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2058 Lentiviral Gene Therapy with Low Dose Busulfan for Infants with X-SCID Results in the Development of a Functional Normal Immune System: Interim Results of an Ongoing Phase I/II Clinical Study

Program: Oral and Poster Abstracts
Session: 801. Gene Therapy and Transfer: Poster I
Hematology Disease Topics & Pathways:
HSCs, Diseases, Pediatric, immunodeficiency, Cell Lineage, Immune Disorders, Study Population, Clinically relevant
Saturday, December 7, 2019, 5:30 PM-7:30 PM
Hall B, Level 2 (Orange County Convention Center)

Ewelina Mamcarz, MD1, Sheng Zhou, Ph.D.2, Timothy Lockey, Ph.D.3*, Shannon Boi, Ph.D.4*, Yan Koon-Kiu, Ph.D.5*, Shane Cross, Pharm.D.6*, Guolian Kang, PhD7*, Zhijun Ma, M.D.1*, Jose Marcos Condori, Ph.D.1, Jolanta Dowdy, M.S.8*, Jean-Yves Metais, Ph.D.1*, Deanna Langfitt, Ph.D.9*, Brandon Triplett, M.D.1*, Chen Li, M.S.7*, Xiwen Zhao, MSPH7*, Gabriela Maron, M.D.10*, Sneha Suresh, M.D.11*, Juan Carlos Aldave Becerra, M.D.12*, Joseph Church, M.D.13*, Elif Dokmeci, M.D.14*, James T Love, M.D., Ph.D15*, Hedi van der Watt, M.D.16*, Ana C da Matta Ain, M.D.17*, Christa Krupski, DO, MPH18*, Jiyang Yu, Ph.D.5*, Lance E. Palmer, Ph.D.5*, William Janssen, Ph.D.19*, Suk See De Ravin, M.D., Ph.D.20*, Mitchell J. Weiss, MD, PhD19, Benjamin Youngblood, Ph.D.4*, Janel R Long-Boyle, PharmD, PhD21*, Michael M Meagher, Ph.D.22*, Harry L. Malech, MD23, Jennifer Puck, M.D.24*, Morton J Cowan, M.D.25 and Stephen Gottschalk, M.D.1

1Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, TN
2Experimental Cellular Therapeutics Laboratory, St. Jude Children's Research Hospital, Memphis, TN
3Department of Therapeutics Production & Quality, St. Jude Children's Research Hospital, Memphis, TN
4Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN
5Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN
6Department of Pharmaceutical Services, St. Jude Children's Research Hospital, Memphis, TN
7Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN
8Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN
9Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children’s Research Hospital, Memphis, TN
10Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN
11Division of immunology,Hematology, Oncology and Palliative care, University of Alberta, Edmonton, Canada
12Division of Allergy and Clinical Immunology, Hospital Nacional Edgardo Rebagliati Martins, Lima, Peru
13Department of Pediatrics, Allergy/Immunology Division, Children's Hospital Los Angeles, Los Angeles
14Department of Pediatrics, Pediatric Allergy and Immunology, University of New Mexico, Albuquerque, NM
15University of Oklahoma Health Sciences Center, Tulsa, OK
16Coperfield Childcare, Claremont, South Africa
17Universidade de Taubate, Conselho Nacional de Medicina, Sao Paulo, Brazil
18Department of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
19St. Jude Children's Research Hospital, Memphis, TN
20Laboratory of Clinical Immunology and Microbiology, NIAID, NIH, Bethesda, MD
21Division of Pediatric Allergy, Immunology, and Bone Marrow Transplantation, University of California San Francisco, Benioff Children's Hospital, San Francisco, CA
22Department of Therapeutics Production and Quality, St. Jude Children's Research Hospital, Memphis, TN
23National Institute of Allergy and Infectious Diseases, LCIM, NIAID, NIH, Bethesda, MD
24Department of Pediatrics, Division of Pediatric Allergy, Immunology, and Bone Marrow Transplantation, UCSF Benioff Children's Hospital, San Francisco, CA
25Division of Pediatric Allergy, Immunology, and Bone Marrow Transplantation, UCSF Benioff Children's Hospital, San Francisco, CA

Early clinical studies of gene therapy for patients with X-linked Severe Combined Immunodeficiency (XSCID) only restored T cell immunity and carried a significant risk of iatrogenic leukemia. We developed a new gene therapy approach that utilizes a safety-modified lentiviral (LV) vector together with reduced exposure busulfan conditioning for newly diagnosed infants with XSCID (NCT01512888). Of the first enrolled 8 patients, 7 demonstrated robust reconstitution of T-, NK-, and B-cells with a median follow up of 16.4 months (range: 6.7 to 24.9 months; Mamcarz et al, N Engl J Med, 2019). Here we provide an update on our clinical study, which now includes 3 more patients (n=11 total), 8 months additional median follow-up (23.6 months; range: 1.5 to 33.9 months), more extensive analysis of T and B cell functional recovery, and detailed vector integration site studies.

Overall, we successfully generated transduced autologous bone marrow (BM) CD34+ cells for all patients with a median vector copy number (VCN) of 0.45 VCN/cell (range: 0.16-1.13). Prior to the infusion of transduced CD34+ cells (median cell dose: 8.7 x106/kg; range: 4.5-19.0), patients received two daily doses of busulfan to target a cumulative area-under-the-curve (cAUC) of 22 mg*hr/L (achieved median: 22.3 mg*hr/L; range: 20.0-23.0). No severe adverse events, other than hematologic related to busulfan, were observed. All 11 patients had robust hematopoietic recovery within 3-4 weeks post cell infusion without blood product support. Nine patients, with a follow up of >3 months, achieved normal for age T-cell and NK-cell numbers within 3-4 months post gene therapy. T-cells matured appropriately as assessed by normal receptor excision circles (TREC) levels and TCRvb repertoire analysis. In addition, phytohemagglutinin (PHA) stimulation assays demonstrated normal T-cell function. So far, 5 patients are off IVIG of whom 3 responded to vaccines. As previously reported, patient #1 demonstrated poor immune reconstitution. He received a 2nd infusion of transduced CD34+ cells without conditioning one year after his initial infusion, which resulted in functional T-cell immune reconstitution. Clinically, all patients with a follow up >3 months recovered from pre-existing infections, are off protective isolation and prophylactic antimicrobials, and have normal growth in respect to height and weight. The median VCN at 12 months post gene therapy in seven patients, who have been followed for >12 months, was 2.25 VCN/cell (range: 1.24-3.03) in T cells, 0.34 VCN/cell (range: 0.23-1.25) in B cells, 1.55 VCN/cell (range 1.27-3.39) in NK cells, and 0.08 VCN/cell (range: 0.03-0.76) in myeloid cells in peripheral blood, and 0.10 (range: 0.05-0.66) in CD34+ bone marrow cells, respectively. Detailed integration sites analysis for the first 7 patients, who received a single infusion of transduced CD34+ cells, revealed that the majority of sites were located in introns and intergenic regions throughout the human genome. The integration site pattern was highly consistent across patients with integration site clusters that had been previously described by us and others after LV transduction.

In conclusion, LV gene therapy for XSCID using low dose busulfan conditioning and a novel LV vector is well tolerated and results in the development of a functional normal immune system without evidence of malignant transformation with a median follow up of almost 2 years. Thus, our approach may present a promising alternative to current therapies, which rely in part on high dose chemotherapy followed by allogeneic hematopoietic cell transplantation.

Disclosures: Mamcarz: American Lebanese Syrian Associated Charities: Research Funding; UpToDate: Honoraria; NHLBI: Research Funding; ASSISI Foundation of Memphis: Research Funding; MBIO: Other: St. Jude Children’s Research Hospital has an existing exclusive license and ongoing partnership with Mustang Bio for the further clinical development and commercialization of this XSCID gene therapy; California Institute of Regenerative Medicine: Research Funding. Zhou: MBIO: Other: St. Jude Children’s Research Hospital has an existing exclusive license and ongoing partnership with Mustang Bio for the further clinical development and commercialization of this XSCID gene therapy. Lockey: MBIO: Other: St. Jude Children’s Research Hospital has an existing exclusive license and ongoing partnership with Mustang Bio for the further clinical development and commercialization of this XSCID gene therapy. Boi: MBIO: Other: St. Jude Children’s Research Hospital has an existing exclusive license and ongoing partnership with Mustang Bio for the further clinical development and commercialization of this XSCID gene therapy. Koon-Kiu: MBIO: Other: St. Jude Children’s Research Hospital has an existing exclusive license and ongoing partnership with Mustang Bio for the further clinical development and commercialization of this XSCID gene therapy. Cross: MBIO: Other: St. Jude Children’s Research Hospital has an existing exclusive license and ongoing partnership with Mustang Bio for the further clinical development and commercialization of this XSCID gene therapy; NIH: Research Funding. Kang: MBIO: Other: St. Jude Children’s Research Hospital has an existing exclusive license and ongoing partnership with Mustang Bio for the further clinical development and commercialization of this XSCID gene therapy. Ma: MBIO: Other: St. Jude Children’s Research Hospital has an existing exclusive license and ongoing partnership with Mustang Bio for the further clinical development and commercialization of this XSCID gene therapy. Condori: MBIO: Other: St. Jude Children’s Research Hospital has an existing exclusive license and ongoing partnership with Mustang Bio for the further clinical development and commercialization of this XSCID gene therapy. Dowdy: MBIO: Other: St. Jude Children’s Research Hospital has an existing exclusive license and ongoing partnership with Mustang Bio for the further clinical development and commercialization of this XSCID gene therapy. Metais: MBIO: Other: St. Jude Children’s Research Hospital has an existing exclusive license and ongoing partnership with Mustang Bio for the further clinical development and commercialization of this XSCID gene therapy. Langfitt: MBIO: Other: St. Jude Children’s Research Hospital has an existing exclusive license and ongoing partnership with Mustang Bio for the further clinical development and commercialization of this XSCID gene therapy. Triplett: MBIO: Other: St. Jude Children’s Research Hospital has an existing exclusive license and ongoing partnership with Mustang Bio for the further clinical development and commercialization of this XSCID gene therapy. Li: MBIO: Other: St. Jude Children’s Research Hospital has an existing exclusive license and ongoing partnership with Mustang Bio for the further clinical development and commercialization of this XSCID gene therapy. Zhao: MBIO: Other: St. Jude Children’s Research Hospital has an existing exclusive license and ongoing partnership with Mustang Bio for the further clinical development and commercialization of this XSCID gene therapy. Maron: Chimerix: Research Funding; MBIO: Other: St. Jude Children’s Research Hospital has an existing exclusive license and ongoing partnership with Mustang Bio for the further clinical development and commercialization of this XSCID gene therapy; Astellas: Research Funding. Janssen: MBIO: Other: St. Jude Children’s Research Hospital has an existing exclusive license and ongoing partnership with Mustang Bio for the further clinical development and commercialization of this XSCID gene therapy. Weiss: Cellarity INC: Consultancy; GlaxoSmithKline: Consultancy; Rubius INC: Consultancy; Beam Therapeutics: Consultancy; Esperion: Consultancy. Youngblood: MBIO: Other: St. Jude Children’s Research Hospital has an existing exclusive license and ongoing partnership with Mustang Bio for the further clinical development and commercialization of this XSCID gene therapy. Meagher: MBIO: Other: St. Jude Children’s Research Hospital has an existing exclusive license and ongoing partnership with Mustang Bio for the further clinical development and commercialization of this XSCID gene therapy. Puck: Pfeizer: Other: spouse serves on Rare Disease Advisory Board; NIAID: Research Funding; Invitae: Other: spouse employment. Cowan: NIH NIAD: Research Funding; Leadiant: Consultancy; Rocket Pharma: Consultancy; bluebird bio: Consultancy; California Institute Of Regenerative Medicine: Research Funding; Homology Medicine: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; UpToDate: Honoraria. Gottschalk: Tidal: Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy; TESSA Therapeutics: Other: Research Collaboration; Patents and patent applications in the fields of T-cell & Gene therapy for cancer: Patents & Royalties; EMD Serono: Honoraria; California Institute for Regenerative Medicine: Research Funding; Sanofi: Honoraria; NHLBI: Research Funding; Inmatics: Membership on an entity's Board of Directors or advisory committees; MBIO: Other: St. Jude Children’s Research Hospital has an existing exclusive license and ongoing partnership with Mustang Bio for the further clinical development and commercialization of this XSCID gene therapy; America Lebanese Syrian Associated Charities: Research Funding; ViraCyte: Consultancy; ASSISI fundation of Memphis: Research Funding.

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