >0.1 copies/cell, neutrophilia improvement or normalization, decrease in infections/hospitalizations, and resolution of skin or periodontal abnormalities). Results: Nine patients (ages 5mos-9yrs) have received RP-L201, with available follow-up of 3 to 24 months. All 9 demonstrated sustained leukocyte CD18 restoration and VCN > 0.1 after infusion. RP-L201 cell doses ranged from 2.8x106 to 10x106 CD34+ cells/kg with a drug product VCN from 1.8-3.8 copies/cell. At 1 year, the OS rate is 100% based on the Kaplan-Meier estimate. In the 4 patients that have been followed up for >1 year after infusion, sustained and stable PMN CD18 expression has been observed. The patient with longest follow-up had ~40% PMN CD18 expression at 24-months (vs. < 1% at baseline), with PB VCN of 1.53 copies/cell. Baseline skin lesions resolved and the patient has not had infections requiring hospitalization despite extensive history of severe infections prior to RP-L201 therapy. The subsequent 8 patients have been followed for 3-18 months, demonstrating PMN CD18 expression of 25.6-86.6%, and stable for each patient. Neutrophilia at baseline has resolved in all subjects after therapy. There have been no new infections characteristic of severe LAD-I post-infusion. The safety profile of RP-L201 has been highly favorable in all subjects with no RP-L201-related serious adverse events. Conclusion: RP-L201 confers durable neutrophil CD18 expression and genetic correction and improved clinical course in 9 of 9 patients treated in this phase 1/2 study. Presentation at the meeting will include one-year survival data for the initial 7 of 9 patients.



D. B. Kohn1, J. Sevilla2, G. Rao3, M. Chitty Lopez3, E. Almarza3, D. Terrazas1, J. Zubicaray2, M. González-Vicent2, K. Chetty4, G. O'Toole4, J. Xu-Bayford4, E. Nicoletti3, A. Fernandes1, C. Kuo1, S. de Oliveira1, T. B. Moore1, G. Choi3, M. Zeini3, C. Mesa-Núñez5,6, A. J. Thrasher4, J. Bueren5,6, J. Schwartz3, C. Booth4

1UCLA, Los Angeles, CA,2Hospital Infantil Universitario Niño Jesús/ CIBERER, Madrid, Spain,3Rocket Pharmaceuticals, Cranbury, NJ,4UCL Great Ormond Street Institute of Child Health, London, United Kingdom,5CIEMAT/ CIBERER, Madrid, Spain,6Instituto de Investigación Sanitaria Fundación Jiménez Díaz, Madrid, Spain
  D.B. Kohn: 1; Commercial Interest i.e. Company X; Allogene Therapeutics, MyoGene Bio, Pluto Therapeutics, ImmunoVec. 1; What was received? i.e. Honorarium; Paid Member of Scientific Ad Board. 1; For what role? i.e. Speaker; Advisory Board Member.

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