A Good Manufacturing Practice procedure to engineer donor virus-specific T cells into potent anti-leukemic effector cells

• Published in: Haematologica (Roma) Vol. 99; no. 4; pp. 759 - 768
• Main Authors: van Loenen, Marleen M, de Boer, Renate, van Liempt, Ellis, Meij, Pauline, Jedema, Inge, Falkenburg, J H Frederik, Heemskerk, Mirjam H M
• Format: Journal Article
• Language: English
• Published: Italy Ferrata Storti Foundation 01.04.2014
• Subjects: Adoptive Transfer; Batch Cell Culture Techniques - methods; Batch Cell Culture Techniques - standards; Histocompatibility Antigens Class I - chemistry; Histocompatibility Antigens Class I - immunology; Humans; Immunomagnetic Separation; Leukemia - immunology; Leukemia - therapy; Lymphocyte Activation; Minor Histocompatibility Antigens - immunology; Oligopeptides - immunology; Peptides - chemistry; Peptides - immunology; Receptors, Antigen, T-Cell - immunology; T-Cell Antigen Receptor Specificity - immunology; T-Lymphocytes - immunology; T-Lymphocytes - transplantation; Transduction, Genetic; Viruses - immunology
• ISSN: 0390-6078; 1592-8721
• DOI: 10.3324/haematol.2013.093690

A sequential, two-step procedure in which T-cell-depleted allogeneic stem cell transplantation is followed by treatment with donor lymphocyte infusion at 6 months can significantly reduce the risk and severity of graft-versus-host disease, with postponed induction of the beneficial graft-versus-leukemia effect. However, patients with high-risk leukemia have a substantial risk of relapse early after transplantation, at a time when administration of donor lymphocytes has a high likelihood of resulting in graft-versus-host disease, disturbing a favorable balance between the graft-versus-leukemia effect and graft-versus-host disease. New therapeutic modalities are, therefore, required to allow early administration of T cells capable of exerting a graft-versus-leukemia effect without causing graft-versus-host disease. Here we describe the isolation of virus-specific T cells using Streptamer-based isolation technology and subsequent transfer of the minor histocompatibility antigen HA-1-specific T-cell receptor using retroviral vectors. Isolation of virus-specific T cells and subsequent transduction with HA-1-T-cell receptor resulted in rapid in vitro generation of highly pure, dual-specific T cells with potent anti-leukemic reactivity. Due to the short production procedure of only 10-14 days and the defined specificity of the T cells, administration of virus-specific T cells transduced with the HA-1-T-cell receptor as early as 8 weeks after allogeneic stem cell transplantation is feasible. (This clinical trial is registered at www.clinicaltrialsregister.eu as EudraCT number 2010-024625-20).