Activating systemic T-cell immunity against self tumor antigens to support oncolytic virotherapy with vesicular stomatitis virus

Phonphimon Wongthida, Rosa Maria Diaz, Christine Pulido, Diana Rommelfanger, Feorillo Galivo, Karen Kaluza, Timothy Kottke, Jill Thompson, Alan Melcher, Richard Vile

Research output: Contribution to journalArticle

54 Scopus citations

Abstract

We have shown that the antitumor activity of vesicular stomatitis virus (VSV) against B16ova tumors in C57BL/6 mice is predominantly due to innate antiviral immune effectors. We have also shown that the innate immune-activating properties of VSV can be harnessed to prime adaptive T-cell responses against a tumor-associated antigen (TAA) if the virus is engineered to express the cDNA of the antigen. Here, we show that the combination of VSV expressing OVA as a model tumor antigen, along with adoptive T-cell therapy targeted against the same antigen, is superior to either treatment alone and induces systemic antitumor activity. In addition, we extend our findings with the OVA model to the therapeutic use of VSV expressing hgp100, a self TAA against which tolerance is well established in C57BL/6 mice. In contrast to VSV-ova, T-cell responses raised by VSV-hgp100 were insufficient to improve therapy against B16ova tumors compared with VSV-GFP alone. However, in combination with adoptive transfer of gp100-specific pmel T cells, intratumoral VSV-hgp100 cured significantly more mice than either virus or T cells alone. Even in an aggressive model of metastatic disease, antitumor therapy was generated at levels similar to those observed in the VSV-ova/OT-I model in which a potently immunogenic, nonself TAA was targeted. Therefore, individual poorly effective virotherapies and T-cell therapies that target self TAA of low immunogenicity, which reflects the situation in patients, can be combined to generate very effective antitumor therapy.

Original languageEnglish (US)
Pages (from-to)1343-1353
Number of pages11
JournalHuman gene therapy
Volume22
Issue number11
DOIs
StatePublished - Nov 1 2011

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

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    Wongthida, P., Diaz, R. M., Pulido, C., Rommelfanger, D., Galivo, F., Kaluza, K., Kottke, T., Thompson, J., Melcher, A., & Vile, R. (2011). Activating systemic T-cell immunity against self tumor antigens to support oncolytic virotherapy with vesicular stomatitis virus. Human gene therapy, 22(11), 1343-1353. https://doi.org/10.1089/hum.2010.216