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Exploitation of Langerhans cells for in vivo DNA vaccine delivery into the lymph nodes

Gene Therapy volume 21, pages 566–574 (2014)Cite this article

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Abstract

There is no clinically available cancer immunotherapy that exploits Langerhans cells (LCs), the epidermal precursors of dendritic cells (DCs) that are the natural agent of antigen delivery. We developed a DNA formulation with a polymer and obtained synthetic ‘pathogen-like’ nanoparticles that preferentially targeted LCs in epidermal cultures. These nanoparticles applied topically under a patch-elicited robust immune responses in human subjects. To demonstrate the mechanism of action of this novel vaccination strategy in live animals, we assembled a high-resolution two-photon laser scanning-microscope. Nanoparticles applied on the native skin poorly penetrated and poorly induced LC motility. The combination of nanoparticle administration and skin treatment was essential both for efficient loading the vaccine into the epidermis and for potent activation of the LCs to migrate into the lymph nodes. LCs in the epidermis picked up nanoparticles and accumulated them in the nuclear region demonstrating an effective nuclear DNA delivery in vivo. Tissue distribution studies revealed that the majority of the DNA was targeted to the lymph nodes. Preclinical toxicity of the LC-targeting DNA vaccine was limited to mild and transient local erythema caused by the skin treatment. This novel, clinically proven LC-targeting DNA vaccine platform technology broadens the options on DC-targeting vaccines to generate therapeutic immunity against cancer.

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Acknowledgements

We thank Drs Michael A Ussery and Hao Zhang (Division of AIDS, NIAID) for their support. The study was supported by NIH (N01-AI-70043) and Hungarian National Office for Research and Technology (FIBERSC2, contract no. TECH-09-A2-2009-0134 and DVCLIN01). FH acknowledges the support of the Intramural Research Program of the NICHD, NIH. CHT was in part supported by the COMET Center ONCOTYROL (Cell Therapy Unit), which is funded by the Austrian Federal Ministries for Transport, Innovation and Technology, and Economics, Family and Youth (via the Austrian Research Promotion Agency / FFG) and the Standortagentur Tirol.

Author information

Author notes

  1. E R Tőke, O Lőrincz, Z Csiszovszki, E Somogyi, L Molnár, F Lori & J Lisziewicz

    Present address: 8Current address: eMMUNITY Inc, 4400 East West Hwy, Bethesda, MD 20814, USA.,

  2. G Felföldi

    Present address: 9Current address: Egis Gyógyszergyár Nyrt. H-1106 Budapest, Keresztúri út 30-38., Hungary.,

  3. F Lori

    Present address: 10Current address: ViroStatics srl, 07100 Sassari, Italy.,

  4. J Trocio

    Present address: 11Current address: Department of Outcomes Research, Pfizer Inc, New York, NY, USA.,

  5. N Bakare

    Present address: 12Current address: Janssen Research and Development LLC, Titusville, NJ, USA.,

Authors and Affiliations

  1. Genetic Immunity Kft, H-1045 Budapest, Hungary

    E R Tőke, O Lőrincz, Z Csiszovszki, E Somogyi, G Felföldi, L Molnár & J Lisziewicz

  2. Wigner RCP of HAS, H-1121 Budapest, Hungary

    R Szipőcs & A Kolonics

  3. R&D Ultrafast Lasers Ltd, H-1539 Budapest, Hungary

    R Szipőcs & A Kolonics

  4. Centre d'Immunologie de Marseille-Luminy, INSERM U1104, CNRS UMR7280, Aix Marseille Université, Marseille, France

    B Malissen

  5. Research Institute for Genetic and Human Therapy (RIGHT), Bethesda, MD, USA

    F Lori, J Trocio & N Bakare

  6. Section on Tissue Biophysics and Biomimetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, MD, USA

    F Horkay

  7. Department of Dermatology and Venereology, Innsbruck Medical University, Innsbruck, Austria

    N Romani, C H Tripp & P Stoitzner

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  1. E R Tőke
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Corresponding author

Correspondence to J Lisziewicz.

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Competing interests

JL, ERT, ZC, OL, ES, LM, FL hold shares in Genetic Immunity Inc. The remaining authors declare no conflict of interest.

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Tőke, E., Lőrincz, O., Csiszovszki, Z. et al. Exploitation of Langerhans cells for in vivo DNA vaccine delivery into the lymph nodes. Gene Ther 21, 566–574 (2014). https://doi.org/10.1038/gt.2014.29

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