TY - JOUR
T1 - Randomized trial of calcipotriol combined with 5-fluorouracil for skin cancer precursor immunotherapy
AU - Cunningham, Trevor J.
AU - Tabacchi, Mary
AU - Eliane, Jean Pierre
AU - Tuchayi, Sara Moradi
AU - Manivasagam, Sindhu
AU - Mirzaalian, Hengameh
AU - Turkoz, Ahu
AU - Kopan, Raphael
AU - Schaffer, Andras
AU - Saavedra, Arturo P.
AU - Wallendorf, Michael
AU - Cornelius, Lynn A.
AU - Demehri, Shadmehr
N1 - Funding Information:
We thank Caroline Mann, Milan Anadkat, Amy Musiek, Ian Hornstra, David Sheinbein, Guadalupe Sanches, Laurin Council, and Eva Hurst at Washington University for referring patients to this study. We thank Ethan Lerner, David Fisher, Barbara Gilchrest, Nir Hacohen, and Keith Flaherty (Massachusetts General Hospital, Boston, MA, USA) for critically reading the manuscript. We also thank Warren Leonard (NIH, Bethesda, MD, USA) for the TSLPR-/- mice. SD and TJC were supported by grants from the American Skin Association, the Dermatology Foundation, the Burroughs Wellcome Fund, the American Philosophical Society, the La Roche-Posay Research Foundation, and the NIH (1DP5OD021353). RK, AT, and SM were supported by NIH grant RO1GM055479 (to RK).
PY - 2017/1/3
Y1 - 2017/1/3
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85008414660
U2 - 10.1172/JCI89820
DO - 10.1172/JCI89820
M3 - Article
C2 - 27869649
AN - SCOPUS:85008414660
SN - 0021-9738
VL - 127
SP - 106
EP - 116
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 1
ER -