A recent study by Demehri et al of Mass General Brigham investigates whether calcipotriol—a vitamin D analog—plus fluorouracil may prevent squamous cell carcinoma (SCC), with benefits lasting 5 years after treatment. This combination therapy is the first to activate specific components of the adaptive immune system, particularly CD4+ T helper cells, which are not known to be involved in traditional cancer treatments. This work highlights the potential for similar immunotherapies to prevent other cancers throughout the body. The results were published in the Journal of Clinical Investigation.
“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,” said corresponding author Shawn Demehri, MD, PhD, of the Department of Dermatology and the Krantz Family Center for Cancer Research at Massachusetts General Hospital. “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.”
SCC is the second most common type of skin cancer. 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. Recently, researchers found that using a vitamin D analog (calcipotriol) combined with chemotherapy (fluorouracil) may eliminate precancerous spots and prevent cancer occurrence via activating the patient’s own immune system; yet, prior to this trial, the mechanism remained unclear.
Combination Therapy
The researchers conducted an open-label clinical trial to investigate the mechanism of calcipotriol plus fluorouracil. A total of 18 patients with qualifying precancerous skin lesions were enrolled. Participants applied a treatment of 0.0025% calcipotriol and 2.5% fluorouracil to affected areas—including the face, scalp, and upper extremities—twice daily for 6 days. They were evaluated in the clinic and underwent skin biopsies before treatment, 1 day after completing the regimen, and again 8 weeks after treatment.
The treatment successfully eliminated 95% of precancerous spots on the face and removed all facial lesions in 7 of 10 patients. The therapy cleared 82% of spots on the scalp and 65% and 68% on the right and left upper extremities, respectively. Side effects included some redness and inflammation around spots that the drug eliminated, but all skin reactions resolved within 4 weeks of treatment. Of note, healthy skin appeared unaffected by this immune response to the drug.
Study Details
Researchers studied skin biopsies under the microscope to understand the drug’s mechanism, finding high CD4+ T-cell activity at sites where precancerous lesions were removed. They evaluated the drug’s long-term success by continuing to collect skin biopsies from participants over 5 years after the trial, finding the immunotherapy’s effects persisted.
This study focused on evaluating the long-term efficacy and mode of action of this immunotherapy in patients with competent immune systems. Dr. Demehri is currently working on a multicenter clinical trial to evaluate whether immunocompromised individuals, such as organ transplant recipients at higher risk for skin cancer, would experience similar benefits.
“This trial demonstrates that immunology can be a powerful force in cancer prevention, much like it transformed cancer treatment over the last decade,” said Dr. Demehri. The researchers are also exploring how the mechanism identified in this trial could be employed by other immunotherapies to prevent additional types of cancer, such as oral, breast, or anal cancer.
Disclosure: Support was provided from NIH-NIAMS R01 AR076013, Burroughs Wellcome Fund, and LEO Foundation. For full disclosures of all study authors, visit the Journal of Clinical Investigation.
