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

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

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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

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Biological Therapy
Cell- and Tissue-Based Therapy
Vesicular Stomatitis
Viruses
T-Lymphocytes
Neoplasms
Interleukin-2
Oncolytic Viruses
CD8 Antigens
Oncogenic Viruses
Therapeutics
Natural Killer Cells
Virion

ASJC Scopus subject areas

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

Cite this

Use of biological therapy to enhance both virotherapy and adoptive T-cell therapy for cancer. / Kottke, Timothy; Diaz, Rosa M.; Kaluza, Karen; Pulido, Jose S; Galivo, Feorillo; Wongthida, Phonphimon; Thompson, Jill; Willmon, Candice; Barber, Glen N.; Chester, John; Selby, Peter; Strome, Scott; Harrington, Kevin; Melcher, Alan; Vile, Richard Geoffrey.

In: Molecular Therapy, Vol. 16, No. 12, 2008, p. 1910-1918.

Research output: Contribution to journalArticle

Kottke, T, Diaz, RM, Kaluza, K, Pulido, JS, Galivo, F, Wongthida, P, Thompson, J, Willmon, C, Barber, GN, Chester, J, Selby, P, Strome, S, Harrington, K, Melcher, A & Vile, RG 2008, 'Use of biological therapy to enhance both virotherapy and adoptive T-cell therapy for cancer', Molecular Therapy, vol. 16, no. 12, pp. 1910-1918. https://doi.org/10.1038/mt.2008.212
Kottke, Timothy ; Diaz, Rosa M. ; Kaluza, Karen ; Pulido, Jose S ; Galivo, Feorillo ; Wongthida, Phonphimon ; Thompson, Jill ; Willmon, Candice ; Barber, Glen N. ; Chester, John ; Selby, Peter ; Strome, Scott ; Harrington, Kevin ; Melcher, Alan ; Vile, Richard Geoffrey. / Use of biological therapy to enhance both virotherapy and adoptive T-cell therapy for cancer. In: Molecular Therapy. 2008 ; Vol. 16, No. 12. pp. 1910-1918.
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