Tumor infection by oncolytic reovirus primes adaptive antitumor immunity

Robin J. Prestwich, Fiona Errington, Elizabeth J. Ilett, Ruth S M Morgan, Karen J. Scott, Timothy Kottke, Jill Thompson, Ewan E. Morrison, Kevin J. Harrington, Hardev S. Pandha, Peter J. Selby, Richard Geoffrey Vile, Alan A. Melcher

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Abstract

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-g production, specific anti-Mel888 cell cytotoxicity, and cross-primed CD8+ Tcells 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.

Original languageEnglish (US)
Pages (from-to)7358-7366
Number of pages9
JournalClinical Cancer Research
Volume14
Issue number22
DOIs
StatePublished - Nov 15 2008

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Reoviridae Infections
Adaptive Immunity
Dendritic Cells
Lymphocytes
Immunity
Neoplasms
Lymph Nodes
Neoplasm Antigens
Clinical Trials
Experimental Melanomas
Interleukin-12
Inbred C57BL Mouse
Melanoma
Research Design
Cytokines
Neoplasm Metastasis

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Prestwich, R. J., Errington, F., Ilett, E. J., Morgan, R. S. M., Scott, K. J., Kottke, T., ... Melcher, A. A. (2008). Tumor infection by oncolytic reovirus primes adaptive antitumor immunity. Clinical Cancer Research, 14(22), 7358-7366. https://doi.org/10.1158/1078-0432.CCR-08-0831

Tumor infection by oncolytic reovirus primes adaptive antitumor immunity. / Prestwich, Robin J.; Errington, Fiona; Ilett, Elizabeth J.; Morgan, Ruth S M; Scott, Karen J.; Kottke, Timothy; Thompson, Jill; Morrison, Ewan E.; Harrington, Kevin J.; Pandha, Hardev S.; Selby, Peter J.; Vile, Richard Geoffrey; Melcher, Alan A.

In: Clinical Cancer Research, Vol. 14, No. 22, 15.11.2008, p. 7358-7366.

Research output: Contribution to journalArticle

Prestwich, RJ, Errington, F, Ilett, EJ, Morgan, RSM, Scott, KJ, Kottke, T, Thompson, J, Morrison, EE, Harrington, KJ, Pandha, HS, Selby, PJ, Vile, RG & Melcher, AA 2008, 'Tumor infection by oncolytic reovirus primes adaptive antitumor immunity', Clinical Cancer Research, vol. 14, no. 22, pp. 7358-7366. https://doi.org/10.1158/1078-0432.CCR-08-0831
Prestwich RJ, Errington F, Ilett EJ, Morgan RSM, Scott KJ, Kottke T et al. Tumor infection by oncolytic reovirus primes adaptive antitumor immunity. Clinical Cancer Research. 2008 Nov 15;14(22):7358-7366. https://doi.org/10.1158/1078-0432.CCR-08-0831
Prestwich, Robin J. ; Errington, Fiona ; Ilett, Elizabeth J. ; Morgan, Ruth S M ; Scott, Karen J. ; Kottke, Timothy ; Thompson, Jill ; Morrison, Ewan E. ; Harrington, Kevin J. ; Pandha, Hardev S. ; Selby, Peter J. ; Vile, Richard Geoffrey ; Melcher, Alan A. / Tumor infection by oncolytic reovirus primes adaptive antitumor immunity. In: Clinical Cancer Research. 2008 ; Vol. 14, No. 22. pp. 7358-7366.
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abstract = "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-g production, specific anti-Mel888 cell cytotoxicity, and cross-primed CD8+ Tcells 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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AU - Kottke, Timothy

AU - Thompson, Jill

AU - Morrison, Ewan E.

AU - Harrington, Kevin J.

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