title: Randomized trial of calcipotriol combined with 5-fluorouracil for skin cancer precursor immunotherapy.
abstract: Actinic keratosis is a precursor to cutaneous squamous cell carcinoma. Long treatment durations and severe side effects have limited the efficacy of current actinic keratosis treatments. Thymic stromal lymphopoietin (TSLP) is an epithelium-derived cytokine that induces a robust antitumor immunity in barrier-defective skin. Here, we investigated the efficacy of calcipotriol, a topical TSLP inducer, in combination with 5-fluorouracil (5-FU) as an immunotherapy for actinic keratosis.
  
  
  
  The mechanism of calcipotriol action against skin carcinogenesis was examined in genetically engineered mouse models. The efficacy and safety of 0.005% calcipotriol ointment combined with 5% 5-FU cream were compared with Vaseline plus 5-FU for the field treatment of actinic keratosis in a randomized, double-blind clinical trial involving 131 participants. The assigned treatment was self-applied to the entirety of the qualified anatomical sites (face, scalp, and upper extremities) twice daily for 4 consecutive days. The percentage of reduction in the number of actinic keratoses (primary outcome), local skin reactions, and immune activation parameters were assessed.
  
  
  
  Calcipotriol suppressed skin cancer development in mice in a TSLP-dependent manner. Four-day application of calcipotriol plus 5-FU versus Vaseline plus 5-FU led to an 87.8% versus 26.3% mean reduction in the number of actinic keratoses in participants (P < 0.0001). Importantly, calcipotriol plus 5-FU treatment induced TSLP, HLA class II, and natural killer cell group 2D (NKG2D) ligand expression in the lesional keratinocytes associated with a marked CD4+ T cell infiltration, which peaked on days 10-11 after treatment, without pain, crusting, or ulceration.
  
  
  
  Our findings demonstrate the synergistic effects of calcipotriol and 5-FU treatment in optimally activating a CD4+ T cell-mediated immunity against actinic keratoses and, potentially, cancers of the skin and other organs.
  
  
  
  ClinicalTrials.gov NCT02019355.
  
  
  
  Not applicable (investigator-initiated clinical trial).
authors.forename: Trevor J
authors.initials: TJ
authors.lastname: Cunningham
authors.forename: Mary
authors.initials: M
authors.lastname: Tabacchi
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Eliane
authors.forename: Sara Moradi
authors.initials: SM
authors.lastname: Tuchayi
authors.forename: Sindhu
authors.initials: S
authors.lastname: Manivasagam
authors.forename: Hengameh
authors.initials: H
authors.lastname: Mirzaalian
authors.forename: Ahu
authors.initials: A
authors.lastname: Turkoz
authors.forename: Raphael
authors.initials: R
authors.lastname: Kopan
authors.forename: Andras
authors.initials: A
authors.lastname: Schaffer
authors.forename: Arturo P
authors.initials: AP
authors.lastname: Saavedra
authors.forename: Michael
authors.initials: M
authors.lastname: Wallendorf
authors.forename: Lynn A
authors.initials: LA
authors.lastname: Cornelius
authors.forename: Shadmehr
authors.initials: S
authors.lastname: Demehri
mesh_terms: D000287:Administration, Topical; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D002117:Calcitriol / Q000008:administration & dosage / Q000031:analogs & derivatives; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects / Q000235:genetics; D055623:Keratosis, Actinic / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D011230:Precancerous Conditions / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D000094632:Thymic Stromal Lymphopoietin
chemical_list: D016207:Cytokines; C055085:calcipotriene; D002117:Calcitriol; D005472:Fluorouracil; D000094632:Thymic Stromal Lymphopoietin