Intravenous delivery of a multi-mechanistic cancer-targeted oncolytic poxvirus in humans.

Abstract

The efficacy and safety of biological molecules in cancer therapy, such as peptides and small interfering RNAs (siRNAs), could be markedly increased if high concentrations could be achieved and amplified selectively in tumour tissues versus normal tissues after intravenous administration. This has not been achievable so far in humans. We hypothesized that a poxvirus, which evolved for blood-borne systemic spread in mammals, could be engineered for cancer-selective replication and used as a vehicle for the intravenous delivery and expression of transgenes in tumours. JX-594 is an oncolytic poxvirus engineered for replication, transgene expression and amplification in cancer cells harbouring activation of the epidermal growth factor receptor (EGFR)/Ras pathway, followed by cell lysis and anticancer immunity. Here we show in a clinical trial that JX-594 selectively infects, replicates and expresses transgene products in cancer tissue after intravenous infusion, in a dose-related fashion. Normal tissues were not affected clinically. This platform technology opens up the possibility of multifunctional products that selectively express high concentrations of several complementary therapeutic and imaging molecules in metastatic solid tumours in humans.

• Authors: Caroline J Breitbach, James Burke, Derek Jonker, Joe Stephenson, Andrew R Haas, Laura Q M Chow, Jorge Nieva, Tae-Ho Hwang, Anne Moon, Richard Patt, Adina Pelusio, Fabrice Le Boeuf, Joe Burns, Laura Evgin, Naomi De Silva, Sara Cvancic, Terri Robertson, Ji-Eun Je, Yeon-Sook Lee, Kelley Parato, Jean-Simon Diallo, Aaron Fenster, Manijeh Daneshmand, John C Bell, David H Kirn
• Journal: Nature (Nature) Vol. 477 Issue 7362 Pg. 99-102 (Aug 31 2011) ISSN: 1476-4687 [Electronic] England
• PMID: 21886163 (Publication Type: Clinical Trial, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DNA, Viral
• beta-Galactosidase

Topics

• Adult
• Aged
• Aged, 80 and over
• DNA, Viral (blood)
• Female
• Gene Expression Regulation, Enzymologic
• Humans
• Infusions, Intravenous
• Male
• Middle Aged
• Neoplasms (pathology, surgery, therapy, virology)
• Oncolytic Virotherapy
• Oncolytic Viruses (physiology)
• Organisms, Genetically Modified (physiology)
• Poxviridae (physiology)
• Transgenes (genetics)
• beta-Galactosidase (genetics, metabolism)