title: Improving the safety of cell therapy with the TK-suicide gene.
abstract: While opening new frontiers for the cure of malignant and non-malignant diseases, the increasing use of cell therapy poses also several new challenges related to the safety of a living drug. The most effective and consolidated cell therapy approach is allogeneic hematopoietic stem cell transplantation (HSCT), the only cure for several patients with high-risk hematological malignancies. The potential of allogeneic HSCT is strictly dependent on the donor immune system, particularly on alloreactive T lymphocytes, that promote the beneficial graft-versus-tumor effect (GvT), but may also trigger the detrimental graft-versus-host-disease (GvHD). Gene transfer technologies allow to manipulate donor T-cells to enforce GvT and foster immune reconstitution, while avoiding or controlling GvHD. The suicide gene approach is based on the transfer of a suicide gene into donor lymphocytes, for a safe infusion of a wide T-cell repertoire, that might be selectively controlled in vivo in case of GvHD. The herpes simplex virus thymidine kinase (HSV-TK) is the suicide gene most extensively tested in humans. Expression of HSV-TK in donor lymphocytes confers lethal sensitivity to the anti-herpes drug, ganciclovir. Progressive improvements in suicide genes, vector technology and transduction protocols have allowed to overcome the toxicity of GvHD while preserving the antitumor efficacy of allogeneic HSCT. Several phase I-II clinical trials in the last 20 years document the safety and the efficacy of HSV-TK approach, able to maintain its clear value over the last decades, in the rapidly progressing horizon of cancer cellular therapy.
authors.affiliation: Unit of Hematology and Bone Marrow Transplantation, Division of Regenerative Medicine, Stem Cells and Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan Italy.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Greco
authors.affiliation: Experimental Hematology Unit, Division of Immunology, Transplantation and Infectious Diseases, Program in Immunology and Bio-immunotherapy of Cancer, IRCCS San Raffaele Scientific Institute, Milan Italy.
authors.forename: Giacomo
authors.initials: G
authors.lastname: Oliveira
authors.affiliation: Unit of Hematology and Bone Marrow Transplantation, Division of Regenerative Medicine, Stem Cells and Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan Italy.
authors.forename: Maria Teresa Lupo
authors.initials: MT
authors.lastname: Stanghellini
authors.affiliation: Unit of Hematology and Bone Marrow Transplantation, Division of Regenerative Medicine, Stem Cells and Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan Italy ; Unit of Molecular and Functional Immunogenetics, Division of Regenerative Medicine, Stem Cells and Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Vago
authors.affiliation: Leukemia Immunotherapy Unit, Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan Italy.
authors.forename: Attilio
authors.initials: A
authors.lastname: Bondanza
authors.affiliation: Unit of Hematology and Bone Marrow Transplantation, Division of Regenerative Medicine, Stem Cells and Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan Italy.
authors.forename: Jacopo
authors.initials: J
authors.lastname: Peccatori
authors.affiliation: Experimental Hematology Unit, Division of Immunology, Transplantation and Infectious Diseases, Program in Immunology and Bio-immunotherapy of Cancer, IRCCS San Raffaele Scientific Institute, Milan Italy.
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Cieri
authors.affiliation: Unit of Hematology and Bone Marrow Transplantation, Division of Regenerative Medicine, Stem Cells and Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan Italy.
authors.forename: Sarah
authors.initials: S
authors.lastname: Marktel
authors.affiliation: Experimental Hematology Unit, Division of Immunology, Transplantation and Infectious Diseases, Program in Immunology and Bio-immunotherapy of Cancer, IRCCS San Raffaele Scientific Institute, Milan Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Mastaglio
authors.affiliation: Vita-Salute San Raffaele University, MolMed S.p.A., Milan Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Bordignon
authors.affiliation: Experimental Hematology Unit, Division of Immunology, Transplantation and Infectious Diseases, Program in Immunology and Bio-immunotherapy of Cancer, IRCCS San Raffaele Scientific Institute, Milan Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Bonini
authors.affiliation: Unit of Hematology and Bone Marrow Transplantation, Division of Regenerative Medicine, Stem Cells and Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Ciceri
keywords: TK cells; allogeneic hematopoietic stem cell transplantation; cellular adoptive immunotherapy; gene therapy; suicide gene therapy