St. Louis, MO—Topical combination treatment previously shown to clear actinic keratosis also dramatically reduces the risk of squamous cell carcinomas (SCCs) at the site, a new study suggests.

An article in JCI Insight reports that treatment with the combination of two drugs already FDA approved—a topical chemotherapy and an immune system–activating compound—reduced the risk of SCC development on the face and scalp by almost 75%. That’s especially significant because SCC is the second most common form of skin cancer, according to the Washington University–led researchers.

“This finding provides the first clinical proof-of-concept that an immunotherapy directed against premalignant tumors can prevent cancer,” explained senior author Shawn Demehri, MD, PhD, of Massachusetts General Hospital. “We hope our findings will establish that the use of premalignant lesions as personalized therapeutic targets can train the immune system against the progression to cancer.”

The study points out that topical calcipotriol plus 5-fluorouracil (5-FU) combination is an effective immunotherapy against actinic keratosis (AK), which is a precursor to SCC, although the long-term effectiveness of calcipotriol plus 5-FU treatment for SCC prevention is unknown.

To remedy that, researchers performed a blinded prospective cohort 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 a control AK treatment—Vaseline plus 5-FU.

The study then assessed SCC and basal cell carcinoma (BCC) incidences at 1, 2, and 3 years after the trial, with tissue analysis for calcipotriol plus 5-FU–induced T-cell immunity in the skin.

Results indicate that compared with the control, calcipotriol plus 5-FU–induced tissue-resident memory T (Trm) cell formation in face and scalp skin, which was associated with significantly higher erythema scores.

“Importantly, more participants in the test cohort remained SCC-free over the more than 1,500-day follow-up period (P = .0765), and significantly fewer developed SCC on the treated face and scalp within 3 years (2 of 30 [7%] vs 11 of 40 [28%] in control group, hazard ratio 0.215 [95% CI: 0.048-0.972], P = 0.032),” the researchers wrote.

The researchers note that significantly more epidermal Trm cells persisted in the calcipotriol plus 5-FU–treated face and scalp skin compared with the control, although there was no significant difference in BCC incidence between the treatment groups.

“A short course of calcipotriol plus 5-FU treatment on the face and scalp is associated with induction of robust T-cell immunity and Trm formation against AKs and significantly lowers the risk of SCC development within three years of treatment,” study authors conclude.

“Our previous findings that calcipotriol plus 5-FU is highly effective for actinic keratosis clearance has led to its being increasingly used in clinics around the world, although further clinical studies are required for formal FDA approval,” added Demehri, an assistant professor of dermatology at Harvard Medical School. “The treatment of SCC can be costly and has significant side effects, and it can be deadly, particularly for patients with suppressed immune systems.

“The primary reason for treating actinic keratosis is to prevent SCC development, and our findings suggest this immunotherapy may be an effective way of achieving that goal,” he adds. “Finding that targeting precancerous lesions with a robust T-cell-directed immunotherapy can yield effective cancer prevention may be applicable to other organs than the skin, something we hope to investigate for malignancies such as breast cancer, for which immunoprevention is an urgent, unmet need.”

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