This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Fukuhara, H. Articles by Todo, T. Search for Related Content PubMed PubMed Citation Articles by Fukuhara, H. Articles by Todo, T.

Triple Gene-Deleted Oncolytic Herpes Simplex Virus Vector Double-Armed with Interleukin 18 and Soluble B7-1 Constructed by Bacterial Artificial Chromosome–Mediated System

¹ Molecular Neurosurgery Laboratory, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts and Departments of ² Urology, ³ Neuro-oncology and Molecular Therapeutics, and ⁴ Neurosurgery, The University of Tokyo, Tokyo, Japan

Requests for reprints: Tomoki Todo, Department of Neurosurgery, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. Phone: 81-3-5800-8853; Fax: 81-3-5800-8655; E-mail: toudou-nsu{at}umin.ac.jp.

Conditionally replicating herpes simplex virus type 1 (HSV-1) vectors are promising therapeutic agents for cancer. Certain antitumor functions may be added to oncolytic activities of recombinant HSV-1 vectors by inserting transgenes into the viral genome. Because conventional homologous recombination techniques had required time-consuming processes to create "armed" oncolytic HSV-1 vectors, we established an innovative construction system using bacterial artificial chromosome and two recombinase systems (Cre/loxP and FLPe/FRT). Using G47, a safe and efficacious oncolytic HSV-1 with triple gene mutations, as the backbone, this system allowed a rapid generation of multiple vectors with desired transgenes inserted in the deleted ICP6 locus. Four oncolytic HSV-1 vectors, expressing murine interleukin 18 (mIL-18), soluble murine B7-1 [B7-1-immunoglobulin (B7-1-Ig)], both, or none, were created simultaneously within 3 months. In vitro, all newly created recombinant vectors exhibited virus yields and cytopathic effects similar to the parental G47. In two immunocompetent mouse tumor models, TRAMP-C2 prostate cancer and Neuro2a neuroblastoma, the vector expressing both mIL-18 and B7-1-Ig showed a significant enhancement of antitumor efficacy via T-cell–mediated immune responses. The results show that "arming" with multiple transgenes can improve the efficacy of oncolytic HSV-1 vectors. The use of our system may facilitate the development and testing of various armed oncolytic HSV-1 vectors.

This article has been cited by other articles:

				H. Wakimoto, S. Kesari, C. J. Farrell, W. T. Curry Jr., C. Zaupa, M. Aghi, T. Kuroda, A. Stemmer-Rachamimov, K. Shah, T.-C. Liu, et al. Human Glioblastoma-Derived Cancer Stem Cells: Establishment of Invasive Glioma Models and Treatment with Oncolytic Herpes Simplex Virus Vectors Cancer Res., April 15, 2009; 69(8): 3472 - 3481. [Abstract] [Full Text] [PDF]

				Y. Y. Mahller, S. S. Vaikunth, M. C. Ripberger, W. H. Baird, Y. Saeki, J. A. Cancelas, T. M. Crombleholme, and T. P. Cripe Tissue Inhibitor of Metalloproteinase-3 via Oncolytic Herpesvirus Inhibits Tumor Growth and Vascular Progenitors Cancer Res., February 15, 2008; 68(4): 1170 - 1179. [Abstract] [Full Text] [PDF]

				T.-C. Liu, T. Zhang, H. Fukuhara, T. Kuroda, T. Todo, X. Canron, A. Bikfalvi, R. L. Martuza, A. Kurtz, and S. D. Rabkin Dominant-Negative Fibroblast Growth Factor Receptor Expression Enhances Antitumoral Potency of Oncolytic Herpes Simplex Virus in Neural Tumors. Clin. Cancer Res., November 15, 2006; 12(22): 6791 - 6799. [Abstract] [Full Text] [PDF]

				Y. Ino, Y. Saeki, H. Fukuhara, and T. Todo Triple Combination of Oncolytic Herpes Simplex Virus-1 Vectors Armed with Interleukin-12, Interleukin-18, or Soluble B7-1 Results in Enhanced Antitumor Efficacy Clin. Cancer Res., January 15, 2006; 12(2): 643 - 652. [Abstract] [Full Text] [PDF]