A new study by investigators from Mass General Brigham uncovers how a novel immunotherapy prevents squamous cell carcinoma, with benefits lasting five years after treatment. This 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. Results are 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, a founding member of the Mass General Brigham healthcare system. “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.”

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Squamous cell carcinoma (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 (5-FU) can eliminate precancerous spots and prevent cancer occurrence via activating the patient’s own immune system; yet, prior to this trial, the mechanism remained unclear.

Demehri’s team conducted an open-label clinical trial to investigate the mechanism of calcipotriol plus 5-FU immunotherapy. Eighteen patients with qualifying precancerous skin lesions were enrolled. Participants applied a treatment of 0.0025% calcipotriol and 2.5% 5-FU to affected areas — including the face, scalp, and upper extremities — twice daily for six days. They were evaluated in the clinic and underwent skin biopsies before treatment, one day after completing the regimen, and again eight weeks post-treatment.

The treatment successfully eliminated 95 percent of precancerous spots on the face and removed all facial lesions in 7-of-10 patients. The therapy cleared 82 percent of spots on the scalp and 65 and 68 percent 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 four weeks of treatment. Notably, healthy skin appeared unaffected by this immune response to the drug.

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 five years after the trial, finding that the immunotherapy’s effects persisted.

To better understand the drug’s mechanism, Demehri’s lab created a mouse model, inducing tumor development before treating the mice with the trial immunotherapy. They found that the treatment significantly delayed tumor onset and reduced tumor counts, and that these effects appeared dependent on CD4+ T cell activity.

This study focused on evaluating the long-term efficacy and mode of action of this immunotherapy in patients with competent immune systems. Demehri is currently working on a multi-center clinical trial to evaluate whether immunocompromised individuals, such as organ transplant recipients at higher risk for skin cancer, would experience similar benefits. Demehri and colleagues are also exploring how the mechanism identified in this trial could be employed by other immunotherapies to prevent additional forms of cancer, such as oral, breast, or anal cancer.

“This trial demonstrates that immunology can be a powerful force in cancer prevention, much like it transformed cancer treatment over the last decade,” said Demehri.