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
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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