Retroviral replicating vector-mediated gene therapy achieves long-term control of tumor recurrence and leads to durable anticancer immunity

Kei Hiraoka, Akihito Inagaki, Yuki Kato, Tiffany T. Huang, Leah A. Mitchell, Shuichi Kamijima, Masamichi Takahashi, Hiroshi Matsumoto, Katrin Hacke, Carol A. Kruse, Derek Ostertag, Joan M. Robbins, Harry E. Gruber, Douglas J. Jolly, Noriyuki Kasahara

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

Background. Prodrug-activator gene therapy with Toca 511, a tumor-selective retroviral replicating vector (RRV) encoding yeast cytosine deaminase, is being evaluated in recurrent high-grade glioma patients. Nonlytic retroviral infection leads to permanent integration of RRV into the cancer cell genome, converting infected cancer cell and progeny into stable vector producer cells, enabling ongoing transduction and viral persistence within tumors. Cytosine deaminase in infected tumor cells converts the antifungal prodrug 5-fluorocytosine into the anticancer drug 5-fluorouracil, mediating local tumor destruction without significant systemic adverse effects. Methods. Here we investigated mechanisms underlying the therapeutic efficacy of this approach in orthotopic brain tumor models, employing both human glioma xenografts in immunodeficient hosts and syngeneic murine gliomas in immunocompetent hosts. Results. In both models, a single injection of replicating vector followed by prodrug administration achieved long-term survival benefit. In the immunodeficient model, tumors recurred repeatedly, but bioluminescence imaging of tumors enabled tailored scheduling of multicycle prodrug administration, continued control of disease burden, and long-term survival. In the immunocompetent model, complete loss of tumor signal was observed after only 1-2 cycles of prodrug, followed by long-term survival without recurrence for >300 days despite discontinuation of prodrug. Long-term survivors rejected challenge with uninfected glioma cells, indicating immunological responses against native tumor antigens, and immune cell depletion showed a critical role for CD4+ T cells. Conclusion. These results support dual mechanisms of action contributing to the efficacy of RRV-mediated prodrug-activator gene therapy: long-term tumor control by prodrug conversion-mediated cytoreduction, and induction of antitumor immunity.

Original languageEnglish (US)
Pages (from-to)918-929
Number of pages12
JournalNeuro-Oncology
Volume19
Issue number7
DOIs
StatePublished - Jul 1 2017

Keywords

  • Toca 511
  • antitumor immunity
  • prodrug activator gene therapy
  • retroviral replicating vector

ASJC Scopus subject areas

  • Oncology
  • Clinical Neurology
  • Cancer Research

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    Hiraoka, K., Inagaki, A., Kato, Y., Huang, T. T., Mitchell, L. A., Kamijima, S., Takahashi, M., Matsumoto, H., Hacke, K., Kruse, C. A., Ostertag, D., Robbins, J. M., Gruber, H. E., Jolly, D. J., & Kasahara, N. (2017). Retroviral replicating vector-mediated gene therapy achieves long-term control of tumor recurrence and leads to durable anticancer immunity. Neuro-Oncology, 19(7), 918-929. https://doi.org/10.1093/neuonc/nox038