Randomized trial of calcipotriol combined with 5-fluorouracil for skin cancer precursor immunotherapy
Trevor J. Cunningham, … , Lynn A. Cornelius, Shadmehr Demehri
Trevor J. Cunningham, … , Lynn A. Cornelius, Shadmehr Demehri
Published November 21, 2016
Citation Information: J Clin Invest. 2017;127(1):106-116. https://doi.org/10.1172/JCI89820.
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Clinical Medicine Clinical trials Dermatology

Randomized trial of calcipotriol combined with 5-fluorouracil for skin cancer precursor immunotherapy

Abstract

BACKGROUND. 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.

METHODS. 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.

RESULTS. 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.

CONCLUSION. 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.

TRIAL REGISTRATION. ClinicalTrials.gov NCT02019355.

FUNDING. Not applicable (investigator-initiated clinical trial).

Authors

Trevor J. Cunningham, Mary Tabacchi, Jean-Pierre Eliane, Sara Moradi Tuchayi, Sindhu Manivasagam, Hengameh Mirzaalian, Ahu Turkoz, Raphael Kopan, Andras Schaffer, Arturo P. Saavedra, Michael Wallendorf, Lynn A. Cornelius, Shadmehr Demehri

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Figure 6

Induction of TSLP, HLA class II, and NKG2D ligand in response to calcipotriol plus 5-FU combination therapy.

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Induction of TSLP, HLA class II, and NKG2D ligand in response to calcipo...
(A) Representative images of actinic keratoses stained with H&E, TSLP and keratin 14 (K14), and HLA DP/DQ/DR (class II) and CD4, before and after treatment. K14 staining marks the proliferative keratinocytes of actinic keratoses. Black arrow points to the site’s lymphocytic aggregate at the epidermal-dermal junction, and red arrows point to lesional keratinocytes that expressed HLA class II in the calcipotriol plus 5-FU–treated actinic keratoses. (B) Graphs demonstrate the expression of the cellular stress genes relative to GAPDH in actinic keratoses before and after treatment with calcipotriol plus 5-FU (C+F, n = 11) or Vaseline plus 5-FU (V+F, n = 10). P values are shown in each graph and were determined by paired Student’s t test. Note that the gene expression analysis was performed on actinic keratosis biopsies that were obtained before and after treatment from the same anatomical site on the face or scalp from each participant. Scale bars: 100 μm.