Exploitation of Langerhans cells for in vivo DNA vaccine delivery into the lymph nodes.
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.
Genetic Immunity Kft, H-1045 Budapest, Hungary.
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ER
Tőke
Genetic Immunity Kft, H-1045 Budapest, Hungary.
O
O
Lőrincz
Genetic Immunity Kft, H-1045 Budapest, Hungary.
Z
Z
Csiszovszki
Genetic Immunity Kft, H-1045 Budapest, Hungary.
E
E
Somogyi
Genetic Immunity Kft, H-1045 Budapest, Hungary.
G
G
Felföldi
Genetic Immunity Kft, H-1045 Budapest, Hungary.
L
L
Molnár
1] Wigner RCP of HAS, H-1121 Budapest, Hungary [2] R&D Ultrafast Lasers Ltd, H-1539 Budapest, Hungary.
R
R
Szipőcs
1] Wigner RCP of HAS, H-1121 Budapest, Hungary [2] R&D Ultrafast Lasers Ltd, H-1539 Budapest, Hungary.
A
A
Kolonics
Centre d'Immunologie de Marseille-Luminy, INSERM U1104, CNRS UMR7280, Aix Marseille Université, Marseille, France.
B
B
Malissen
Research Institute for Genetic and Human Therapy (RIGHT), Bethesda, MD, USA.
F
F
Lori
Research Institute for Genetic and Human Therapy (RIGHT), Bethesda, MD, USA.
J
J
Trocio
Research Institute for Genetic and Human Therapy (RIGHT), Bethesda, MD, USA.
N
N
Bakare
Section on Tissue Biophysics and Biomimetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, MD, USA.
F
F
Horkay
Department of Dermatology and Venereology, Innsbruck Medical University, Innsbruck, Austria.
N
N
Romani
Department of Dermatology and Venereology, Innsbruck Medical University, Innsbruck, Austria.
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CH
Tripp
Department of Dermatology and Venereology, Innsbruck Medical University, Innsbruck, Austria.
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P
Stoitzner
Genetic Immunity Kft, H-1045 Budapest, Hungary.
J
J
Lisziewicz
D000287:Administration, Topical; D000818:Animals; D002465:Cell Movement; D016503:Drug Delivery Systems; D000078404:Epidermal Cells; D004817:Epidermis / Q000187:drug effects; D007167:Immunotherapy / Q000379:methods; D007801:Langerhans Cells; D008198:Lymph Nodes / Q000187:drug effects*; D008822:Mice, Transgenic; D018613:Microscopy, Confocal / Q000295:instrumentation / Q000379:methods; D053758:Nanoparticles / Q000008:administration & dosage; D011817:Rabbits; D014018:Tissue Distribution; D019444:Vaccines, DNA / Q000008:administration & dosage* / Q000493:pharmacokinetics
D019444:Vaccines, DNA