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Tumor Infection by Oncolytic Reovirus Primes Adaptive Antitumor Immunity

Authors' Affiliations: ¹ Cancer Research UK Clinical Centre, Leeds Institute of Molecular Medicine, University of Leeds, Leeds, United Kingdom; ² Molecular Medicine Program and ³ Department of Immunology, Mayo Clinic, Rochester, Minnesota; ⁴ Targeted Therapy Laboratory, Institute of Cancer Research, Cancer Research UK, Centre for Cell and Molecular Biology, Chester Beatty Laboratories, London, United Kingdom; and ⁵ Oncology, Postgraduate Medical School, University of Surrey, Guildford, United Kingdom

Requests for reprints: Alan A. Melcher, St. James's University Hospital, Level 5, Welcome Trust Brenner Building, Beckett Street, Leeds LS9 7TF, United Kingdom. Phone: 44-113-3438436; Fax: 44-113-2429886; E-mail: A.A.Melcher{at}leeds.ac.uk.

Purpose: Early clinical trials are under way exploring the direct oncolytic potential of reovirus. This study addresses whether tumor infection by reovirus is also able to generate bystander, adaptive antitumor immunity.

Experimental Design: Reovirus was delivered intravenously to C57BL/6 mice bearing lymph node metastases from the murine melanoma, B16-tk, with assessment of nodal metastatic clearance, priming of antitumor immunity against the tumor-associated antigen tyrosinase-related protein-2, and cytokine responses. In an in vitro human system, the effect of reovirus infection on the ability of Mel888 melanoma cells to activate and load dendritic cells for cytotoxic lymphocyte (CTL) priming was investigated.

Results: In the murine model, a single intravenous dose of reovirus reduced metastatic lymph node burden and induced antitumor immunity (splenocyte response to tyrosinase-related protein-2 and interleukin-12 production in disaggregated lymph nodes). In vitro human assays revealed that uninfected Mel888 cells failed to induce dendritic cell maturation or support priming of an anti-Mel888 CTL response. In contrast, reovirus-infected Mel888 cells (reo-Mel) matured dendritic cells in a reovirus dose-dependent manner. When cultured with autologous peripheral blood lymphocytes, dendritic cells loaded with reo-Mel induced lymphocyte expansion, IFN- production, specific anti-Mel888 cell cytotoxicity, and cross-primed CD8⁺ T cells specific against the human tumor-associated antigen MART-1.

Conclusion: Reovirus infection of tumor cells reduces metastatic disease burden and primes antitumor immunity. Future clinical trials should be designed to explore both direct cytotoxic and immunotherapeutic effects of reovirus.

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				R. J. Prestwich, E. J. Ilett, F. Errington, R. M. Diaz, L. P. Steele, T. Kottke, J. Thompson, F. Galivo, K. J. Harrington, H. S. Pandha, et al. Immune-Mediated Antitumor Activity of Reovirus Is Required for Therapy and Is Independent of Direct Viral Oncolysis and Replication Clin. Cancer Res., July 1, 2009; 15(13): 4374 - 4381. [Abstract] [Full Text] [PDF]