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

Abstract

Premalignant lesions of cutaneous squamous cell carcinoma (SCC) are identified clinically as actinic keratoses (12,13). Several field-directed treatments including 5-fluorouracil (5-FU), diclofenac, ingenol, and imiquimod have been approved for the treatment of sun-damaged skin with multiple actinic keratoses (13-15). However, the long treatment duration and the severity 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).

A randomized split-scalp study comparing calcipotriol-assisted methyl aminolaevulinate photodynamic therapy (MAL-PDT) with conventional MAL-PDT for the treatment of actinic keratosis

“…Cunningham et al . demonstrated the synergistic effects of calcipotriol and 5‐fluorouracil treatment by activating a CD4 + T‐cell‐mediated immunity against AKs …”

“…Although they are not completely understood, the mechanisms for calcipotriol‐enhanced PpIX production are partly increased uptake of the photosensitizer in differentiated cells and partly increased expression of the porphyrin synthesis enzyme coproporphyrinogen oxidase and decreased ferrochelatase . Another possible mechanism of action of topical calcipotriol is the induction of antitumour immune response . However, the potential impact of topical vitamin D in combination with PDT for the treatment of AKs in human skin is still uncertain.…”

Skin cancer precursor immunotherapy for squamous cell carcinoma prevention

“…Previously, we discovered calcipotriol plus 5-FU combination as a novel topical immunotherapy for AKs (19). Calcipotriol is a low-calcemic vitamin D analog that is FDA approved for the treatment of psoriasis (20).…”

Update on protease‐activated receptor 2 in cutaneous barrier, differentiation, tumorigenesis and pigmentation, and its role in related dermatologic diseases

“…A possible yet uninvestigated immunologic link between PAR2 and tumorigenesis also exists through TSLP. Recent trial data showing that topical calcipotriol, an inducer of TSLP expression, promotes CD4 T cell–mediated antitumor activity has helped justify its use in treating actinic keratosis . The reported ability of PAR2 to promote expression of TSLP makes this an important implication.…”