Synergy of adoptive T-cell therapy and intratumoral suicide gene therapy is mediated by host NK cells

L. Sanchez-Perez, M. Gough, J. Qiao, Uma Thanarajasingam, T. Kottke, A. Ahmed, J. M. Thompson, R. Maria Diaz, Richard Geoffrey Vile

Research output: Contribution to journalArticle

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Abstract

In situ tumor cell killing by the herpes simplex virus thymidine kinase (HSVtk) gene can effectively prime antitumor T-cell responses, at least in part through local induction of a pro-inflammatory environment. Therefore, we reasoned that tumor-associated HSVtk expression would significantly enhance the efficacy of adoptive T-cell transfer (ACT) of (tumor) antigen-specific T cells into tumor-bearing hosts. When B16ovaHSVtk tumors were treated with ganciclovir (GCV), along with suboptimal numbers of activated OT-1T cells, complete tumor regressions were observed where GCV, or ACT, alone was completely ineffective. To our surprise, analysis of regressing tumors showed no increases in intratumoral OT-1T cell trafficking. However, the intratumoral percentages of both OT-1 and endogenous natural killer (NK) cells were substantially increased over controls. Depletion of endogenous NK cells abrogated the efficacy of the combination therapy and reduced the percentages of interferon-γ(IFNγ)-secreting OT-1T cells in mice that received combined therapy to levels similar to those of control mice. These data suggest that even relatively low levels of gene transfer of suicide genes into tumors may have therapeutic value as an adjuvant for other T-cell therapies, by providing immunological signals that support T-cell activation and expansion in vivo.

Original languageEnglish (US)
Pages (from-to)998-1009
Number of pages12
JournalGene Therapy
Volume14
Issue number13
DOIs
StatePublished - Jul 2007

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Cell- and Tissue-Based Therapy
Natural Killer Cells
Genetic Therapy
Suicide
T-Lymphocytes
Neoplasms
Ganciclovir
Thymidine Kinase
Adoptive Transfer
Simplexvirus
Genes
Satellite Viruses
Neoplasm Antigens
Interferons
Therapeutics

ASJC Scopus subject areas

  • Genetics

Cite this

Synergy of adoptive T-cell therapy and intratumoral suicide gene therapy is mediated by host NK cells. / Sanchez-Perez, L.; Gough, M.; Qiao, J.; Thanarajasingam, Uma; Kottke, T.; Ahmed, A.; Thompson, J. M.; Maria Diaz, R.; Vile, Richard Geoffrey.

In: Gene Therapy, Vol. 14, No. 13, 07.2007, p. 998-1009.

Research output: Contribution to journalArticle

Sanchez-Perez, L, Gough, M, Qiao, J, Thanarajasingam, U, Kottke, T, Ahmed, A, Thompson, JM, Maria Diaz, R & Vile, RG 2007, 'Synergy of adoptive T-cell therapy and intratumoral suicide gene therapy is mediated by host NK cells', Gene Therapy, vol. 14, no. 13, pp. 998-1009. https://doi.org/10.1038/sj.gt.3302935
Sanchez-Perez, L. ; Gough, M. ; Qiao, J. ; Thanarajasingam, Uma ; Kottke, T. ; Ahmed, A. ; Thompson, J. M. ; Maria Diaz, R. ; Vile, Richard Geoffrey. / Synergy of adoptive T-cell therapy and intratumoral suicide gene therapy is mediated by host NK cells. In: Gene Therapy. 2007 ; Vol. 14, No. 13. pp. 998-1009.
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