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

Nature volume 477, pages 99–102 (2011)Cite this article

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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 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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Figure 1: Ex vivo infection of explants of tumour and normal tissue from patients reveals tumour-selective JX-594 gene expression.
Figure 2: JX-594 is selectively delivered to, and amplified within, tumours after intravenous infusion.
Figure 3: Immunohistochemical staining reveals JX-594 infection and β-galactosidase expression in tumours.

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Acknowledgements

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.

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Author notes

  1. James Burke

    Present address: Present address: Jennerex Inc., 450 Sansome Street, 16th floor, San Francisco, California 94111, USA.,

  2. John C. Bell and David H. Kirn: These authors contributed equally to this work.

Authors and Affiliations

  1. Jennerex Inc., 450 Sansome Street, 16th floor, San Francisco, 94111, California, USA

    Caroline J. Breitbach, Anne Moon, Adina Pelusio, Terri Robertson & David H. Kirn

  2. Department of Hematology/Oncology, 801 North 29th Street, Billings Clinic, Billings, 59101, Montana, USA

    James Burke & Jorge Nieva

  3. Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, Ontario K1H 8L6, Canada

    Derek Jonker, Laura Q. M. Chow, Fabrice Le Boeuf, Joe Burns, Laura Evgin, Naomi De Silva, Sara Cvancic, Kelley Parato, Jean-Simon Diallo, Manijeh Daneshmand & John C. Bell

  4. University of Ottawa, 75 Laurier Avenue East, Ottawa, Ontario K1N 6N5, Canada

    Derek Jonker, Laura Q. M. Chow, Joe Burns, Laura Evgin, Naomi De Silva, Sara Cvancic, Manijeh Daneshmand & John C. Bell

  5. Cancer Centers of the Carolinas, 3 Butternut Drive, Greenville, 29605, South Carolina, USA

    Joe Stephenson

  6. University of Pennsylvania Medical Center, 3400 Spruce Street, Philadelphia, 19104, Pennsylvania, USA

    Andrew R. Haas

  7. Pusan National University, Jangjeon-dong GeumJeong-gu, Busan 609-735, South Korea

    Tae-Ho Hwang, Ji-Eun Je & Yeon-Sook Lee

  8. RadMD, 712 Hyde Park, Doylestown, 18901, Pennsylvania, USA

    Richard Patt

  9. Robarts Research Institute, 100 Perth Drive, P.O. Box 5015, London, Ontario N6A 5K8, Canada

    Aaron Fenster

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  1. Caroline J. Breitbach
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Contributions

Study design: D.H.K. and J.C.B. Data analysis and study write-up: C.J.B., D.H.K., T.-H.H., A.M., R.P., A.P., T.R., J.C.B. and A.F. Enrolment and management of patients: J.B., D.J., J.S., A.R.H., L.Q.M.C. and J.N. Laboratory work: F.L.B., J.B., N.D.S., S.C., J.-E.J., L.E., Y.-S.L., K.P., J.S.D., M.D. and J.-S.D. C.J.B. and D.H.K. had access to all the data in the trial. C.J.B. and D.H.K. took the final decision to submit for publication.

Corresponding author

Correspondence to David H. Kirn.

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Competing interests

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.

Supplementary information

Supplementary Information

The file contains Supplementary Figures 1-4 with legends, a Supplementary Discussion and Supplementary References. (PDF 636 kb)

Supplementary Movie 1

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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