This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services 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 Ino, Y. Articles by Todo, T. Search for Related Content PubMed PubMed Citation Articles by Ino, Y. Articles by Todo, T.

Triple Combination of Oncolytic Herpes Simplex Virus-1 Vectors Armed with Interleukin-12, Interleukin-18, or Soluble B7-1 Results in Enhanced Antitumor Efficacy

Authors' Affiliations: ¹ Molecular Neurosurgery Laboratory and ² Molecular Neuro-oncology Laboratory, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts and Departments of ³ Neuro-oncology and Molecular Therapeutics, ⁴ Urology, and ⁵ Neurosurgery, University of Tokyo, Tokyo, Japan

Requests for reprints: Tomoki Todo, Department of Neurosurgery, 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-1 (HSV-1) vectors are promising therapeutic agents for cancer. Insertion of therapeutic transgenes into the viral genome should confer desired anticancer functions in addition to oncolytic activities. Herein, using bacterial artificial chromosome and two recombinase-mediated recombinations, we simultaneously created four "armed" oncolytic HSV-1, designated vHsv-B7.1-Ig, vHsv-interleukin (IL)-12, vHsv-IL-18, and vHsv-null, which express murine soluble B7.1 (B7.1-Ig), murine IL-12, murine IL-18, and no transgene, respectively. These vHsv vectors possess deletions in the 34.5 genes and contain the green fluorescent protein gene as a histochemical marker and the immunostimulatory transgene inserted in the deleted ICP6 locus. The vHsv showed similar replicative capabilities in vitro. The in vivo efficacy was tested in A/J mice harboring s.c. tumors of syngeneic and poorly immunogenic Neuro2a neuroblastoma. The triple combination of vHsv-B7.1-Ig, vHsv-IL-12, and vHsv-IL-18 exhibited the highest efficacy among all single vHsv or combinations of two viruses. Combining 1 x 10⁵ plaque-forming units each of the three armed viruses showed stronger antitumor activities than any single armed virus at 3 x 10⁵ plaque-forming units in inoculated tumors as well as in noninoculated remote tumors. Studies using athymic mice indicated that this enhancement of antitumor efficacy was likely mediated by T-cell immune responses. The combined use of multiple oncolytic HSV-1 armed with different immunostimulatory genes may be a useful strategy for cancer therapy.

This article has been cited by other articles:

				C. J. Farrell, C. Zaupa, Z. Barnard, J. Maley, R. L. Martuza, S. D. Rabkin, and W. T. Curry Jr. Combination Immunotherapy for Tumors via Sequential Intratumoral Injections of Oncolytic Herpes Simplex Virus 1 and Immature Dendritic Cells Clin. Cancer Res., December 1, 2008; 14(23): 7711 - 7716. [Abstract] [Full Text] [PDF]

				G. Fulci, N. Dmitrieva, D. Gianni, E. J. Fontana, X. Pan, Y. Lu, C. S. Kaufman, B. Kaur, S. E. Lawler, R. J. Lee, et al. Depletion of Peripheral Macrophages and Brain Microglia Increases Brain Tumor Titers of Oncolytic Viruses Cancer Res., October 1, 2007; 67(19): 9398 - 9406. [Abstract] [Full Text] [PDF]

				A. Vigil, M.-S. Park, O. Martinez, M. A. Chua, S. Xiao, J. F. Cros, L. Martinez-Sobrido, S. L.C. Woo, and A. Garcia-Sastre Use of Reverse Genetics to Enhance the Oncolytic Properties of Newcastle Disease Virus Cancer Res., September 1, 2007; 67(17): 8285 - 8292. [Abstract] [Full Text] [PDF]

				R. M. Diaz, F. Galivo, T. Kottke, P. Wongthida, J. Qiao, J. Thompson, M. Valdes, G. Barber, and R. G. Vile Oncolytic Immunovirotherapy for Melanoma Using Vesicular Stomatitis Virus Cancer Res., March 15, 2007; 67(6): 2840 - 2848. [Abstract] [Full Text] [PDF]

				H. Li, A. Dutuor, L. Tao, X. Fu, and X. Zhang Virotherapy with a Type 2 Herpes Simplex Virus-Derived Oncolytic Virus Induces Potent Antitumor Immunity against Neuroblastoma Clin. Cancer Res., January 1, 2007; 13(1): 316 - 322. [Abstract] [Full Text] [PDF]

				P. S. Adusumilli, D. P. Eisenberg, B. M. Stiles, S. Chung, M.-K. Chan, V. W. Rusch, and Y. Fong Intraoperative localization of lymph node metastases with a replication-competent herpes simplex virus. J. Thorac. Cardiovasc. Surg., November 1, 2006; 132(5): 1179 - 1188. [Abstract] [Full Text] [PDF]