Cooperative effects of adenoviral vector-mediated interleukin 12 gene therapy with radiotherapy in a preclinical model of metastatic prostate cancer

T. Fujita, T. L. Timme, K. Tabata, K. Naruishi, N. Kusaka, Masami Watanabe, E. Abdelfattah, J. X. Zhu, C. Ren, C. Ren, G. Yang, A. Goltsov, H. Wang, M. T. Vlachaki, B. S. Teh, E. B. Butler, T. C. Thompson

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Abstract

We investigated the potential benefits of combining adenoviral vector mediated in situ interleukin-12 (AdmIL-12) gene therapy with radiation therapy (XRT) to enhance therapeutic efficacy. In a metastatic mouse prostate cancer cell line, 178-2 BMA, AdmIL-12+XRT demonstrated enhanced therapeutic activities in vitro as determined by clonogenic survival, apoptosis, and mIL-12 levels. At the molecular level, increased expression of tumor necrosis factor-α mRNA was specific for the combined therapy. In a subcutaneous 178-2 BMA in vivo model, the combination of AdmIL-12+XRT produced statistically significant tumor growth suppression compared to control vector Adβgal, Adβgal XRT, or AdmIL-12 as monotherapy. In addition, significant prolongation of survival was demonstrated for the combination of AdmIL-12+XRT. The combination of AdmIL-12+XRT significantly suppressed both spontaneous and pre-established lung metastases, and led to a prolonged elevation of serum IL-12 and significantly increased natural killer (NK) activities. Importantly, in vivo depletion of NK cells resulted in significant attenuation of the antimetastatic activities of AdmIL-12 alone or AdmIL-12+XRT. These combined effects suggest that AdIL-12 gene therapy together with radiotherapy may achieve maximal tumor control (both local and systemic) in selected prostate cancer patients via radio-gene therapy induced local cytotoxicity and local and systemic antitumor immunity.

Original languageEnglish
Pages (from-to)227-236
Number of pages10
JournalGene Therapy
Volume14
Issue number3
DOIs
Publication statusPublished - Feb 2007
Externally publishedYes

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ASJC Scopus subject areas

  • Genetics

Cite this

Fujita, T., Timme, T. L., Tabata, K., Naruishi, K., Kusaka, N., Watanabe, M., Abdelfattah, E., Zhu, J. X., Ren, C., Ren, C., Yang, G., Goltsov, A., Wang, H., Vlachaki, M. T., Teh, B. S., Butler, E. B., & Thompson, T. C. (2007). Cooperative effects of adenoviral vector-mediated interleukin 12 gene therapy with radiotherapy in a preclinical model of metastatic prostate cancer. Gene Therapy, 14(3), 227-236. https://doi.org/10.1038/sj.gt.3302788