Journal of the National Cancer Institute Advance Access originally published online on October 30, 2007
JNCI Journal of the National Cancer Institute 2007 99(21):1623-1633; doi:10.1093/jnci/djm198
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Seneca Valley Virus, a Systemically Deliverable Oncolytic Picornavirus, and the Treatment of Neuroendocrine Cancers
Affiliations of authors: Neotropix, Inc, Malvern, PA (PSR, KDB, LMH, BHJ, NI, SSL, KLS, AJV, PLH); Cell Genesys, Inc, South San Francisco, CA (SG); MedImmune, Inc, Gaithersburg, MD (CH); SuperArray Bioscience Corp, Frederick, MD (JY); Kimmel Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD (DNW, CMR)
Correspondence to: Paul L. Hallenbeck, PhD, Neotropix, Inc, 351 Phoenixville Pike, Malvern, PA 19355 (e-mail: phallenbeck{at}neotropix.com).
Background: Numerous clinical trials have demonstrated that oncolytic viruses can elicit antitumor responses when they are administered directly into localized cancers. However, the treatment of metastatic disease with oncolytic viruses has been challenging due to the inactivation of viruses by components of human blood and/or to inadequate tumor selectivity.
Methods: We determined the cytolytic potential and selectivity of Seneca Valley Virus-001 (SVV-001), a newly discovered native picornavirus, in neuroendocrine and pediatric tumor cell lines and normal cells. Suitability of the virus for intravenous delivery in humans was assessed by blood inactivation assays. Safety was evaluated in vivo using an immune-competent mouse model, and efficacy was evaluated in vivo in athymic mice bearing tumors derived from human small-cell lung cancer and retinoblastoma cell lines.
Results: Cell lines derived from small-cell lung cancers and solid pediatric cancers were at least 10000-fold more sensitive to the cytolytic activity of SVV-001 than were any of the adult normal human cells tested. Viral infectivity was not inhibited by human blood components. Intravenous doses up to 1 x 1014 virus particles (vp) per kg were well tolerated, and no dose-limiting toxicity was observed in immune-competent mice. A single intravenous dose of 1 x 108 vp per kg into athymic mice bearing preestablished small-cell lung or retinoblastoma tumors resulted in complete, durable responses in ten of ten and five of eight mice, respectively.
Conclusions: SVV-001 has potent cytolytic activity and high selectivity for tumor cell lines having neuroendocrine properties versus adult normal cells. Systemically administered SVV-001 has potential for the treatment of metastatic neuroendocrine cancers.
| CONTEXT AND CAVEATS Prior knowledge Oncolytic viruses have potential as cancer therapies, but many are inactivated by components in the blood and/or are toxic to normal cells. Study design In vitro cytotoxicity assays in tumor and normal cell lines, inactivation assays with human blood samples, and in vivo mouse models of small-cell lung cancer and retinoblastoma. Contributions Seneca Valley Virus-001 (SVV-001) was more cytotoxic to small-cell lung cancer cell lines and solid pediatric cancer cell lines than other tumor cell lines and normal cell lines; this activity was not inhibited by components in human blood. Single intravenous treatment with SVV-001 in mouse models led to complete responses of all mice carrying small-cell lung cancer xenograft tumors and a majority of mice carrying retinoblastoma xenograft tumors. SVV-001 was well tolerated in mice. Implications SVV-001 may be useful as a treatment for metastatic tumors with neuroendocrine properties, such as small-cell lung cancer. Limitations It is unclear whether these results from immune-deficient mouse models would be similar to those of patients with metastatic cancer. In particular, it is unknown whether the patients' immune responses would reduce the effectiveness of SVV-001.
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P. S. Reddy, K. D. Burroughs, L. M. Hales, S. Ganesh, and P. L. Hallenbeck contributed equally to this work.
Drs Reddy, Burroughs, Hayes, Idamakanti, and Hallenbeck and Mr Jones and Ms Skele are employees of Neotropix, Inc, hold stock in the company, and are performing research for Neotropix, Inc, with the goal of developing SVV-001 as a treatment for cancer. Dr Li and Ms Vasko are former employees of Neotropix, Inc.
We thank Dr Shizuko Sei for leading NCI-60 screen of the Developmental Therapeutics Program, Dr John Minna for select small-cell lung cancer tumor cell lines, Dr Alan Shuldiner for serum samples, Kimberly Schneider for technical assistance, Dr Richard Peluso for critical review of the manuscript, and Janice Ingram for assisting with the manuscript preparation.
Manuscript received March 15, 2007; revised August 27, 2007; accepted September 19, 2007.
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  L. M. Hales, N. J. Knowles, P. S. Reddy, L. Xu, C. Hay, and P. L. Hallenbeck Complete genome sequence analysis of Seneca Valley virus-001, a novel oncolytic picornavirus J. Gen. Virol., May 1, 2008; 89(5): 1265 - 1275. [Abstract] [Full Text] [PDF]
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