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TALEN-mediated genetic inactivation of the glucocorticoid receptor in cytomegalovirus-specific T cells.
Menger, Laurie; Gouble, Agnes; Marzolini, Maria A V; Pachnio, Annette; Bergerhoff, Katharina; Henry, Jake Y; Smith, Julianne; Pule, Martin; Moss, Paul; Riddell, Stanley R; Quezada, Sergio A; Peggs, Karl S.
Affiliation
  • Menger L; Cancer Immunology Unit, Research Department of Haematology, University College London Cancer Institute, London, United Kingdom;
  • Gouble A; Cellectis, Paris, France;
  • Marzolini MA; Cancer Immunology Unit, Research Department of Haematology, University College London Cancer Institute, London, United Kingdom;
  • Pachnio A; School of Cancer Sciences, University of Birmingham, Birmingham, United Kingdom; and.
  • Bergerhoff K; Cancer Immunology Unit, Research Department of Haematology, University College London Cancer Institute, London, United Kingdom;
  • Henry JY; Cancer Immunology Unit, Research Department of Haematology, University College London Cancer Institute, London, United Kingdom;
  • Smith J; Cellectis, Paris, France;
  • Pule M; Cancer Immunology Unit, Research Department of Haematology, University College London Cancer Institute, London, United Kingdom;
  • Moss P; School of Cancer Sciences, University of Birmingham, Birmingham, United Kingdom; and.
  • Riddell SR; Fred Hutchinson Cancer Research Center, Seattle, WA.
  • Quezada SA; Cancer Immunology Unit, Research Department of Haematology, University College London Cancer Institute, London, United Kingdom;
  • Peggs KS; Cancer Immunology Unit, Research Department of Haematology, University College London Cancer Institute, London, United Kingdom;
Blood ; 126(26): 2781-9, 2015 Dec 24.
Article in En | MEDLINE | ID: mdl-26508783
Cytomegalovirus (CMV) infection is responsible for substantial morbidity and mortality after allogeneic hematopoietic stem cell transplant. T-cell immunity is critical for control of CMV infection, and correction of the immune deficiency induced by transplant is now clinically achievable by the adoptive transfer of donor-derived CMV-specific T cells. It is notable, however, that most clinical studies of adoptive T- cell therapy exclude patients with graft-versus-host disease (GVHD) from receiving systemic corticosteroid therapy, which impairs cellular immunity. This group of patients remains the highest clinical risk group for recurrent and problematic infections. Here, we address this unmet clinical need by genetic disruption of the glucocorticoid receptor (GR) gene using electroporation of transcription activator-like effector nuclease (TALEN) messenger RNA. We demonstrate efficient inactivation of the GR gene without off-target activity in Streptamer-selected CMV-specific CD8(+) T cells (HLA-A02/NLV peptide), conferring resistance to glucocorticoids. TALEN-modified CMV-specific T cells retained specific killing of target cells pulsed with the CMV peptide NLV in the presence of dexamethasone (DEX). Inactivation of the GR gene also conferred resistance to DEX in a xenogeneic GVHD model in sublethally irradiated NOD-scid IL2rγ(null) mice. This proof of concept provides the rationale for the development of clinical protocols for producing and administering high-purity genetically engineered virus-specific T cells that are resistant to the suppressive effects of corticosteroids.
Subject(s)

Full text: 1 Database: MEDLINE Main subject: Receptors, Glucocorticoid / Cytomegalovirus Infections / Hematopoietic Stem Cell Transplantation / CD8-Positive T-Lymphocytes / Adoptive Transfer / Gene Knockdown Techniques Type of study: Guideline Limits: Animals / Humans Language: En Year: 2015 Type: Article

Full text: 1 Database: MEDLINE Main subject: Receptors, Glucocorticoid / Cytomegalovirus Infections / Hematopoietic Stem Cell Transplantation / CD8-Positive T-Lymphocytes / Adoptive Transfer / Gene Knockdown Techniques Type of study: Guideline Limits: Animals / Humans Language: En Year: 2015 Type: Article