Improving the safety of cell therapy with the TK-suicide gene

Raffaella Greco, Giacomo Oliveira, Maria Teresa Lupo Stanghellini, Luca Vago, Attilio Bondanza, Jacopo Peccatori, Nicoletta Cieri, Sarah Marktel, Sara Mastaglio, Claudio Bordignon, Chiara Bonini, Fabio Ciceri

Research output: Contribution to journalArticle

40 Citations (Scopus)

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.

Original languageEnglish
Article number95
JournalFrontiers in Pharmacology
Volume6
Issue numberMAY
DOIs
Publication statusPublished - 2015

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Cell- and Tissue-Based Therapy
Suicide
Graft vs Host Disease
Thymidine Kinase
Hematopoietic Stem Cell Transplantation
Safety
Simplexvirus
Tissue Donors
Genes
T-Lymphocytes
Lymphocytes
Technology Transfer
Transplants
Neoplasms
Phase II Clinical Trials
Clinical Trials, Phase I
Ganciclovir
Hematologic Neoplasms
Pharmaceutical Preparations
Immune System

Keywords

  • Allogeneic hematopoietic stem cell transplantation
  • Cellular adoptive immunotherapy
  • Gene therapy
  • Suicide gene therapy
  • TK cells

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology

Cite this

Improving the safety of cell therapy with the TK-suicide gene. / Greco, Raffaella; Oliveira, Giacomo; Lupo Stanghellini, Maria Teresa; Vago, Luca; Bondanza, Attilio; Peccatori, Jacopo; Cieri, Nicoletta; Marktel, Sarah; Mastaglio, Sara; Bordignon, Claudio; Bonini, Chiara; Ciceri, Fabio.

In: Frontiers in Pharmacology, Vol. 6, No. MAY, 95, 2015.

Research output: Contribution to journalArticle

Greco, R, Oliveira, G, Lupo Stanghellini, MT, Vago, L, Bondanza, A, Peccatori, J, Cieri, N, Marktel, S, Mastaglio, S, Bordignon, C, Bonini, C & Ciceri, F 2015, 'Improving the safety of cell therapy with the TK-suicide gene', Frontiers in Pharmacology, vol. 6, no. MAY, 95. https://doi.org/10.3389/fphar.2015.00095
Greco, Raffaella ; Oliveira, Giacomo ; Lupo Stanghellini, Maria Teresa ; Vago, Luca ; Bondanza, Attilio ; Peccatori, Jacopo ; Cieri, Nicoletta ; Marktel, Sarah ; Mastaglio, Sara ; Bordignon, Claudio ; Bonini, Chiara ; Ciceri, Fabio. / Improving the safety of cell therapy with the TK-suicide gene. In: Frontiers in Pharmacology. 2015 ; Vol. 6, No. MAY.
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