A PHASE I/II STUDY OF AUTOLOGOUS HEMATOPOIETIC STEM CELLS GENETICALLY MODIFIED WITH GLOBE LENTIVIRAL VECTOR FOR THE TREATMENT OF TRANSFUSION DEPENDENT BETA-THALASSEMIA
(Abstract release date: 05/19/16)
EHA Library. Marktel S. 06/11/16; 135221; S465
Dr. Sarah Marktel
Contributions
Contributions
Abstract
Abstract: S465
Type: Oral Presentation
Presentation during EHA21: On Saturday, June 11, 2016 from 12:15 - 12:30
Location: Hall C14
Background
A clinical trial was initiated in April 2015 at Scientific Institute San Raffaele to evaluate safety and efficacy of autologous hematopoietic stem cells (HSCs) genetically modified with the GLOBE lentiviral vector for the treatment of transfusion dependent beta thalassemia (TIGET-BTHAL; EudraCT number 2014‐004860‐39).
Aims
The financial sponsor is the Italian charity organization Fondazione Telethon. The manufacture is MolMed S.p.A. The therapeutic potential of GLOBE was validated in thalassemic mice (Miccio et al., PNAS 2008; Miccio et al. PlosONE, 2011) and human thalassemic cells (Roselli et al., EMBO MolMed 2010) showing persistent transgene expression and disease correction. Preclinical GLP studies included a toxicology and tumorigenicity study in th3/+ mice and a biodistribution study of human of CD34+ cells in NSG mice demonstrating safety of the approach.
Methods
The clinical protocol will treat 3 adults followed by 7 minors, with a staggered enrolment strategy based on evaluation of safety and preliminary efficacy in adult patients by an independent data safety monitoring board before inclusion of pediatric subjects. Inclusion criteria: transfusion dependent beta thalassemia, age 3-65 years, adequate cardiac, renal, hepatic and pulmonary functions, absence of severe liver or cardiac iron overload, absence of severe liver fibrosis or cirrhosis. Exclusion criteria include active hepatitis, HIV infection or a previous allogeneic BMT and for pediatric patients availability of a well matched donor. The HSC source is mobilized peripheral blood stem cells (PBSCs) obtained after administration of lenograstim and plerixafor. PBSCs are transduced after apheresis and kept frozen in 10%DMSO until administration to the patient. Conditioning: treosulfan and thiotepa for adult and elderly children (≥ 8years), busulfan for younger children (age 3-7yrs old). The chosen route of administration of thawed and washed gene modified cells is intraosseous in the posterior-superior iliac crests, bilaterally. The aim of intraosseous infusion is to enhance engraftment and minimize first-pass intravenous filter. Autologous lymphocytes (previously cryopreserved from apheresis or phlebotomy) are re-infused at a target dose of 5x10^7 CD3+ cells/kg on day+3 to speed adaptive immune recovery.
Results
Between May and October 2015 three patients were included. As of March 2016, one patient is 6 months post gene therapy, one 1.5 months and one has completed mobilization. Age at enrollment: 31, 35, 35 years. Stem cell harvest was 30x10^6 CD34+/kg, 21.3x10^6 CD34+/kg and 23.5x10^6 CD34+/kg, respectively. Cell dose of gene modified cells of the 2 treated patients: 19.4x10^6 CD34+/kg and 18.4x10^6 CD34+/kg. Adverse events recorded as of March 2016 were mild, reversible and related to the conditioning regimen and transplant procedure. The first patient had a neutrophil engraftment (>500 ANC/µl) on day+21 and platelet engraftment (>20.000/µl unsupported) on day+16. The second patient had a neutrophil engraftment on +25 and platelet engraftment on +21. The first patient treated showed multilineage engraftment of gene corrected cells with higher levels in erythroid lineage and received the last red blood cell transfusion 2 months after gene therapy. At 6 months follow up the patient was transfusion-free and conducting a normal working activity with a haemoglobin of 9.2 g/dL.
Conclusion
In conclusion, preliminary data on adult patients showed a good yield of PBSCs, a high number of cells infused, good tolerability of the procedure overall with reversible adverse events and preliminary positive efficacy data.
Session topic: Red blood cells and iron - Clinical
Keyword(s): Autologous bone marrow transplant, Gene therapy, Thalassemia
Type: Oral Presentation
Presentation during EHA21: On Saturday, June 11, 2016 from 12:15 - 12:30
Location: Hall C14
Background
A clinical trial was initiated in April 2015 at Scientific Institute San Raffaele to evaluate safety and efficacy of autologous hematopoietic stem cells (HSCs) genetically modified with the GLOBE lentiviral vector for the treatment of transfusion dependent beta thalassemia (TIGET-BTHAL; EudraCT number 2014‐004860‐39).
Aims
The financial sponsor is the Italian charity organization Fondazione Telethon. The manufacture is MolMed S.p.A. The therapeutic potential of GLOBE was validated in thalassemic mice (Miccio et al., PNAS 2008; Miccio et al. PlosONE, 2011) and human thalassemic cells (Roselli et al., EMBO MolMed 2010) showing persistent transgene expression and disease correction. Preclinical GLP studies included a toxicology and tumorigenicity study in th3/+ mice and a biodistribution study of human of CD34+ cells in NSG mice demonstrating safety of the approach.
Methods
The clinical protocol will treat 3 adults followed by 7 minors, with a staggered enrolment strategy based on evaluation of safety and preliminary efficacy in adult patients by an independent data safety monitoring board before inclusion of pediatric subjects. Inclusion criteria: transfusion dependent beta thalassemia, age 3-65 years, adequate cardiac, renal, hepatic and pulmonary functions, absence of severe liver or cardiac iron overload, absence of severe liver fibrosis or cirrhosis. Exclusion criteria include active hepatitis, HIV infection or a previous allogeneic BMT and for pediatric patients availability of a well matched donor. The HSC source is mobilized peripheral blood stem cells (PBSCs) obtained after administration of lenograstim and plerixafor. PBSCs are transduced after apheresis and kept frozen in 10%DMSO until administration to the patient. Conditioning: treosulfan and thiotepa for adult and elderly children (≥ 8years), busulfan for younger children (age 3-7yrs old). The chosen route of administration of thawed and washed gene modified cells is intraosseous in the posterior-superior iliac crests, bilaterally. The aim of intraosseous infusion is to enhance engraftment and minimize first-pass intravenous filter. Autologous lymphocytes (previously cryopreserved from apheresis or phlebotomy) are re-infused at a target dose of 5x10^7 CD3+ cells/kg on day+3 to speed adaptive immune recovery.
Results
Between May and October 2015 three patients were included. As of March 2016, one patient is 6 months post gene therapy, one 1.5 months and one has completed mobilization. Age at enrollment: 31, 35, 35 years. Stem cell harvest was 30x10^6 CD34+/kg, 21.3x10^6 CD34+/kg and 23.5x10^6 CD34+/kg, respectively. Cell dose of gene modified cells of the 2 treated patients: 19.4x10^6 CD34+/kg and 18.4x10^6 CD34+/kg. Adverse events recorded as of March 2016 were mild, reversible and related to the conditioning regimen and transplant procedure. The first patient had a neutrophil engraftment (>500 ANC/µl) on day+21 and platelet engraftment (>20.000/µl unsupported) on day+16. The second patient had a neutrophil engraftment on +25 and platelet engraftment on +21. The first patient treated showed multilineage engraftment of gene corrected cells with higher levels in erythroid lineage and received the last red blood cell transfusion 2 months after gene therapy. At 6 months follow up the patient was transfusion-free and conducting a normal working activity with a haemoglobin of 9.2 g/dL.
Conclusion
In conclusion, preliminary data on adult patients showed a good yield of PBSCs, a high number of cells infused, good tolerability of the procedure overall with reversible adverse events and preliminary positive efficacy data.
Session topic: Red blood cells and iron - Clinical
Keyword(s): Autologous bone marrow transplant, Gene therapy, Thalassemia
Abstract: S465
Type: Oral Presentation
Presentation during EHA21: On Saturday, June 11, 2016 from 12:15 - 12:30
Location: Hall C14
Background
A clinical trial was initiated in April 2015 at Scientific Institute San Raffaele to evaluate safety and efficacy of autologous hematopoietic stem cells (HSCs) genetically modified with the GLOBE lentiviral vector for the treatment of transfusion dependent beta thalassemia (TIGET-BTHAL; EudraCT number 2014‐004860‐39).
Aims
The financial sponsor is the Italian charity organization Fondazione Telethon. The manufacture is MolMed S.p.A. The therapeutic potential of GLOBE was validated in thalassemic mice (Miccio et al., PNAS 2008; Miccio et al. PlosONE, 2011) and human thalassemic cells (Roselli et al., EMBO MolMed 2010) showing persistent transgene expression and disease correction. Preclinical GLP studies included a toxicology and tumorigenicity study in th3/+ mice and a biodistribution study of human of CD34+ cells in NSG mice demonstrating safety of the approach.
Methods
The clinical protocol will treat 3 adults followed by 7 minors, with a staggered enrolment strategy based on evaluation of safety and preliminary efficacy in adult patients by an independent data safety monitoring board before inclusion of pediatric subjects. Inclusion criteria: transfusion dependent beta thalassemia, age 3-65 years, adequate cardiac, renal, hepatic and pulmonary functions, absence of severe liver or cardiac iron overload, absence of severe liver fibrosis or cirrhosis. Exclusion criteria include active hepatitis, HIV infection or a previous allogeneic BMT and for pediatric patients availability of a well matched donor. The HSC source is mobilized peripheral blood stem cells (PBSCs) obtained after administration of lenograstim and plerixafor. PBSCs are transduced after apheresis and kept frozen in 10%DMSO until administration to the patient. Conditioning: treosulfan and thiotepa for adult and elderly children (≥ 8years), busulfan for younger children (age 3-7yrs old). The chosen route of administration of thawed and washed gene modified cells is intraosseous in the posterior-superior iliac crests, bilaterally. The aim of intraosseous infusion is to enhance engraftment and minimize first-pass intravenous filter. Autologous lymphocytes (previously cryopreserved from apheresis or phlebotomy) are re-infused at a target dose of 5x10^7 CD3+ cells/kg on day+3 to speed adaptive immune recovery.
Results
Between May and October 2015 three patients were included. As of March 2016, one patient is 6 months post gene therapy, one 1.5 months and one has completed mobilization. Age at enrollment: 31, 35, 35 years. Stem cell harvest was 30x10^6 CD34+/kg, 21.3x10^6 CD34+/kg and 23.5x10^6 CD34+/kg, respectively. Cell dose of gene modified cells of the 2 treated patients: 19.4x10^6 CD34+/kg and 18.4x10^6 CD34+/kg. Adverse events recorded as of March 2016 were mild, reversible and related to the conditioning regimen and transplant procedure. The first patient had a neutrophil engraftment (>500 ANC/µl) on day+21 and platelet engraftment (>20.000/µl unsupported) on day+16. The second patient had a neutrophil engraftment on +25 and platelet engraftment on +21. The first patient treated showed multilineage engraftment of gene corrected cells with higher levels in erythroid lineage and received the last red blood cell transfusion 2 months after gene therapy. At 6 months follow up the patient was transfusion-free and conducting a normal working activity with a haemoglobin of 9.2 g/dL.
Conclusion
In conclusion, preliminary data on adult patients showed a good yield of PBSCs, a high number of cells infused, good tolerability of the procedure overall with reversible adverse events and preliminary positive efficacy data.
Session topic: Red blood cells and iron - Clinical
Keyword(s): Autologous bone marrow transplant, Gene therapy, Thalassemia
Type: Oral Presentation
Presentation during EHA21: On Saturday, June 11, 2016 from 12:15 - 12:30
Location: Hall C14
Background
A clinical trial was initiated in April 2015 at Scientific Institute San Raffaele to evaluate safety and efficacy of autologous hematopoietic stem cells (HSCs) genetically modified with the GLOBE lentiviral vector for the treatment of transfusion dependent beta thalassemia (TIGET-BTHAL; EudraCT number 2014‐004860‐39).
Aims
The financial sponsor is the Italian charity organization Fondazione Telethon. The manufacture is MolMed S.p.A. The therapeutic potential of GLOBE was validated in thalassemic mice (Miccio et al., PNAS 2008; Miccio et al. PlosONE, 2011) and human thalassemic cells (Roselli et al., EMBO MolMed 2010) showing persistent transgene expression and disease correction. Preclinical GLP studies included a toxicology and tumorigenicity study in th3/+ mice and a biodistribution study of human of CD34+ cells in NSG mice demonstrating safety of the approach.
Methods
The clinical protocol will treat 3 adults followed by 7 minors, with a staggered enrolment strategy based on evaluation of safety and preliminary efficacy in adult patients by an independent data safety monitoring board before inclusion of pediatric subjects. Inclusion criteria: transfusion dependent beta thalassemia, age 3-65 years, adequate cardiac, renal, hepatic and pulmonary functions, absence of severe liver or cardiac iron overload, absence of severe liver fibrosis or cirrhosis. Exclusion criteria include active hepatitis, HIV infection or a previous allogeneic BMT and for pediatric patients availability of a well matched donor. The HSC source is mobilized peripheral blood stem cells (PBSCs) obtained after administration of lenograstim and plerixafor. PBSCs are transduced after apheresis and kept frozen in 10%DMSO until administration to the patient. Conditioning: treosulfan and thiotepa for adult and elderly children (≥ 8years), busulfan for younger children (age 3-7yrs old). The chosen route of administration of thawed and washed gene modified cells is intraosseous in the posterior-superior iliac crests, bilaterally. The aim of intraosseous infusion is to enhance engraftment and minimize first-pass intravenous filter. Autologous lymphocytes (previously cryopreserved from apheresis or phlebotomy) are re-infused at a target dose of 5x10^7 CD3+ cells/kg on day+3 to speed adaptive immune recovery.
Results
Between May and October 2015 three patients were included. As of March 2016, one patient is 6 months post gene therapy, one 1.5 months and one has completed mobilization. Age at enrollment: 31, 35, 35 years. Stem cell harvest was 30x10^6 CD34+/kg, 21.3x10^6 CD34+/kg and 23.5x10^6 CD34+/kg, respectively. Cell dose of gene modified cells of the 2 treated patients: 19.4x10^6 CD34+/kg and 18.4x10^6 CD34+/kg. Adverse events recorded as of March 2016 were mild, reversible and related to the conditioning regimen and transplant procedure. The first patient had a neutrophil engraftment (>500 ANC/µl) on day+21 and platelet engraftment (>20.000/µl unsupported) on day+16. The second patient had a neutrophil engraftment on +25 and platelet engraftment on +21. The first patient treated showed multilineage engraftment of gene corrected cells with higher levels in erythroid lineage and received the last red blood cell transfusion 2 months after gene therapy. At 6 months follow up the patient was transfusion-free and conducting a normal working activity with a haemoglobin of 9.2 g/dL.
Conclusion
In conclusion, preliminary data on adult patients showed a good yield of PBSCs, a high number of cells infused, good tolerability of the procedure overall with reversible adverse events and preliminary positive efficacy data.
Session topic: Red blood cells and iron - Clinical
Keyword(s): Autologous bone marrow transplant, Gene therapy, Thalassemia
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