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Thessaloníki, Greece

Sadelain M.,Sloan Kettering Cancer Center | Riviere I.,Sloan Kettering Cancer Center | Wang X.,Sloan Kettering Cancer Center | Boulad F.,Sloan Kettering Cancer Center | And 5 more authors.
Annals of the New York Academy of Sciences | Year: 2010

Globin gene transfer in autologous hematopoietic stem cells offers a potentially curative treatment option for patients suffering from β-thalassemia major who lack an HLA-matched hematopoietic stem cell donor. Based on extensive preclinical investigation, we are initiating a phase I clinical trial using G-CSF mobilized, autologous CD34+ cells transduced with a vector similar to the original TNS9 vector. Our first mobilizations in adult β-thalassemic subjects have been well tolerated and yielded the required CD34+ cell dose. To minimize toxicity to enrolled subjects, and in the absence of a demonstrated requirement for myeloablative conditioning, our trial will use a reduced intensity conditioning regimen. Because low vector titers may adversely affect efficacy and safety, we have focused on vector manufacturing processes. We are now in a position to transfer our globin lentiviral vectors in a clinically relevant dosage (averaging 0.8 vector copy per cell in bulk CD34+ cells) and to supply clinical grade vector to collaborating centers in the U.S.A. and in Europe. We anticipate that the first U.S. trial of globin gene transfer will start in 2010. © 2010 New York Academy of Sciences.

Yannaki E.,Gene and Cell Therapy Center | Emery D.W.,University of Washington | Stamatoyannopoulos G.,University of Washington
Expert Reviews in Molecular Medicine | Year: 2010

The β-thalassaemias are inherited anaemias that form the most common class of monogenic disorders in the world. Treatment options are limited, with allogeneic haematopoietic stem cell transplantation offering the only hope for lifelong cure. However, this option is not available for many patients as a result of either the lack of compatible donors or the increased risk of transplant-related mortality in subjects with organ damage resulting from accumulated iron. The paucity of alternative treatments for patients that fall into either of these categories has led to the development of a revolutionary treatment strategy based on gene therapy. This approach involves replacing allogeneic stem cell transplantation with the transfer of normal globin genes into patient-derived, autologous haematopoietic stem cells. This highly attractive strategy offers several advantages, including bypassing the need for allogeneic donors and the immunosuppression required to achieve engraftment of the transplanted cells and to eliminate the risk of donor-related graft-versus-host disease. This review discusses the many advances that have been made towards this endeavour as well as the hurdles that must still be overcome before gene therapy for β-thalassaemia, as well as many other gene therapy applications, can be widely applied in the clinic. © Cambridge University Press 2010.

Yannaki E.,Gene and Cell Therapy Center | Stamatoyannopoulos G.,University of Washington
Annals of the New York Academy of Sciences | Year: 2010

Effective gene therapy for hemoglobinopathies will require high numbers of autologous gene-engineered hematopoetic stem cells to be reintroduced into the patients. Stem cell mobilization using G-CSF is the most convenient and effective approach to achieve this goal, but it can have severe side effects in sickle cell anemia and be potentially harmful in the case of severe thalassemia. Hence, the optimal way of collection of hematopoetic stem cells from patients with thalassemia and sickle cell disease needs to be determined. In this paper, we review the possible risks of G-CSF mobilization in hemoglobinopathies and we outline the approaches used in an on-going clinical trial in which pretreatment with hydroxyurea is used to reduce potential risks of G-CSF administration to patients with severe beta thalassemia. © 2010 New York Academy of Sciences.

Papadopoulou A.,Gene and Cell Therapy Center | Papadopoulou A.,Center for Research and Technology Hellas | Kaloyannidis P.,Adult Hematology and Stem cell Transplant | Yannaki E.,Gene and Cell Therapy Center | And 2 more authors.
Critical Reviews in Oncology/Hematology | Year: 2016

Although newer antifungal drugs have substantially altered the natural history of invasive aspergillosis, the disease still accounts for significant morbidity and mortality in hematopoietic stem cell transplant recipients. Both the evidence supporting a protective role of T cells against this fungal pathogen and the documented efficacy of adoptive transfer of antigen-specific T cells for prophylaxis and treatment of viral infections post-transplant have stimulated much interest towards development of Aspergillus-specific T cells (Asp-STs) for adoptive immunotherapy in the allogeneic transplant setting. In contrast to the remarkable progress with virus-specific T cells, clinical development of fungus-specific T cells is still in its infancy. Several groups have characterized Asp-STs in healthy individuals and patients with malignant hematological diseases, while others sought to develop GMP-compliant methods of expanding or bioengineering Asp-STs ex vivo as immunotherapy. This review highlights the recent advances in this field, and discusses critical issues involved in development and protocol design of Asp-ST immunotherapy. © 2015 Elsevier Ireland Ltd.

Yannaki E.,Gene and Cell Therapy Center | Papayannopoulou T.,University of Washington | Jonlin E.,University of Washington | Zervou F.,Gene and Cell Therapy Center | And 14 more authors.
Molecular Therapy | Year: 2012

The safety and efficacy of hematopoietic stem cell (HSC) mobilization was investigated in adult splenectomized (SPL) and non-SPL patients with thalassemia major, in two clinical trials, using different mobilization modes granulocyte-colony-stimulating factor (G-CSF)-alone, G-CSF following pretreatment with hydroxyurea (HU), plerixafor-alone. G-CSF-mobilization was both safe and effective in non-SPL patients. However, in SPL patients the procedure resulted in excessive response to G-CSF, expressed as early hyperleukocytosis necessitating significant dose reduction, and suboptimal CD34 + cells yields. One-month HU-pretreatment prevented hyperleukocytosis and allowed successful CD34 + cell collections when an optimal washout period was maintained, but it significantly prolonged the mobilization procedure. Plerixafor resulted in rapid and effective mobilization in both SPL and non-SPL patients and was well-tolerated. For gene therapy of thalassemia, G-CSF or Plerixafor could be used as mobilization agents in non-SPL patients whereas Plerixafor appears to be the mobilization agent of choice in SPL adult thalassemics in terms of safety and efficacy. © The American Society of Gene & Cell Therapy.

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