Immunotherapy Directed Against Skin Cancer Precursors Prevents Skin Cancer
29 Pages Posted: 30 Sep 2018More...
BACKGROUND: Topical calcipotriol plus 5-fluorouracil (5-FU) combination is an effective immunotherapy against actinic keratosis (AK), which is a precursor to squamous cell carcinoma (SCC). However, the long-term effectiveness of calcipotriol plus 5-FU treatment for SCC prevention is unknown.
METHODS: We performed a blinded longitudinal study on participants of a randomized double-blind clinical trial in which a 4-day course of topical calcipotriol plus 5-FU combination was compared to Vaseline plus 5-FU (control) for AK treatment. SCC and basal cell carcinoma (BCC) incidence were assessed at 1, 2, and 3 years after trial. Tissues were analyzed for calcipotriol plus 5-FU-induced T cell immunity in the skin.
FINDINGS: Calcipotriol plus 5-FU combination induced tissue-resident memory T (TRM) cell formation in face and scalp skin associated with significantly higher erythema scores compared to control (p<0.01). Importantly, more participants in the test cohort remained SCC-free over the >1500-day follow-up period (p=0.0765), and significantly fewer developed SCC on the treated face and scalp within 3 years (2 of 30 [7%] versus 11 of 40 [28%] in control group, hazard ratio 0.215 [95% CI: 0.048-0.972], p=0.032). Accordingly, higher numbers of epidermal TRM cells persisted in the calcipotriol plus 5-FU-treated face and scalp skin compared to control (p=0.0028). There was no significant difference in BCC incidence between treatment groups. I
NTERPRETATION: A short course of calcipotriol plus 5-FU treatment on the face or scalp induces robust T cell immunity and TRM formation against AKs, significantly lowering the risk of SCC development within 3 years of treatment (ClinicalTrials.gov number: NCT02019355).
Funding: Shadmehr Demehri, M.D., Ph.D., holds a Career Award for Medical Scientists award from the Burroughs Wellcome Fund. KHN and SD were supported by grants from the Burroughs Wellcome Fund, Sidney Kimmel Foundation, Cancer Research Institute and NIH (5K08AR068619 and DP5OD021353091).
Declaration of Interest: Authors have no conflict of interest to report.
Ethical Approval: The clinical trial and longitudinal study protocols were approved by the academic IRBs of Washington University and Massachusetts General Hospital.
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