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Published on: January 9, 2018
Ad6-Based GM-CSF Expressing Vector Displays Oncolytic and Immunostimulatory Effects in an Immunocompetent Syrian
Daria S Zabelina1, Ivan D Osipov1, Denis E Maslov1
1Faculty of Natural Sciences, Novosibirsk State University, Pirogov 2, Novosibirsk 630090, Russia.
Abstract:
Cholangiocarcinoma (CCA), the second most common liver cancer, remains highly resistant to chemotherapy and radiotherapy, leaving patients with unresectable tumors in urgent need of innovative therapeutic approaches. Adenovirus type 6 (Ad6), a species C human adenovirus, offers significant potential for cancer therapy due to its low seroprevalence compared to Adenovirus type 5 (Ad5) and its ability to evade Kupffer cells during systemic delivery. In this study, we developed a novel oncolytic adenovirus vector based on the Ad6 engineered to express human GM-CSF (Ad6-d24-GM) and evaluated its therapeutic efficacy in a novel immunocompetent, replication-permissive Syrian hamster model of CCA. Intratumoral administration of Ad6-d24-GM significantly suppressed tumor growth and prolonged survival without evidence of toxicity, as indicated by stable body weights and normal liver enzyme levels. Both Ad6-d24-GM and wild-type Ad6 induced robust infiltration of CD4+ and CD8+ T cells, as well as CD68+ macrophages within tumors, demonstrating activation of antitumor immunity. Notably, the Ad6-d24-GM group exhibited a statistically significant increase in CD68+ cells compared to wild-type Ad6, highlighting the immunomodulatory effect of GM-CSF transgene. These results demonstrate the oncolytic and immunostimulatory potential of Ad6-based vectors for CCA treatment and validate the Syrian hamster syngeneic CCA-OF model as a valuable platform for studying oncolytic adenovirus therapies.
Insights
Novel oncolytic adenovirus (Ad6) engineered to express GM-CSF effectively treats cholangiocarcinoma (CCA) in a hamster model. This therapy suppressed tumor growth and activated antitumor immunity, offering a promising new approach for liver cancer.
Area of Science:
- Oncolytic virotherapy
- Cancer immunology
- Hepatobiliary cancers
Background:
- Cholangiocarcinoma (CCA) is a challenging liver cancer with limited treatment options.
- Adenovirus type 6 (Ad6) shows promise for cancer therapy due to low pre-existing immunity and effective delivery.
- Developing novel therapeutic strategies for unresectable CCA is critical.
Purpose of the Study:
- To develop and evaluate a novel Ad6-based oncolytic adenovirus vector expressing GM-CSF (Ad6-d24-GM).
- To assess the therapeutic efficacy and safety of Ad6-d24-GM in a Syrian hamster model of CCA.
- To investigate the immunomodulatory effects of Ad6-d24-GM on the tumor microenvironment.
Main Methods:
- Engineered Ad6 vector (Ad6-d24-GM) to express human GM-CSF.
- Utilized a novel immunocompetent Syrian hamster CCA model (CCA-OF).
- Administered Ad6-d24-GM intratumorally and assessed tumor growth, survival, toxicity, and immune cell infiltration (CD4+, CD8+ T cells, CD68+ macrophages).
Main Results:
- Intratumoral Ad6-d24-GM significantly suppressed CCA tumor growth and prolonged survival.
- No significant toxicity was observed, evidenced by stable body weights and normal liver enzymes.
- Both Ad6-d24-GM and wild-type Ad6 increased infiltration of immune cells; Ad6-d24-GM showed a significant increase in CD68+ macrophages, indicating GM-CSF's immunomodulatory effect.
Conclusions:
- Ad6-based oncolytic adenovirus vectors exhibit significant oncolytic and immunostimulatory potential for CCA treatment.
- The Syrian hamster CCA-OF model is a valuable platform for evaluating oncolytic adenovirus therapies.
- GM-CSF expression enhances the immunomodulatory capacity of Ad6 vectors in CCA.
