J. Clin. Invest.
doi:10.1172/JCI32727.
Copyright © 2007, The American Society for Clinical Investigation
Research Article
Rational strain selection and engineering creates a broad-spectrum, systemically effective oncolytic poxvirus, JX-963
Steve H. Thorne1,2,
Tae-Ho H. Hwang3,
William E. O’Gorman4,
David L. Bartlett5,
Shizuko Sei6,
Femina Kanji7,
Christopher Brown8,
Joel Werier9,
Jin-Han Cho10,
Dong-Ewon Lee11,
Yaohe Wang12,
John Bell2,7 and
David H. Kirn2
1Department of Pediatrics and Bio-X Program, James H. Clark Center, Stanford University School of Medicine, Stanford, California, USA.
2Jennerex Biotherapeutics, San Francisco, California, USA.
3Department of Pharmacology, Medical College of Dong-A University, Busan, Republic of Korea.
4Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California, USA.
5Division of Surgical Oncology, Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
6Viral Vector Toxicology Section, LHTP, SAIC-Frederick Inc., National Cancer Institute–Frederick, Frederick, Maryland, USA.
7Ottawa Health Research Institute, Ottawa, Ontario, Canada.
8Biochemistry, Microbiology and Immunology Department, University of Ottawa, Ottawa, Ontario, Canada.
9Ottawa General Hospital, Ottawa, Ontario, Canada.
10Department of Radiology and
11Department of Pharmacology, Medical College of Dong-A University, Busan, Republic of Korea.
12Barts and the London School of Medicine and Dentistry, Queen Mary’s University of London, London, United Kingdom.
Address correspondence to: David H. Kirn, Jennerex Biotherapeutics, One Market Street, San Francisco, California 94105, USA. Phone: (415) 281-8886; Fax: (415) 598-2600; E-mail:
dkirn@jennerex.com.
Published
October 25, 2007
Received for publication May 18, 2007, and accepted in revised form August 15, 2007.
Replication-selective oncolytic viruses (virotherapeutics) are being developed as novel cancer therapies with unique mechanisms of action, but limitations in i.v. delivery to tumors and systemic efficacy have highlighted the need for improved agents for this therapeutic class to realize its potential. Here we describe the rational, stepwise design and evaluation of a systemically effective virotherapeutic (JX-963). We first identified a highly potent poxvirus strain that also trafficked efficiently to human tumors after i.v. administration. This strain was then engineered to target cancer cells with activation of the transcription factor E2F and the EGFR pathway by deletion of the thymidine kinase and vaccinia growth factor genes. For induction of tumor-specific cytotoxic T lymphocytes, we further engineered the virus to express human GM-CSF. JX-963 was more potent than the previously used virotherapeutic Onyx-015 adenovirus and as potent as wild-type vaccinia in all cancer cell lines tested. Significant cancer selectivity of JX-963 was demonstrated in vitro in human tumor cell lines, in vivo in tumor-bearing rabbits, and in primary human surgical samples ex vivo. Intravenous administration led to systemic efficacy against both primary carcinomas and widespread organ-based metastases in immunocompetent mice and rabbits. JX-963 therefore holds promise as a rationally designed, targeted virotherapeutic for the systemic treatment of cancer in humans and warrants clinical testing.
