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 immunity1. 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.
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Jennerex Inc. was involved in the study design, data monitoring, analysis and interpretation, and in writing and submission of the report for publication. Jennerex Inc. funded the clinical study. Translational work was supported by grants to J.B. from the Terry Fox Foundation and the Canadian Institute for Health Research (CIHR) and by grants to T.-H.H. from the Korea Healthcare technology R&D Project, Ministry for Health, Welfare and Family Affairs, Republic of Korea (A091047). N.D.S. is supported by a Vanier Scholarship. C.J.B. was supported by a Natural Sciences and Engineering Research Council of Canada (NSERC) studentship. L.E. is supported by Ontario Graduate Scholarships in Science and Technology (OGSST). F.L.B. is supported by a Canadian Institutes of Health Research/Small and Medium Enterprises (CIHR/SME) Collaborative Research Program Fellowship. A.F. and J.C.B. are supported by Ontario Institute for Cancer Research.
C.J.B., J.B., A.M., A.P., T.R. and D.H.K. are employees of Jennerex Inc. and hold stock options in Jennerex Inc. T.-H.H. and J.C.B. consult for and hold stock options in Jennerex Inc. R.P., Y.-S.L. and M.D. consult for Jennerex Inc.
The file contains Supplementary Figures 1-4 with legends, a Supplementary Discussion and Supplementary References. (PDF 636 kb)
This movie shows the 360° view of a colorectal carcinoma tumour in which vaccinia (JX-594) antigens were detected by immunohistochemistry. Green staining represents areas of tumour staining for vaccinia (JX-594). (MOV 1573 kb)
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Breitbach, C., Burke, J., Jonker, D. et al. Intravenous delivery of a multi-mechanistic cancer-targeted oncolytic poxvirus in humans. Nature 477, 99–102 (2011). https://doi.org/10.1038/nature10358
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