Tumor-Preferential Induction of Immune Responses and Epidermal Cell Death in Actinic Keratoses by Ingenol Mebutate.
The rapid and strong clinical efficacy of the first-in-class, ingenol mebutate, against actinic keratosis (AK) has resulted in its recent approval. We conducted the first comprehensive analysis of the cellular and molecular mode of action of topical ingenol mebutate 0.05% gel in both AK and uninvolved skin of 26 patients in a phase I, single-center, open-label, within-patient comparison. As early as 1 day after application, ingenol mebutate induced profound epidermal cell death, along with a strong infiltrate of CD4+ and CD8+ T-cells, neutrophils, and macrophages. Endothelial ICAM-1 activation became evident after 2 days. The reaction pattern was significantly more pronounced in AK compared with uninvolved skin, suggesting a tumor-preferential mode of action. Extensive molecular analyses and transcriptomic profiling of mRNAs and microRNAs demonstrated alterations in gene clusters functionally associated with epidermal development, inflammation, innate immunity, and response to wounding. Ingenol mebutate reveals a unique mode of action linking directly to anti-tumoral effects.


BACKGROUND
ClinicalTrials.gov NCT01387711.
Department of Dermatology, Venereology and Allergology, University Medical Center Göttingen, Göttingen, Germany.
Steffen
S
Emmert
Department of Dermatology, Venereology and Allergology, University Medical Center Göttingen, Göttingen, Germany.
Holger A
HA
Haenssle
LEO Pharma A/S, Ballerup, Denmark.
John R
JR
Zibert
Department of Dermatology, Venereology and Allergology, University Medical Center Göttingen, Göttingen, Germany.
Margarete
M
Schön
LEO Pharma A/S, Ballerup, Denmark.
Andreas
A
Hald
LEO Pharma A/S, Ballerup, Denmark.
Maria H
MH
Hansen
LEO Pharma A/S, Ballerup, Denmark.
Thomas
T
Litman
Department of Dermatology, Venereology and Allergology, University Medical Center Göttingen, Göttingen, Germany.
Michael P
MP
Schön
D000287:Administration, Topical; D000328:Adult; D015415:Biomarkers; D016923:Cell Death / Q000187:drug effects; D016000:Cluster Analysis; D004224:Diterpenes / Q000494:pharmacology* / Q000627:therapeutic use; D004817:Epidermis / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D007113:Immunity, Innate; D055623:Keratosis, Actinic / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D007962:Leukocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D035683:MicroRNAs / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics
C486592:3-ingenyl angelate; D015415:Biomarkers; D004224:Diterpenes; D035683:MicroRNAs; D012333:RNA, Messenger