Use of biological therapy to enhance both virotherapy and adoptive T-cell therapy for cancer

Timothy Kottke, Rosa M. Diaz, Karen Kaluza, Jose Pulido, Feorillo Galivo, Phonphimon Wongthida, Jill Thompson, Candice Willmon, Glen N. Barber, John Chester, Peter Selby, Scott Strome, Kevin Harrington, Alan Melcher, Richard G. Vile

Research output: Contribution to journalArticle

38 Scopus citations

Abstract

To protect viral particles from neutralization, sequestration, nonspecific adhesion, and mislocalization following systemic delivery, we have previously exploited the natural tumor-homing properties of antigen-specific CD8+ T cells. Thus, OT-I T cells, preloaded in vitro with the oncolytic vesicular stomatitis virus (VSV), can deliver virus to established B16ova tumors to generate significantly better therapy than that achievable with OT-I T cells, or systemically delivered VSV, alone. Here, we demonstrate that preconditioning immune-competent mice with Treg depletion and interleukin-2 (IL-2), before adoptive T-cell therapy with OT-I T cells loaded with VSV, leads to further highly significant increases in antitumor therapy. Therapy was associated with antitumor immune memory, but with no detectable toxicities associated with IL-2, Treg depletion, or systemic dissemination of the oncolytic virus. Efficacy was contributed by multiple factors, including improved persistence of T cells; enhanced delivery of VSV to tumors; increased persistence of OT-I cells in vivo resulting from tumor oncolysis; and activation of NK cells, which acquire potent antitumor and proviral activities. By controlling the levels of virus loaded onto the OT-I cells, adoptive therapy was still effective in mice preimmune to the virus, indicating that therapy with virus-loaded T cells may be useful even in virus-immune patients. Taken together, our data show that it is possible to combine adoptive T-cell therapy, with biological therapy (Treg depletion+IL-2), and VSV virotherapy, to treat established tumors under conditions where none of the individual modalities alone is successful.

Original languageEnglish (US)
Pages (from-to)1910-1918
Number of pages9
JournalMolecular Therapy
Volume16
Issue number12
DOIs
StatePublished - 2008

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

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    Kottke, T., Diaz, R. M., Kaluza, K., Pulido, J., Galivo, F., Wongthida, P., Thompson, J., Willmon, C., Barber, G. N., Chester, J., Selby, P., Strome, S., Harrington, K., Melcher, A., & Vile, R. G. (2008). Use of biological therapy to enhance both virotherapy and adoptive T-cell therapy for cancer. Molecular Therapy, 16(12), 1910-1918. https://doi.org/10.1038/mt.2008.212