Retroviral replicating vector-mediated gene therapy achieves long-term control of tumor recurrence and leads to durable anticancer immunity
Autor: | Joan M. Robbins, Douglas J. Jolly, Leah Mitchell, Yuki Kato, Tiffany T. Huang, Masamichi Takahashi, Derek Ostertag, Katrin Hacke, Hiroshi Matsumoto, Carol A. Kruse, Harry E. Gruber, Shuichi Kamijima, Noriyuki Kasahara, Akihito Inagaki, Kei Hiraoka |
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Rok vydání: | 2017 |
Předmět: |
0301 basic medicine
Cancer Research Genetic enhancement Cytosine Deaminase Mice 0302 clinical medicine Medicine Tumor Brain Neoplasms Cytosine deaminase Glioma Prodrug 3. Good health Editorial Local Oncology 030220 oncology & carcinogenesis Basic and Translational Investigations Female prodrug activator gene therapy Cell Survival antitumor immunity Oncology and Carcinogenesis Genetic Vectors Brain tumor Toca 511 Cell Line 03 medical and health sciences Immune system Cell Line Tumor Bioluminescence imaging Animals Humans Oncology & Carcinogenesis business.industry Neurosciences Genetic Therapy medicine.disease Virology Survival Analysis Neoplasm Recurrence 030104 developmental biology retroviral replicating vector Retroviridae Cancer cell Neurology (clinical) Neoplasm Recurrence Local business |
Zdroj: | Neuro-Oncology Neuro-oncology, vol 19, iss 7 |
ISSN: | 1523-5866 |
Popis: | Author(s): Hiraoka, Kei; Inagaki, Akihito; Kato, Yuki; Huang, Tiffany T; Mitchell, Leah A; Kamijima, Shuichi; Takahashi, Masamichi; Matsumoto, Hiroshi; Hacke, Katrin; Kruse, Carol A; Ostertag, Derek; Robbins, Joan M; Gruber, Harry E; Jolly, Douglas J; Kasahara, Noriyuki | Abstract: BackgroundProdrug-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.MethodsHere 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.ResultsIn 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 g300 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.ConclusionThese 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. |
Databáze: | OpenAIRE |
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