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Purging metastases in lymphoid organs using a combination of antigen-nonspecific adoptive T cell therapy, oncolytic virotherapy and immunotherapy

Nature Medicine volume 14, pages 37–44 (2008)Cite this article

Abstract

In many common cancers, dissemination of secondary tumors via the lymph nodes poses the most significant threat to the affected individual. Metastatic cells often reach the lymph nodes by mimicking the molecular mechanisms used by hematopoietic cells to traffic to peripheral lymphoid organs. Therefore, we exploited naive T cell trafficking in order to chaperone an oncolytic virus to lymphoid organs harboring metastatic cells. Metastatic burden was initially reduced by viral oncolysis and was then eradicated, as tumor cell killing in the lymph node and spleen generated protective antitumor immunity. Lymph node purging of tumor cells was possible even in virus-immune mice. Adoptive transfer of normal T cells loaded with oncolytic virus into individuals with cancer would be technically easy to implement both to reduce the distribution of metastases and to vaccinate the affected individual in situ against micrometastatic disease. As such, this adoptive transfer could have a great therapeutic impact, in the adjuvant setting, on many different cancer types.

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Figure 1: VSV loaded onto lymphocytes can be released to kill tumor cells.
Figure 2: B16-ova tumors metastasize to the lymph node and spleen.
Figure 3: VSV-loaded lymphocytes purge spleens and lymph nodes of metastatic cells.
Figure 4: Lymph node– or spleen-localized oncolysis primes antitumor immunity.
Figure 5: Adoptive transfer of VSV-loaded lymphocytes in virus-immune mice.
Figure 6: Lymph node purging of LLC-ova and CMT93tk metastases.

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Acknowledgements

We thank T. Higgins for expert secretarial assistance. This work was supported by the Mayo Foundation and by US National Institutes of Health grant CA RO1107082-02.

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Author notes

  1. Alan Melcher and Richard G Vile: These authors contributed equally to this work.

Authors and Affiliations

  1. Molecular Medicine Program, Mayo Clinic, Rochester, 55905, Minnesota, USA

    Jian Qiao, Timothy Kottke, Candice Willmon, Feorillo Galivo, Phonphimon Wongthida, Rosa Maria Diaz, Jill Thompson, Pamela Ryno & Richard G Vile

  2. Department of Microbiology and Immunology, Sylvester Comprehensive Cancer Center, University of Miami School of Medicine, Miami, 33136, Florida, USA

    Glen N Barber

  3. Cancer Research UK Clinical Centre, Leeds Teaching Hospitals UK National Health Service Trust and Leeds Institute of Molecular Medicine, University of Leeds, Leeds, LS9 7TF, UK

    John Chester, Peter Selby, Alan Melcher & Richard G Vile

  4. The Institute of Cancer Research, London, SW7 3RP, UK

    Kevin Harrington

  5. Department of Immunology, Mayo Clinic, Rochester, 55905, Minnesota, USA

    Richard G Vile

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Contributions

J.Q., T.K., C.W., F.G., P.W., R.M.D. and R.G.V. conducted most of the experiments; J.T. and P.R., conducted the in vivo experiments. G.N.B. developed the VSV virus used in these studies; J.C., P.S., K.H., A.M. and R.G.V. designed the project and developed its theoretical basis. J.Q., K.H., A.M. and R.G.V. wrote the manuscript.

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Correspondence to Richard G Vile.

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Qiao, J., Kottke, T., Willmon, C. et al. Purging metastases in lymphoid organs using a combination of antigen-nonspecific adoptive T cell therapy, oncolytic virotherapy and immunotherapy. Nat Med 14, 37–44 (2008). https://doi.org/10.1038/nm1681

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