Researchers at Mass General Brigham have reported promising results from a trial of a novel topical immunotherapy for skin cancer prevention, offering a new pathway for managing actinic keratosis (AK) and reducing the risk of squamous cell carcinoma (SCC). The therapy combines topical calcipotriol with 5-fluorouracil (5-FU) and has demonstrated the ability to eliminate precancerous lesions and prevent SCC for up to five years post-treatment. This approach activates specific components of the adaptive immune system, particularly CD4+ T helper cells, marking a departure from traditional cancer treatments. The findings, published in the Journal of Clinical Investigation, highlight the potential for similar immunotherapies to prevent other cancers throughout the body.
Activating the Immune System
The open-label clinical trial, led by Shawn Demehri from Massachusetts General Hospital, enrolled 18 subjects with qualifying pre-cancerous skin lesions. Participants applied a therapy combining 0.0025% calcipotriol and 2.5% 5-FU to affected areas twice daily for six days. Post-treatment evaluations revealed that the immunotherapy eliminated 95% of pre-cancerous spots on subjects’ faces, with complete clearance of facial lesions in 7 out of 10 subjects. Additionally, 82% of spots on the scalp and over 65% on both upper extremities were cleared. Adverse events were limited to inflammation and redness, which resolved within four weeks, while healthy skin remained unaffected.
Novel Mechanism of Action
Researchers studied skin biopsies to understand the drug's mechanism, finding high CD4+ T cell activity at sites where precancerous lesions were removed. The study found that the combination therapy triggers Th2 immunity, 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.
Implications for Skin Cancer Prevention
SCC is the second most common type of skin cancer, affecting an estimated 1.8 million individuals in the US each year. Precancerous spots, often caused by sun damage, signal an increased risk of SCC, but removing individual spots does not notably reduce the likelihood of developing this cancer. The new immunotherapy offers a more comprehensive approach by activating the patient's own immune system to target and eliminate these precancerous lesions.
Future Directions
Demehri is currently working on a multi-center trial to determine if immunocompromised patients, such as organ transplant recipients who are at a greater risk for skin cancer, will benefit similarly from this treatment. His team is also exploring how this trial’s identified mechanism could be applied to other immunotherapies to prevent additional forms of malignancies. "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," said Demehri.
