TG6002: A novel oncolytic and vectorized gene pro-drug therapy approach to treat glioblastoma
| Autor: | Charlotte Schmitt, Jean-Yves Delattre, Ludovic Nguyen Them, Philippe Erbs, Juliette Kempf, Hervé Chneiweiss, Ahmed Idbaih, Michel Homerin, Johann Foloppe |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
Cancer Research
Cytosine deaminase 02 engineering and technology Biology Suicide gene 021001 nanoscience & nanotechnology 030226 pharmacology & pharmacy Virology Virus Oncolytic virus 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Oncology Antigen chemistry Thymidine kinase Cytotoxic T cell Vaccinia 0210 nano-technology |
| Zdroj: | Journal of Clinical Oncology. 35:e13510-e13510 |
| ISSN: | 1527-7755 0732-183X |
| Popis: | e13510 Background: Glioblastoma (GBM) is an incurable disease challenging innovations for significant therapeutic progress. TG6002 is a vaccinia virus that replicates mainly in tumor cells after deletion of genes coding for thymidine kinase and ribonucleotide reductase. TG6002 alsoexpresses the yeast-originated gene FCU1 encoding cytosine deaminase and uracilphosphoribosyltransferase that transforms the pro-drug flucytosine (5-FC) into cytotoxic 5-fluorouracil (5-FU) and 5-fluoro-uridilyl monophosphate (5-FUMP), respectively. The proof of this ‘suicide gene’ concept has been demonstrated in man, using a non-replicative vaccinia virus hosting the FCU1gene (Husseini F et al, ASCO 2012). TG6002 mechanism of action then associates oncolysis of tumor cells, immune reaction against released tumor antigens and local chemotherapy. Methods: Prior to initiating clinical development, the anti-tumor activity of the TG6002/5-FC combination was investigated, using U-87MG human GBM cell line and patient-derived cell lines (PDCL). Results: The growth of U-87MG subcutaneous tumors implanted in nude mice was inhibited by systemic administration of TG6002 with or without 5-FC. Mice treated with TG6002 only survived significantly longer than controls; this survival benefit was not modified by addition of 5-FC to TG6002. In contrast, in an orthotopic brain tumor model, mice survived significantly longer when treated intravenously by TG6002 alone, and oral 5-FC added a significant survival benefit. In this model, TG6002 was found in the brain of xenografted mice but not in that of control mice without tumor, indicating a tumor-specific replication of TG6002. PDCL were also exposed in vitro to TG6002. Evidences of virus replication and tumor cells death were detected. In addition, TG6002 exhibited a synergistic cytotoxic effect when combined with temozolomide in this model, suggesting a potential interest for clinical development of this combination. Conclusions: Taken together, our results support initiation, in recurrent GBM patients, of a phase 1 clinical trial testing TG6002 safety in combination with 5-FC, as a first step toward investigation of clinical efficacy of this therapeutic combination in GBM. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|