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355 Gene Therapy for Beta Thalassemia: Preliminary Results from the PHASE I/II Tiget-Bthal Trial of Autologous Hematopoietic Stem Cells Genetically Modified with GLOBE Lentiviral Vector

Program: Oral and Poster Abstracts
Type: Oral
Session: 112. Thalassemia and Globin Gene Regulation II
Sunday, December 10, 2017: 9:30 AM
Bldg B, Lvl 2, B213-B214 (Georgia World Congress Center)

Sarah Marktel, MD1*, Maria Pia Cicalese2*, Fabio Giglio, MD1*, Samantha Scaramuzza3*, Valeria Calbi2*, Miriam Casiraghi2*, Francesca Ciotti2*, Maria Rosa Lidonnici3*, Claudia Rossi3*, Nicoletta Masera4*, Emanuela D'Angelo5*, Nadia Mirra5*, Raffaella Origa, MD6*, Immacolata Tartaglione7*, Giacomo Mandelli3*, Raffaella Milani8*, Salvatore Gattillo8*, Milena Coppola8*, Gianluca Viarengo9*, Luca Santoleri8*, Andrea Calabria3*, Silverio Perrotta10*, Eugenio Montini3*, Giovanna Graziadei, MD11*, Luigi Naldini, MD, PhD12*, Maria Domenica Cappellini, MD11, Fabio Ciceri, MD1*, Alessandro Aiuti2 and Giuliana Ferrari3

1Hematology and BMT Unit IRCCS San Raffaele Scientific Institute, Milan, Italy
2Pediatric Immunohematology and BMT Unit IRCCS San Raffaele Scientific Institute, Milan, Italy
3San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), Milan, Italy
4Pediatric Department University of Milano-Bicocca, San Gerardo Hospital, Monza, Italy
5Pediatric Clinic/DH Fondazione IRCCS Ca' Granda, Milan, Italy
6Department of Biomedical Science and Biotechnology University of Cagliari, Cagliari, Italy
7Department of Woman, Child and General and Specialist Surgery, Università degli studi della Campania "Luigi Vanvitelli", Naples, ITA
8Blood Transfusion Service IRCCS San Raffaele Scientific Institute, Milan, Italy
9Immunohematology and Transfusion Medicine Service Fondazione IRCCS Policlinico S. Matteo, Pavia, Italy
10Department of Woman, Child and General and Specialist Surgery, Università degli Studi della Campania "Luigi Vanvitelli", Napoli, ITA
11Rare Disease Center Fondazione IRCCS Ca' Granda Milano, Milan, ITA
12San Raffaele Telethon Institute for Gene Therapy, Milan, Italy

Gene therapy for transfusion dependent beta-thalassemia is based on the autologous transplantation of hematopoietic stem cells (HSCs) engineered by lentiviral vectors expressing a transcriptionally regulated human beta-globin gene.Gene therapy (GT) could represent an alternative to HSCT with the following potential advantages: use of autologous stem cells, tailored conditioning with no need for immune suppression post GT, no risk of GVHD or rejection.Our contribution to this field was devoted to the clinical development of a gene therapy protocol based on the high-titer vector GLOBE, a 3rd generation self-inactivating lentiviral vector encoding for the human beta globin gene. Transfusion dependent beta thalassemia patients (any genotype) undergo peripheral blood stem cell harvest following mobilization with the lenograstim and plerixafor. After transduction of immune-selected autologous CD34+ cells and successful release of the frozen drug substance, patient undergo a conditioning regimen based on myeloablative treosulfan and thiotepa favoring efficient engraftment of corrected cells with reduced extra-medullary toxicity (TIGET-BTHAL; EudraCT number 2014‐004860‐39). The route of administration of gene modified HSCs is intraosseous in the posterior-superior iliac crests with the aim of enhancing engraftment and minimizing first-pass intravenous filter. Three days after gene therapy, previously collected unstimulated autologous peripheral blood leucocytes (1-10 x107 CD3+/kg) are reinfused intravenously to favor immune-reconstitution. After 2 years follow-up, patients will be followed up for a further six years in a long-term follow-up study. On the basis of extensive efficacy and safety preclinical studies the clinical trial TIGET-BTHAL was approved and started in 2015 at Scientific Institute San Raffaele, Milan, Italy. The clinical study foresees treatment of 10 patients: 3 adults (group 1) followed by 3 patients aged 8-17 years (group 2) and 4 patients aged 3-7 years (group 3), with a staggered enrolment strategy based on evaluation of safety and preliminary efficacy in adult patients by an independent data safety monitoring board (DSMB) before inclusion of pediatric subjects. In March 2016 the DSMB approved enrolment of group 2 patients and, in September 2016, of group 3 patients. As of August 2017, seven patients (3 adults aged 31-35 years and 4 pediatric patients aged 6-13 years) with different genotypes (β00, β++ and β0+) have been treated with GLOBE-transduced CD34+ cells at a dose of 16x106-19.5x106 cells/kg and a vector copy number (VCN)/cell ranging from 0.7 to 1.5. Median follow-up is 13 months (range 8-22). The procedure was well tolerated by all patients, with no product-related adverse events, no evidence of replication competent lentivirus nor of abnormal clonal proliferation on regular peripheral blood and bone marrow analyses. Grade 3-4 adverse events or serious adverse events were principally of infectious origin as expected after a myeloablative autograft. Median time to neutrophil engraftment was 19 days (range 17-25) and to platelet engraftment 15 days (range 10-21). Multilineage engraftment of gene-marked cells was observed in peripheral blood and bone marrow, with a median of 0.58 (range 0.37-1.55) vector copy number/cell in GlyA+ bone marrow erythroid cells at 6 months post GT. Polyclonal vector integrations profiles have been detected in the first 3 patients tested. The three adult patients had a reduction of transfusion requirement but are still transfusion dependent at the last follow-up (22, 18 and 16 months respectively). Among the 4 pediatric patients, 3 have discontinued transfusion shortly after gene therapy and are transfusion independent at the last follow-up (13, 10 and 8 months respectively). One pediatric patient is still receiving regular blood transfusions. A correlation was observed between level of engraftment of gene-marked cells in peripheral blood and bone marrow and transfusion requirement. Preliminary data suggest that the applied clinical protocol for gene therapy with GLOBE LV is well tolerated and leads to significantly reduced transfusion requirement. Follow up analysis are ongoing and updated clinical outcome will be presented.

Disclosures: Marktel: GSK: Other: B-thalassemia gene therapy was developed by Fondazione Telethon and Ospedale San Raffaele and has been inlicenced by GSK that provides funding for the clinical trial, Research Funding. Naldini: San Raffaele Institute: Employment, Patents & Royalties; Telethon Foundation: Consultancy, Patents & Royalties; Bioverativ: Research Funding; Editas: Research Funding; Genenta Sciences: Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Magenta: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Oncorus: Membership on an entity's Board of Directors or advisory committees; Sangamo Biosciences: Membership on an entity's Board of Directors or advisory committees. Cappellini: Sanofi-Genzyme: Honoraria, Research Funding, Speakers Bureau; Celgene: Honoraria; Vifor: Honoraria; Novartis: Speakers Bureau. Ciceri: GSK: Other: B-thalassemia gene therapy was developed by Fondazione Telethon and Ospedale San Raffaele and has been inlicenced by GSK that provides funding for the clinical trial, Research Funding. Aiuti: GSK: Other: B-thalassemia gene therapy was developed by Fondazione Telethon and Ospedale San Raffaele and has been inlicenced by GSK that provides funding for the clinical trial, Research Funding. Ferrari: GSK: Other: B-thalassemia gene therapy was developed by Fondazione Telethon and Ospedale San Raffaele and has been inlicenced by GSK that provides funding for the clinical trial, Research Funding.

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