OUTCOMES OF GENE THERAPY FOR ?-THALASSEMIA MAJOR AND SEVERE SICKLE DISEASE VIA TRANSPLANTATION OF AUTOLOGOUS HEMATOPOIETIC STEM CELLS TRANSDUCED EX VIVO WITH A LENTIVIRAL BETA GLOBIN VECTOR
Author(s): ,
Marina Cavazzana
Affiliations:
Hopital Universitaire Necker - Enfants Malades,Paris,France
,
Jean-Antoine Ribeil^
Affiliations:
Hopital Universitaire Necker - Enfants Malades,Paris,France
,
Emmanuel Payen^
Affiliations:
CEA, Institut of Emerging Diseases and Innovative Therapies, and University of Paris-Sud,Fontenay-aux-Roses,France
,
Felipe Suarez
Affiliations:
Paris Descartes - Sorbonne Paris Cite University, Imagine Institute, Hopital Necker, Hematology Department,Paris,France
,
Yves Beuzard
Affiliations:
CEA, Institut of Emerging Diseases and Innovative Therapies, and University of Paris-Sud,Fontenay-aux-Roses,France
,
Fabien Touzot
Affiliations:
Hopital Universitaire Necker - Enfants Malades,Paris,France
,
Resy Cavellesco
Affiliations:
Brigham & Women's Hospital and Harvard Medical School,Boston,United States
,
François Lefrere
Affiliations:
Paris Descartes - Sorbonne Paris Cite University, Necker University Hospital AP-HP Hematology,Paris,France
,
Stany Chretien
Affiliations:
CEA, Institut of Emerging Diseases and Innovative Therapies, and University of Paris-Sud,Fontenay-aux-Roses,France
,
Philippe Bourget
Affiliations:
Hopital Universitaire Necker - Enfants Malades,Paris,France
,
Fabrice Monpoux
Affiliations:
Centre Hospitalier de Nice Sophia-Antipolis,Nice,France
,
Corrine Pondarre
Affiliations:
Centre Hospitalier lntercommunal de Creteil (CHIC),Creteil,France
,
Bénédicte Neven
Affiliations:
Hopital Universitaire Necker - Enfants Malades,Paris,France
,
Manfred Schmidt
Affiliations:
National Center for Tumor Diseases (NCT), German Cancer Research Center (DKFZ),Heidelberg,Germany
,
Christof von Kalle
Affiliations:
Department of Translational Oncology, National Center for Tumor Diseases, German Cancer Research Center,Heidelberg,Germany
,
Frans Kuypers
Affiliations:
Children's Hospital Oakland Research Institute,Oakland,United States
,
Laura Sandler
Affiliations:
bluebird bio,Cambridge,United States
,
Sandeep Soni
Affiliations:
bluebird bio,Cambridge,United States
,
Olivier Hermine
Affiliations:
Hopital Universitaire Necker - Enfants Malades,Paris,France
,
Stéphane Blanche
Affiliations:
Hopital Universitaire Necker - Enfants Malades,Paris,France
,
M. de Montalembert
Affiliations:
Hopital Universitaire Necker - Enfants Malades,Paris,France
,
Salima Hacein-Bey-Abina
Affiliations:
Hopital Universitaire Necker - Enfants Malades,Paris,France;Groupe Hospitalier Universitaire Paris-Sud,Paris,France
Philippe Leboulch
Affiliations:
CEA, Institut of Emerging Diseases and Innovative Therapies, and University of Paris-Sud,Fontenay-aux-Roses,France;Brigham & Women's Hospital and Harvard Medical School,Boston,United States;Mahidol University and Ramathibodi Hospital,Bangkok,Thail
EHA Library. Cavazzana-Calvo M. Jun 13, 2015; 103175; S466
Prof. Marina Cavazzana-Calvo
Prof. Marina Cavazzana-Calvo
Contributions
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Abstract
Abstract: S466

Type: Oral Presentation

Presentation during EHA20: From 13.06.2015 11:30 to 13.06.2015 11:45

Location: Room Stolz 2

Background
In patients with hemoglobinopathies, hematopoietic stem cell (HSC) gene therapy has the potential to induce production of functional β-globin in the red blood cell lineage with the aim of reducing or eliminating the symptoms of disease. Results for 2 subjects with β0E-thalassemia major treated in clinical study HGB-205 that were previously presented (EHA 2014, ASH 2014) suggested that transplantation with autologous CD34+ cells transduced with the self-inactivating LentiGlobin BB305 lentiviral vector containing an engineered βA-T87Q?globin gene  resulted in near-normal levels of total hemoglobin (Hb) and early transfusion independence.

Aims

Herein, we provide additional follow-up data on these two subjects as well as early safety and efficacy data on the first subject with sickle cell disease (SCD) treated with gene therapy.



Methods

After obtaining informed consent, subjects with β-thalassemia major undergo HSC collection via peripheral blood apheresis, while subjects with severe sickle cell disease undergo HSC collection via bone marrow harvest. CD34+ cells were selected and transduced with LentiGlobin BB305 lentiviral vector. Estimation of the mean ex- vivo vector copy number (VCN) was obtained by quantitative PCR performed on pooled colony-forming progenitors. Subjects underwent myeloablation with intravenous busulfan, followed by infusion of transduced CD34+ cells. Subjects were monitored for overall safety including hematological engraftment, βA-T87Q?globin expression (by high performance liquid chromatography) and transfusion requirements. Integration site analysis (ISA, by linear amplification-mediated PCR and high-throughput sequencing on nucleated cells) and replication-competent lentivirus (RCL) assays were performed. Prophylactic pRBC transfusions are continued in sickle cell subjects who are transfusion dependent pre-treatment to maintain HbS <30%, followed by gradual tapering over time.



Results

As of February 2015, 2 subjects with β0/βE thalassemia major (Subjects 1201 and 1202) and 1 subject with βSS severe sickle cell disease (Subject 1204, who was on prophylactic transfusion therapy for multiple veno-occlusive crises and acute chest syndrome) have undergone treatment. The outcome of these subjects to date is shown in Table 1.  No subject has experienced a drug product related adverse event, and ISA analyses demonstrate highly polyclonal reconstitution without clonal dominance. Both β-thalassemia major subjects remain transfusion-free for 14 and 11 months respectively, post-treatment.  Subject 1204, at his most recent visit (Month 4.5 post-treatment), has a total hemoglobin of 12.0 g/dl, of which 24% is HbAT87Q (from 9.6% at Month 3) and 33% is HbS (from 14.7% at Month 3), with increasing levels of transduced cells detected in peripheral blood (PBL VCN of 2.4 at Month 4.5). This subject has not had a post-treatment hospitalization for a SCD-related event and his transfusion support is being tapered.



Summary
The subjects with β-thalassemia major remain transfusion-free for 14 and 11 months. The subject with SCD demonstrates increasing production of HbAT87Q over time. Gene therapy using autologous HSC transduced with LentiGlobin BB305 lentiviral vector ex vivo is a promising approach for the treatment of patients with both β-thalassemia major and severe SCD.

Keyword(s): Beta thalassemia, Gene therapy, Lentiviral vector, Sickle cell disease



Session topic: Gene therapy, cellular immunotherapy and vaccination

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