title: Cancer suicide gene therapy with TK.007: superior killing efficiency and bystander effect.
abstract: Suicide gene therapy is a promising concept in oncology. We have recently introduced a novel suicide gene, TK.007, which was shown to excel established herpes simplex virus thymidine kinase (HSVtk) variants when used for donor-lymphocyte modification in adoptive immunotherapy models. Here, the potential of TK.007 in killing cancer cells was studied. Initially, we transduced tumour cell lines derived from different neoplasias (glioblastoma, melanoma, lung cancer, colon cancer) with lentiviral LeGO vectors encoding TK.007 or the splice-corrected (sc)HSVtk together with an eGFP/Neo-marker. Based on direct in vitro comparison, we found that TK.007 facilitates more efficient tumour cell killing at significantly lower ganciclovir doses in all tumour cell lines tested. Also, using different readout systems, we found a significantly stronger bystander effect of TK.007 as compared to scHSVtk. Importantly, in vitro data were confirmed in vivo using a subcutaneous G62 glioblastoma model in NOD/SCID mice. In mice transplanted with scHSVtk-positive tumours, treatment with low (10 mg/kg) or standard (50 mg/kg) ganciclovir doses resulted only in short-term growth inhibition or transient tumour remission, respectively. In striking contrast, in the TK.007 group, all animals achieved continuous complete remission after both standard and low-dose ganciclovir. Finally, a substantial bystander effect for TK.007 was also confirmed with the G62 model in vivo, where significantly prolonged survival for mice bearing tumours containing only 10% or 50% TK.007-expressing cells was observed. In summary, our data indicate strongly improved anti-tumour activity of TK.007 as compared to conventional HSVtk. We therefore suppose that TK.007 is an excellent candidate for cancer suicide gene therapy.
authors.affiliation: Research Department Cell and Gene Therapy, Clinic for Stem Cell Transplantation, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Ellen
authors.initials: E
authors.lastname: Preuss
authors.forename: Alexander
authors.initials: A
authors.lastname: Muik
authors.forename: Kristoffer
authors.initials: K
authors.lastname: Weber
authors.forename: Jürgen
authors.initials: J
authors.lastname: Otte
authors.forename: Dorothee
authors.initials: D
authors.lastname: von Laer
authors.forename: Boris
authors.initials: B
authors.lastname: Fehse
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D024201:Bystander Effect; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D015774:Ganciclovir / Q000494:pharmacology; D041722:Genes, Transgenic, Suicide; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000208:ethnology / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D018139:Simplexvirus / Q000201:enzymology* / Q000235:genetics; D013937:Thymidine Kinase / Q000235:genetics / Q000378:metabolism*; D014183:Transplantation, Heterologous; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000998:Antiviral Agents; D014764:Viral Proteins; D013937:Thymidine Kinase; D015774:Ganciclovir