Cell Carriage, Delivery, and Selective Replication of an Oncolytic Virus in Tumor in Patients

Sci Transl Med 13 June 2012:
Vol. 4, Issue 138, p. 138ra77
Sci. Transl. Med. DOI: 10.1126/scitranslmed.3003578

• Research Article

CANCER

Cell Carriage, Delivery, and Selective Replication of an Oncolytic Virus in Tumor in Patients

1. Robert A. Adair¹,*,
2. Victoria Roulstone²,*,
3. Karen J. Scott¹,
4. Ruth Morgan¹,
5. Gerard J. Nuovo³,
6. Martin Fuller⁴,
7. Deborah Beirne¹,
8. Emma J. West¹,
9. Victoria A. Jennings¹,
10. Ailsa Rose¹,
11. Joan Kyula²,
12. Sheila Fraser¹,
13. Rajiv Dave¹,
14. David A. Anthoney¹,
15. Alison Merrick¹,
16. Robin Prestwich¹,
17. Amer Aldouri¹,
18. Oliver Donnelly¹,
19. Hardev Pandha⁵,
20. Matt Coffey⁶,
21. Peter Selby¹,
22. Richard Vile⁷,
23. Giles Toogood¹,
24. Kevin Harrington²,* and
25. Alan A. Melcher¹,*,†

+ Author Affiliations

1. ¹Leeds Institute of Molecular Medicine, St. James’s University Hospital, Leeds LS9 7TF, UK.
2. ²Institute of Cancer Research, Centre for Cell and Molecular Biology, Chester Beatty Laboratories, London SW3 6JB, UK.
3. ³Comprehensive Cancer Centre, Ohio State University, Columbus, OH 43210, USA.
4. ⁴Institute of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, UK.
5. ⁵Postgraduate Medical School, University of Surrey, Guildford GU2 7WG, UK.
6. ⁶Oncolytics Biotech Inc., Calgary, Alberta T2N 1X7, Canada.
7. ⁷Molecular Medicine Program and Department of Immunology, Mayo Clinic, Rochester, MN 55905, USA.

+ Author Notes

• ↵* These authors contributed equally to this work.

1. ↵†To whom correspondence should be addressed. E-mail: a.a.melcher@leeds.ac.uk

Abstract

Oncolytic viruses, which preferentially lyse cancer cells and stimulate an antitumor immune response, represent a promising approach to the treatment of cancer. However, how they evade the antiviral immune response and their selective delivery to, and replication in, tumor over normal tissue has not been investigated in humans. Here, we treated patients with a single cycle of intravenous reovirus before planned surgery to resect colorectal cancer metastases in the liver. Tracking the viral genome in the circulation showed that reovirus could be detected in plasma and blood mononuclear, granulocyte, and platelet cell compartments after infusion. Despite the presence of neutralizing antibodies before viral infusion in all patients, replication-competent reovirus that retained cytotoxicity was recovered from blood cells but not plasma, suggesting that transport by cells could protect virus for potential delivery to tumors. Analysis of surgical specimens demonstrated greater, preferential expression of reovirus protein in malignant cells compared to either tumor stroma or surrounding normal liver tissue. There was evidence of viral factories within tumor, and recovery of replicating virus from tumor (but not normal liver) was achieved in all four patients from whom fresh tissue was available. Hence, reovirus could be protected from neutralizing antibodies after systemic administration by immune cell carriage, which delivered reovirus to tumor. These findings suggest new preclinical and clinical scheduling and treatment combination strategies to enhance in vivo immune evasion and effective intravenous delivery of oncolytic viruses to patients in vivo.

• Copyright © 2012, American Association for the Advancement of Science

Citation: R. A. Adair, V. Roulstone, K. J. Scott, R. Morgan, G. J. Nuovo, M. Fuller, D. Beirne, E. J. West, V. A. Jennings, A. Rose, J. Kyula, S. Fraser, R. Dave, D. A. Anthoney, A. Merrick, R. Prestwich, A. Aldouri, O. Donnelly, H. Pandha, M. Coffey, P. Selby, R. Vile, G. Toogood, K. Harrington, A. A. Melcher, Cell Carriage, Delivery, and Selective Replication of an Oncolytic Virus in Tumor in Patients. Sci. Transl. Med. 4, 138ra77 (2012).

Read the Full Text

The editors suggest the following Related Resources on Science sites Back to Top

In Science Translational Medicine

• Focus: Cancer The Virus That Came In from the Cold

  • John C. Bell

  Sci Transl Med 13 June 2012 4:138fs17
  • Abstract
  • Full Text
  • Full Text (PDF)

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:

• The Virus That Came In from the Cold Sci Transl Med 13 June 2012 4:138fs17
  • Full Text
  • Full Text (PDF)