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Suppression of antiviral innate immunity by sunitinib enhances oncolytic virotherapy
Babal K Jha1, Beihua Dong, Carvell T Nguyen
1Department of Cancer Biology, Lerner Research Institute, Cleveland, Ohio, USA.
Abstract:
The use of lytic viruses to preferentially infect and eliminate cancer cells while sparing normal cells is a promising experimental therapeutic approach for treating cancer. However, the efficacy of oncolytic virotherapy is often limited by two innate immunity pathways, the protein kinase PKR and the 2'-5'-oligoadenylate (OAS)/RNase L systems, which are widely present in many but not all tumor cell types. Previously, we reported that the anticancer drug, sunitinib, an inhibitor of VEGF-R and PDGF-R, has off-target effects against both PKR and RNase L. Here we show that combining sunitinib treatments with infection by an oncolytic virus, vesicular stomatitis virus (VSV), led to the elimination of prostate, breast, and kidney malignant tumors in mice. In contrast, either virus or sunitinib alone slowed tumor progression but did not eliminate tumors. In prostate tumors excised from treated mice, sunitinib decreased levels of the phosphorylated form of translation initiation factor, eIF2-α, a substrate of PKR, by 10-fold while increasing median viral titers by 23-fold. The sunitinib/VSV regimen caused complete and sustained tumor regression in both immunodeficient and immunocompetent animals. Results indicate that transient inhibition of innate immunity with sunitinib enhances oncolytic virotherapy allowing the recovery of tumor-bearing animals.
Insights
Combining sunitinib with vesicular stomatitis virus (VSV) eliminated tumors in mice by inhibiting innate immunity. This oncolytic virotherapy approach offers a promising new strategy for cancer treatment.
Area of Science:
- Oncology
- Virology
- Immunology
Background:
- Oncolytic virotherapy uses viruses to target cancer cells, but innate immunity pathways like protein kinase PKR and the 2'-5'-oligoadenylate (OAS)/RNase L systems limit efficacy.
- Sunitinib, an anticancer drug, has shown off-target effects against both PKR and RNase L.
Purpose of the Study:
- To investigate the efficacy of combining sunitinib with vesicular stomatitis virus (VSV) for cancer treatment.
- To determine if sunitinib can enhance the effectiveness of VSV-based oncolytic virotherapy by targeting innate immunity pathways.
Main Methods:
- Mice with prostate, breast, and kidney tumors were treated with either VSV, sunitinib, or a combination of both.
- Tumor progression and elimination were monitored.
- Levels of phosphorylated translation initiation factor eIF2-α and viral titers in prostate tumors were measured.
Main Results:
- The combination of sunitinib and VSV led to the complete elimination of tumors in mice, whereas monotherapy only slowed tumor progression.
- Sunitinib treatment decreased phosphorylated eIF2-α levels by 10-fold and increased VSV viral titers by 23-fold in prostate tumors.
- Complete and sustained tumor regression was observed in both immunodeficient and immunocompetent animals.
Conclusions:
- Transient inhibition of innate immunity with sunitinib significantly enhances oncolytic virotherapy using VSV.
- The combination therapy promotes complete tumor regression and recovery in tumor-bearing animals.
- This strategy represents a promising advancement in oncolytic virotherapy for cancer treatment.
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