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Retroviral replicating vector-mediated gene therapy achieves long-term control of tumor recurrence and leads to
Kei Hiraoka1, Akihito Inagaki1, Yuki Kato1
1Department of Medicine, University of California Los Angeles (UCLA), Los Angeles, California; Department of Cell Biology and Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida; Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California; Tocagen Inc., San Diego, California; Department of Neurosurgery, University of California Los Angeles, Los Angeles, California.
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.
Insights
Prodrug-activator gene therapy using Toca 511 shows promise for high-grade glioma. This approach leverages a retroviral replicating vector (RRV) to convert a prodrug into an anticancer agent, demonstrating dual mechanisms of tumor destruction and immune activation.
Area of Science:
- Oncolytic virotherapy
- Gene therapy
- Immunotherapy
Background:
- Toca 511, a retroviral replicating vector (RRV), is being evaluated for recurrent high-grade glioma.
- RRV integrates into cancer cells, creating persistent vector producer cells.
- Infected cells convert a prodrug (5-fluorocytosine) into an anticancer drug (5-fluorouracil), enabling localized tumor destruction.
Purpose of the Study:
- Investigate the mechanisms of therapeutic efficacy for Toca 511 prodrug-activator gene therapy.
- Evaluate the approach in both immunodeficient and immunocompetent orthotopic brain tumor models.
Main Methods:
- Utilized human glioma xenografts in immunodeficient hosts.
- Employed syngeneic murine gliomas in immunocompetent hosts.
- Applied bioluminescence imaging for monitoring and tailored prodrug administration scheduling.
Main Results:
- Single administration of RRV and prodrug led to long-term survival benefits in both models.
- Multicycle prodrug administration controlled disease burden and improved survival in immunodeficient models.
- Complete tumor eradication and long-term survival without recurrence were observed in immunocompetent models after limited prodrug cycles, indicating induced antitumor immunity.
Conclusions:
- Toca 511 prodrug-activator gene therapy exhibits dual mechanisms of action.
- Efficacy is attributed to both prodrug conversion-mediated tumor cell killing and the induction of antitumor immunity.
- CD4+ T cells play a critical role in the observed long-term survival and tumor rejection.