Oncolytic vaccinia virus as a vector for therapeutic sodium iodide symporter gene therapy in prostate cancer

D. C. Mansfield, J. N. Kyula, N. Rosenfelder, J. Chao-Chu, G. Kramer-Marek, A. A. Khan, V. Roulstone, M. McLaughlin, A. A. Melcher, Richard Geoffrey Vile, H. S. Pandha, V. Khoo, K. J. Harrington

Research output: Contribution to journalArticle

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Abstract

Oncolytic strains of vaccinia virus are currently in clinical development with clear evidence of safety and promising signs of efficacy. Addition of therapeutic genes to the viral genome may increase the therapeutic efficacy of vaccinia. We evaluated the therapeutic potential of vaccinia virus expressing the sodium iodide symporter (NIS) in prostate cancer models, combining oncolysis, external beam radiotherapy and NIS-mediated radioiodide therapy. The NIS-expressing vaccinia virus (VV-NIS), GLV-1h153, was tested in in vitro analyzes of viral cell killing, combination with radiotherapy, NIS expression, cellular radioiodide uptake and apoptotic cell death in PC3, DU145, LNCaP and WPMY-1 human prostate cell lines. In vivo experiments were carried out in PC3 xenografts in CD1 nude mice to assess NIS expression and tumor radioiodide uptake. In addition, the therapeutic benefit of radioiodide treatment in combination with viral oncolysis and external beam radiotherapy was measured. In vitro viral cell killing of prostate cancers was dose- and time-dependent and was through apoptotic mechanisms. Importantly, combined virus therapy and iodizing radiation did not adversely affect oncolysis. NIS gene expression in infected cells was functional and mediated uptake of radioiodide both in vitro and in vivo. Therapy experiments with both xenograft and immunocompetent Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) mouse models showed that the addition of radioiodide to VV-NIS-infected tumors was more effective than each single-agent therapy, restricting tumor growth and increasing survival. In conclusion, VV-NIS is effective in prostate cancer models. This treatment modality would be an attractive complement to existing clinical radiotherapy practice.Gene Therapy advance online publication, 18 February 2016; doi:10.1038/gt.2016.5.

Original languageEnglish (US)
JournalGene Therapy
DOIs
StateAccepted/In press - Jan 27 2016

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Oncolytic Viruses
Vaccinia virus
Genetic Therapy
Prostatic Neoplasms
Radiotherapy
Therapeutics
Heterografts
Prostate
sodium-iodide symporter
Vaccinia
Neoplasms
Viral Genome
Nude Mice
Transgenic Mice
Publications
Adenocarcinoma
Cell Death
Viruses
Safety
Gene Expression

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

Cite this

Mansfield, D. C., Kyula, J. N., Rosenfelder, N., Chao-Chu, J., Kramer-Marek, G., Khan, A. A., ... Harrington, K. J. (Accepted/In press). Oncolytic vaccinia virus as a vector for therapeutic sodium iodide symporter gene therapy in prostate cancer. Gene Therapy. https://doi.org/10.1038/gt.2016.5

Oncolytic vaccinia virus as a vector for therapeutic sodium iodide symporter gene therapy in prostate cancer. / Mansfield, D. C.; Kyula, J. N.; Rosenfelder, N.; Chao-Chu, J.; Kramer-Marek, G.; Khan, A. A.; Roulstone, V.; McLaughlin, M.; Melcher, A. A.; Vile, Richard Geoffrey; Pandha, H. S.; Khoo, V.; Harrington, K. J.

In: Gene Therapy, 27.01.2016.

Research output: Contribution to journalArticle

Mansfield, DC, Kyula, JN, Rosenfelder, N, Chao-Chu, J, Kramer-Marek, G, Khan, AA, Roulstone, V, McLaughlin, M, Melcher, AA, Vile, RG, Pandha, HS, Khoo, V & Harrington, KJ 2016, 'Oncolytic vaccinia virus as a vector for therapeutic sodium iodide symporter gene therapy in prostate cancer', Gene Therapy. https://doi.org/10.1038/gt.2016.5
Mansfield, D. C. ; Kyula, J. N. ; Rosenfelder, N. ; Chao-Chu, J. ; Kramer-Marek, G. ; Khan, A. A. ; Roulstone, V. ; McLaughlin, M. ; Melcher, A. A. ; Vile, Richard Geoffrey ; Pandha, H. S. ; Khoo, V. ; Harrington, K. J. / Oncolytic vaccinia virus as a vector for therapeutic sodium iodide symporter gene therapy in prostate cancer. In: Gene Therapy. 2016.
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