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Enhanced therapeutic efficacy of IL-12, but not GM-CSF, expressing oncolytic herpes simplex virus for transgenic mouse derived prostate cancers

Cancer Gene Therapy volume 13, pages 253–265 (2006)Cite this article

Abstract

Replication competent oncolytic herpes simplex viruses (HSV) with broad-spectrum activity against various cancers, including prostate cancer, exert a dual effect by their direct cytocidal action and by eliciting tumor-specific immunity. These viruses can deliver immunoregulatory molecules to tumors so as to enhance the cumulative antitumor response. This is particularly desirable for prostate cancers, which are usually poorly immunogenic. Initial studies described herein comparing the efficacy of three different oncolytic HSVs (G207, G47Δ, and NV1023) to inhibit the growth of the poorly immunogenic TRAMP-C2 mouse prostate tumors demonstrated that NV1023 was most effective in treating established tumors. The expression of IL-12 on an NV1023 background (NV1042), but not the expression of GM-CSF (NV1034), further enhanced the efficacy of NV1023 in two murine prostate cancer models with highly variable MHC class I levels, Pr14-2 with 91% and TRAMP-C2 with 2% of cells staining. NV1042 also inhibited the growth of distant noninoculated tumors in both prostate cancer models. NV1042 treated tumors exhibited increased immune cell infiltration and decreased levels of angiogenesis. Thus, an IL-12 expressing oncolytic herpes virus, which is capable of direct cytotoxicity and can modulate the otherwise suboptimal immune response through concomitant expression of the cytokine at the site of tumor destruction, could serve as a valuable clinical agent to seek out both overt and occult prostate cancers.

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Acknowledgements

We thank Tomoki Todo for his valuable scientific assistance, and Wenzheng Zhang, Dana Xu, Thanh Thao Huynh and Usha Macgarvey for their technical assistance. RLM and SDR are consultants to MediGene AG, which has a license from Georgetown University to commercialize G207. This research was supported by grants to RLM from NIH (1R01CA102139-01A1), Department of Defense (DAMD17-98-1-8490), and the CapCure Foundation.

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  1. R Liu

    Present address: The first affiliated hospital of Sun Yat-sen University, Guangzhou, 510080, P.R. China

Authors and Affiliations

  1. Department of Neurosurgery, Molecular Neurosurgery Laboratory, Massachusetts General Hospital, Charlestown, MA, USA

    S Varghese, S D Rabkin, R Liu, T Ipe & R L Martuza

  2. Department of Surgery (Neurosurgery), Harvard Medical School, Boston, MA, USA

    S Varghese, S D Rabkin, R Liu, T Ipe & R L Martuza

  3. Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

    P G Nielsen

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Correspondence to S D Rabkin.

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Varghese, S., Rabkin, S., Liu, R. et al. Enhanced therapeutic efficacy of IL-12, but not GM-CSF, expressing oncolytic herpes simplex virus for transgenic mouse derived prostate cancers. Cancer Gene Ther 13, 253–265 (2006). https://doi.org/10.1038/sj.cgt.7700900

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