Combination Immunotherapy Offers New Pathway for Skin Cancer Prevention

This article was originally published by Pharmacy Times^®. This version has been lightly edited.

Topical calcipotriol (Calcitrene; Glenmark Generics Ltd) plus 5-Fluorouracil (5-FU, Carac; Bausch Health Companies Inc) immunotherapy promotes T-helper type 2 (Th2) immunity and successfully eliminates premalignant keratinocytes to prevent cutaneous squamous cell carcinoma (SCC), according to study findings published in The Journal of Clinical Investigation.¹

Data showed significance reductions in AK lesions on the face, scalp, and left and right upper extremities. | Image credit: Medical Works – stock.adobe.com

These results indicate that Th2 cell activation releases cytokines such as IL-24, a key mediator in suppressing development of skin cancer in patients with actinic keratosis (AK).

According to the Skin Cancer Foundation, SCC is the second most common type of skin cancer affecting an estimated 1.8 million individuals in the US each year. SCC is characterized by the growth of squamous cells on the surface of the skin and can develop anywhere on the body, with the most common cause being excessive exposure to ultraviolet (UV) radiation from the sun, tanning beds, or lamps. Thereby, protection from UV is crucial for prevention.^2,3

SCC is typically nonfatal with a 5-year survival rate of 99% and is most curable in early stages. If left untreated, it can grow larger or spread to other part of the body, which can lead to more serious complication. As of 2025, there are various FDA-approved topical products for AK and SCC, such as tirbanibulin (Klisyri; Almirall), Imiquimod (Aldara; 3M Pharmaceuticals), and 5-FU. Only 5-FU has been proven to treat AK as well as reduce the risk of SCC within 1 year after treatment; however, this benefit is no longer apparent 2 years after treatment.^3-6

In an open-label clinical trial (NCT02019355), researchers aimed to identify the mechanism of 5-FU in combination with calcipotriol, a low-calcemic vitamin D analog used for psoriasis treatment.⁷ Their investigation included 18 patients with AKs on the face, scalp, and upper extremities who received calcipotriol (0.0025%) plus 5-FU (2.5%) topical treatment twice daily for 6 days. Skin biopsies were taken before treatment (day 0), 1-day post-treatment (day 7), and 8 weeks post-treatment. The end points included reduction in AK lesions, immune response in skin biopsies, and long-term effects on SCC risk.^1,7

Data showed significance reductions in AK lesions on the face (95%), scalp (82%), right upper extremity (65%), and left upper extremity (68%), with 7 of 10 patients achieving complete clearance of lesions. Adverse effects included redness and inflammation around the application site, which was resolved within 4 weeks of treatment.¹

The most significant finding from the trial was the mechanism underlying calcipotriol plus 5-FU. The researchers discovered that the combination therapy triggers Th2 immunity, thereby activating Th2 cells to release Th2-associated and IL-24 cytokines, which are critical to induce processes such as apoptosis and autophagy. According to the authors, these findings not only demonstrate the potential of the therapy in reducing AK lesions and preventing SCC, but they also underscore the critical role of IL-24 in suppressing skin carcinogenesis.

“One of the unique challenges with squamous cell carcinoma is that individuals who develop it are at an increased risk of developing multiple new lesions over time. This makes prevention an essential part of care,” Shawn Demehri, MD, PhD, corresponding author of the Department of Dermatology and the Krantz Family Center for Cancer Research at Massachusetts General Hospital, said in a news release.⁸ “We found that this drug combination prevents cancer through a mechanism distinct from those used by current immunotherapies, suggesting that these drugs may treat and prevent cancer via distinct mechanisms.”⁸

The results of this trial have significant implications for both the prevention and treatment of SCC, particularly in individuals at high risk of developing multiple lesions over time. By identifying a distinct immunological pathway for cancer prevention, calcipotriol plus 5-FU offers an alternative approach to existing treatments, potentially broadening therapeutic options for patients with actinic keratosis and those at risk for SCC.

References

1. Oka T, Smith S, Heehwa S, et al. T helper 2 cell–directed immunotherapy eliminates precancerous skin lesions. J Clin Invest. January 2, 2025. doi:10.1172/JCI183274
2. Skin cancer facts & statistics. Skin Cancer Foundation. Updated November 2024. Accessed January 3, 2025. https://www.skincancer.org/skin-cancer-information/skin-cancer-facts/
3. Squamous cell carcinoma of the skin. Mayo Clinic. August 11, 2023. Accessed January 3, 2025. https://www.mayoclinic.org/diseases-conditions/squamous-cell-carcinoma/symptoms-causes/syc-20352480
4. FDA approves Almirall’s Klisyri (tirbanibulin) for the treatment of actinic keratosis on expanded area of face or scalp up to 100 cm2. News release. Almirall. June 10, 2024. Accessed January 3, 2025. https://www.almirall.com/newsroom/news/fda-approves-almirall-s-klisyri-tirbanibulin-for-the-treatment-of-actinic-keratosis-on-expanded-area-of-face-or-scalp-up-to-100-cm2
5. FDA. U.S. Food and Drug Administration. Imiquimod Cream. February 25, 2010. Accessed January 3, 2025. https://www.accessdata.fda.gov/drugsatfda_docs/anda/2010/078548Orig1s000.pdf
6. Prince G, Cameron M, Fathi R, et al. Topical 5-fluorouracil in dermatologic disease. Int J Dermatol. September 6, 2018. doi:10.1111/ijd.14106
7. Actinic keratosis study (AK). Updated May 19, 2016. Accessed January 3, 2025. https://clinicaltrials.gov/study/NCT02019355
8. Cancer-preventing topical immunotherapy trains the immune system to fight precancers. News release. Mass General Brigham. January 2, 2025. Accessed January 3, 2025. https://www.massgeneralbrigham.org/en/about/newsroom/articles/topical-immunotherapy-trains-immune-system-to-fight-precancers