Topical Immunotherapy Reduces Squamous Cell Carcinoma Risk

Kristin Jenkins

April 01, 2019

A topical therapy applied to sun-damaged skin twice a day for 4 days induced a long-lasting T-cell immunity that was associated with a 3-year decrease in the risk of squamous cell carcinoma (SCC), researchers report.

The treatment comprised calcipotriol (Dovonex, Leo Pharma) ointment plus 5-fluorouracil (5-FU) cream, which were applied twice a day for 4 days to actinic keratosis — UV-light induced skin lesions that are a precursor to SCC — occurring on the head, neck, and upper extremities.  

The study, led by Lynn A. Cornelius, MD, chief of the Division of Dermatology at Washington University School of Medicine in St. Louis, Missouri, was published online March 21 in JCI Insight.

The team randomly assigned 130 patients, comparing calcipotriol with 5-FU to a control group that used Vaseline plus 5-FU.  This latest analysis, looking at SCC after 3 years, was carried out in 86 of these patients.

Although a higher proportion of patients treated with calcipotriol plus 5-FU remained SCC-free over the 1500-day follow-up, this number did not reach statistical significance, the authors note. This was "likely due to our limited sample size and follow-up duration," they write.

Nevertheless, the results provide evidence that the "immunological memory" created by the regimen is effective. They also indicate that the chemopreventive strategy "may be broadly applicable to skin and internal malignancies," the investigators suggest.

"This finding provides the first clinical proof-of-concept that an immunotherapy directed against premalignant tumors can prevent cancer," said senior author Shawn Demehri, MD, PhD, of Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.

"We hope our findings will establish that the use of premalignant lesions as personalized therapeutic targets can train the immune system to fight against the progression to cancer," Demehri added.

"This skin cancer and its treatment can be disfiguring, costly, and even life-threatening, making it essential to improve preventive strategies," said Cornelius.

"We believe this is an effective and viable option for our patients," Cornelius and Demehri told Medscape Medical News.

We believe this is an effective and viable option for our patients. Dr Lynn Cornelius

They noted that the study did not demonstrate that the immunotherapy had any impact on the development of basal cell carcinomas (BCC). Unlike actinic keratosis, which is the common precursor to SCC, BCC does not have a precursor lesion, the authors pointed out.

"We hypothesize that the UV [ultraviolet]-induced mutations that are present in the precancerous actinic keratosis, as well as in the UV-damaged skin, more closely align with the mutational profile of the SCCs," Cornelius and Demerhi said.

The authors noted that calcipotriol is a low-calcemic vitamin D analog approved by the US Food and Drug Administration (FDA) for the treatment of psoriasis. It has been shown to eliminate actinic keratosis by initiating a robust CD4+ T-cell immune response.

"Skin cancer prevention is an urgent, unmet need," the investigators emphasize, adding that SCC is the second most common skin cancer in the US.

Between 1992 and 2012, the incidence of keratinocyte carcinomas increased by 100%. The cost of treatment, estimated to be more than $1 billion annually, "represents a growing public health challenge in the US," the researchers say.

Study Details

In a previous randomized clinical trial, the investigators compared a 4-day course of topical calcipotriol plus 5-FU to Vaseline plus 5-FU for the treatment of actinic keratosis in 130 patients.

They reported that a 4-day course of 0.005% calcipotriol ointment plus 5% 5-FU cream was superior to Vaseline plus 5-FU in eliminating actinic keratosis.

It also reduced the risk of SCC on the face and ears for up to 1 year. By 2 years, however, this effect had completely dissipated.

For the current analysis, Cornelius and colleagues looked at the incidence of SCC and BCC at periods of 1, 2 and 3 years after treatment in a cohort of 86 patients from the earlier trial.

The results showed that more participants treated with the combined regimen remained SCC-free on the face and scalp after 1500 days (4.1 years) than did controls receiving standard 5-FU monotherapy (P = .0765).

Three years after treatment, SCC was diagnosed on the face and scalp in 2 of 30 patients (7%) treated with the combination regimen compared with 11 of 40 controls (28%) treated with standard monotherapy (hazard ratio [HR] 0.215; 95% confidence interval [CI], 0.048 – 0.972; P = .032).

There was no evidence of reduced SCC risk at any other anatomical site for either treatment group. The researchers suggest that a regimen longer than 4 days may be required to effectively treat actinic keratosis in areas other than the face and scalp.

An analysis of tissue samples for evidence of T-cell immunity revealed tissue-resident memory T (Trm) cell formation in skin on the face and scalp. This was associated with significantly higher erythema scores in treated patients compared with controls  (P < .01).

More studies are needed to determine the optimal treatment to reduce SCC risk anywhere on the body, Cornelius and colleagues point out.

Longer follow-up is also required to find out whether SCC risk reduction can be extended beyond 3 years and offered to high-risk populations such as organ transplant recipients, the researchers say.

This study was funded by the Burroughs Wellcome Fund, the Sidney Kimmel Foundation, the Cancer Research Institute, and the National Institutes of Health. Cornelius and Demehri reported that they have filed a patent for the use of this immunotherapy in the treatment of actinic keratosis. Demehri reported receiving a Career Award for Medical Scientists from the Burroughs Wellcome Fund. Two coauthors also reported relationships with the Burroughs Wellcome Fund.

JCI Insight. Published online March 21, 2019. Full text

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