BLUE at EHA presenting beta thalassemia data
>>24. Gene therapy, cellular immunotherapy and vaccination ABSSUB-3287
OUTCOMES OF GENE THERAPY FOR BETA-THALASSEMIA MAJOR VIA TRANSPLANTATION OF AUTOLOGOUS HEMATOPOIETIC STEM CELLS TRANSDUCED EX VIVO WITH A LENTIVIRAL BETA GLOBIN VECTOR.
Marina Cavazzana* 1, Jean-Antoine Ribeil^1, Emmanuel Payen^2, 3, Felipe Suarez4, Olivier Negre5, Yves Beuzard2, 3, Fabien Touzot1, Resy Cavallesco6, François Lefrere1, Stany Chretien2, 3, Philippe Bourget7, Fabrice Monpoux8, Corinne Pondarre9, Benedicte Neven10, Frederic D. Bushman11, Manfred Schmidt12, Christof von Kalle12, Laura Sandler13, Sandeep Soni13, Byoung Ryu13, Robert Kutner13, Gabor Veres13, Mitchell Finer13, Stéphane Blanche10, Olivier Hermine4, Salima Hacein-Bey-Abina1, Philippe Leboulch2, 3, 6
1Département de Biothérapie, Hôpital Universitaire Necker - Enfants Malades, Paris, 2CEA, Institute of Emerging Diseases and Innovative Therapies (iMETI), 3UMR 962 (Inserm-CEA-University of Paris-Sud), Fontenay-aux-Roses, 4Service d'hématologie Adulte, Hôpital Universitaire Necker - Enfants Malades, Paris, 5bluebird bio France, CEA-iMETI, Fontenay-aux-Roses, France, 6Harvard Medical School and Brigham & Women's Hospital, Boston, United States, 7Clinical Pharmacy Department, Hôpital Universitaire Necker - Enfants Malades, Paris, 8Unité d’Hemato-Oncologie infantile, Centre Hospitalier de Nice Sophia-Antipolis, Nice, 9Service de pédiatrie, Centre de référence de la Drépanocytose, Centre Hospitalier Intercommunal de Créteil (CHIC), Créteil, 10Unité d'Immunologie-Hématologie Pédiatrique, Hôpital Universitaire Necker - Enfants Malades, Paris, France, 11Department of Microbiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States, 12Translational Oncology, National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), Heidelberg, Germany, 13bluebird bio, Cambridge, United States
Background: In patients with ß-thalassemia major, haematopoietic stem cell (HSC) gene therapy has the potential to induce production of ß-globin, ?-globin or modified ß-globin in the RBC lineage and reduce or stop the need for transfusions. A prior clinical trial (LG001) demonstrated benefit of autologous CD34+ cells transduced with a replication-defective, self-inactivating lentiviral vector (HPV569) containing an engineered ß-globin gene (ßA-T87Q). A further modified ßA-T87Q vector (LentiGlobin BB305) has achieved greater transduction efficiency and a similar pre-clinical safety profile. LentiGlobin BB305 is now being evaluated in the HGB-205 clinical trial.
Aims: To provide (i) long-term follow-up data on two subjects treated in LG001 and (ii) initial results from the HGB-205 study.
Methods: After the provision of informed consent, subjects with ß-thalassemia major underwent HSC collection via peripheral blood apheresis and CD34+ cells were selected. Estimation of the mean ex vivo vector copy number (VCN) was obtained by qPCR performed on pooled in vitro colony-forming progenitors. Subjects underwent myeloablation with intravenous busulfan, followed by infusion of transduced CD34+ cells. Subjects were monitored for haematological engraftment, ßA-T87Q expression (by HPLC) and transfusion requirements. Integration site analysis (by LAM-PCR and high-throughput sequencing on nucleated cells) and replication-competent lentivirus assays were performed.
Results: In LG001, two subjects (#1003 and #1004) with ßE/ß0 thalassemia major successfully engrafted following gene therapy with autologous HSCs transduced with HPV569. Neither subject experienced a cell infusion related adverse event. As reported previously (Nature 2010), #1003 became transfusion-independent one year post–transplant and remains so 5 years later, with the production of 2.5 - 3.5 g/dL ßA-T87Q-globin (~30% of total haemoglobin). The most recent VCN in #1003's peripheral neutrophils is 0.23. Subject #1003 also demonstrated partial dominance of a clone with vector integration within the HMGA2 gene that peaked at 4 years post-treatment (22% of the nucleated cells) and has now fallen to 6.8% while maintaining transfusion independence. For #1004, the current VCN (2 years post-treatment) in neutrophils is 0.016 and ßA-T87Q–globin accounts for ~5% of total haemoglobin. This subject remains transfusion dependent.
Two subjects with ßE/ß0 thalassemia major (#1201 and #1202) have enrolled in the current HGB-205 trial and one has undergone transplantation. Transduction efficiency of the new BB305 vector compared to HPV569 is shown in Table 1. Data on the transplant outcomes and up to 6 months of follow-up in subjects treated in the HGB-205 trial will be presented at the meeting.
Summary/Conclusion: Long-term transfusion independence is achievable with gene therapy for ß thalassemia major. Use of the LentiGlobin BB305 vector has resulted in substantially higher VCN in CD34+ cells. It remains to be seen how the clinical outcomes will reflect this improvement.
Table1. Comparison of gene transfer efficiencies and transplantation outcomes with HPV569 vs. BB305 ßA-T87Q-LentiGlobin vectors
Subject
| Age (years) and
gender
| Vector
| Drug product VCN
| CD34+ cell dose infused
(x106 per kg)
| Neutrophil engraftment day
| Infusion related adverse events
| Transfusion status
| #1003
| 18 M
| HPV569
| 0.61
| 4.9
| Day +29
| None
| Independent
| #1004
| 22 F
| HPV569
| 0.31
| 4.3
| Day +20
| None
| Dependent
| #1201
| 19 F
| BB305
| 1.52
| 8.9
| Day +14
| None
| P
| #1202
| 16 M
| BB305
| 2.12
| P
| P
| P
| P
|
1,2 according to qPCRs performed using different methods over the years; P: pending, available at the time of the meeting.
^these authors contributed equally
Keywords: beta thalassemia, Gene therapy, Lentiviral vector, Transduction
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Anticipation of this data caused some wild swings in the share price lately, and given that initial clinical outcomes of the patients dosed with the new vector is still pending till the actual presentation (6/14), that could be an interesting day (actually, it's a Saturday, so the following Monday). I don't know enough about the disease. When is transfusion independence established? Is six months too early for such a signal? I would guess if both patients turned out to be transfusion independent at this point, it might move the stock.
Cheers, Tuck |
