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Development of an adenovirus vector vaccine platform for targeting dendritic cells

Cancer Gene Therapy volume 25, pages 27–38 (2018)Cite this article

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Abstract

Adenoviral (Ad) vector vaccines represent one of the most promising modern vaccine platforms, and Ad vector vaccines are currently being investigated in human clinical trials for infectious disease and cancer. Our studies have shown that specific targeting of adenovirus to dendritic cells dramatically enhanced vaccine efficacy. However, this was achieved using a molecular adapter, thereby necessitating a two component vector approach. To address the mandates of clinical translation of our strategy, we here sought to accomplish the goal of DC targeting with a single-component adenovirus vector approach. To redirect the specificity of Ad vector vaccines, we replaced the Ad fiber knob with fiber–fibritin chimeras fused to DC1.8, a single-domain antibody (sdAb) specific for murine immature DC. We engineered a fiber–fibritin–sdAb chimeric molecule using the coding sequence for DC1.8, and then replaced the native Ad5 fiber knob sequence by homologous recombination. The resulting Ad5 virus, Ad5FF1.8, expresses the chimeric fiber–fibritin sdAb chimera. Infection with Ad5FF1.8 dramatically enhances transgene expression in DC2.4 dendritic cells compared with infection with native Ad5. Ad5FF1.8 infection of bone marrow-derived DC demonstrates that Ad5FF1.8 selectively infects immature DC consistent with the known specificity of DC1.8. Thus, sdAb can be used to selectively redirect the tropism of Ad5 vector vaccines, providing the opportunity to engineer Ad vector vaccines that are specifically targeted to DC, or specific DC subsets.

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Fig. 1: Validation of Nb-DC1.8 incorporation into the Ad5FF1.8 capsid.
Fig. 2: Ad5FF1.8 efficiently transduces DCs in a CAR-independent manner.
Fig. 3: sdAb DC1.8 and Ad5FF1.8 compete for binding to DC.
Fig. 4: Subset specific targeting by Ad5FF1.8.
Fig. 5: Biodistribution of Ad5 and Ad5FF1.8.
Fig. 6: In vivo immunogenicity of Ad5 vs. Ad5FF1.8.

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Acknowledgements

We thank the Alvin J. Siteman Cancer Center at Washington University School of Medicine and Barnes-Jewish Hospital in St. Louis, MO, for the use of the Flow Cytometry Shared Resource Core. The Siteman Cancer Center is supported in part by an NCI Cancer Center Support Grant #P30 CA91842. Sam Kim was supported by an NCI training grant, T32 CA 009621.

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Authors and Affiliations

  1. Department of Surgery, Washington University School of Medicine, St. Louis, MO, USA

    Piyush K. Sharma, Lijin Li, Samuel W. Kim, Zhi-Hong Lu, Jeffrey M. Arbeit, Timothy P. Fleming, S. Peter Goedegebuure & William E. Gillanders

  2. Cancer Biology Division, Biologic Therapeutics Center, Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, USA

    Igor P. Dmitriev, Elena A. Kashentseva, Sergey A. Kaliberov & David T. Curiel

  3. Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium

    Geert Raes

  4. VIB Center for Inflammation Research, Myeloid Cell Immunology Laboratory, Brussels, Belgium

    Geert Raes

  5. The Alvin J. Siteman Cancer Center, Barnes-Jewish Hospital and Washington University School of Medicine, St. Louis, MO, USA

    Jeffrey M. Arbeit, Timothy P. Fleming, S. Peter Goedegebuure & William E. Gillanders

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  1. Piyush K. Sharma
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Sharma, P.K., Dmitriev, I.P., Kashentseva, E.A. et al. Development of an adenovirus vector vaccine platform for targeting dendritic cells. Cancer Gene Ther 25, 27–38 (2018). https://doi.org/10.1038/s41417-017-0002-1

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