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RNA-loaded CD40-activated B cells stimulate antigen-specific T-cell responses in dogs with spontaneous lymphoma

Gene Therapy volume 15, pages 955–965 (2008)Cite this article

Abstract

Cell-based vaccination strategies to induce functional tumor-specific T cells in cancer patients have focused on using autologous dendritic cells. An alternative approach is to use RNA-loaded CD40 activated B cells (CD40-B) that are highly efficient antigen-presenting cells capable of priming naive T cells, boosting memory T-cell responses and breaking tolerance to tumor antigens. The use of tumor RNA as the antigenic payload allows for gene transfer without viruses or vectors and permits major histocompatibility complex (MHC)-independent, multiple-antigen targeting. Here, we use CD40L transfected K562 cells to generate functional CD40-B cells from the peripheral blood of humans and dogs. Testing of RNA-loaded CD40-B cells in dogs allows not only for its development in veterinary medicine but also for determination of its safety and efficacy in a large animal model of spontaneous cancer prior to initiation of human clinical trials. We found that CD40-B cells from healthy humans, healthy dogs and tumor-bearing dogs express increased levels of immune molecules such as MHC and CCR7. Moreover, RNA-loaded CD40-B cells induce functional, antigen-specific T cells from healthy dogs and dogs with lymphoma. These findings pave the way for immunotherapy trials using tumor RNA-loaded CD40-B cells to stimulate antitumor immunity in a large animal model of spontaneous neoplasia.

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Acknowledgements

We thank Ms Amy LaBlanc, Ms Rachel Cohen, Ms Roxanne Buchanan and Ms Patty O'Donnell for their excellent technical assistance and Dr William Lee and Dr Carl June for helpful discussions and mentorship. This work was supported by grants from the Alliance for Cancer Gene Therapy (to RHV), the Barry and Savannah Poodle Memorial Fund (to NJM) and institutional funds from the University of Pennsylvania Abramson Cancer Center (to RHV) and the University of Pennsylvania School of Veterinary Medicine (to NJM and KUS).

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Author notes

  1. N J Mason and C M Coughlin: These authors contributed equally to this work.

Authors and Affiliations

  1. Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

    N J Mason, C M Coughlin, J N Cohen, E L Mitchell, T A Colligon & R H Vonderheide

  2. Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA, USA

    N J Mason

  3. Department of Clinical Studies, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA, USA

    N J Mason, B Overley & K U Sorenmo

  4. Division of Oncology, Department of Pediatrics, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

    C M Coughlin

  5. Oncology Service, Red Bank Veterinary Hospital, Red Bank, NJ, USA

    C A Clifford

  6. Institute of Animal Neurology, University of Bern, Bern, Switzerland

    A Zurbriggen

  7. Hematology-Oncology Division, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

    R H Vonderheide

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  1. N J Mason
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Correspondence to R H Vonderheide.

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Mason, N., Coughlin, C., Overley, B. et al. RNA-loaded CD40-activated B cells stimulate antigen-specific T-cell responses in dogs with spontaneous lymphoma. Gene Ther 15, 955–965 (2008). https://doi.org/10.1038/gt.2008.22

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  • DOI: https://doi.org/10.1038/gt.2008.22

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