Prophylactic topical immunotherapy trains the immune system to fight skin precancer

A new study by Mass General Brigham scientists describes how a novel immunotherapy prevents the development of squamous cell carcinoma while maintaining the effect for five years after treatment. This therapy was the first to activate specific components of the adaptive immune system, particularly CD4+ T-helper cells, which are not known to be utilized in traditional cancer therapies.

This work highlights the potential of such immunotherapy techniques to prevent other cancers throughout the body. The results of the study are published in the Journal of Clinical Investigation.

“One of the unique challenges of squamous cell carcinoma is that people who develop it are at increased risk of developing multiple new lesions over time. This makes prevention an important part of treatment,” said study author Shawn Demehri, MD, PhD, of the Department of Dermatology and the Krantz Family Center for Cancer Research at Massachusetts General Hospital, part of Mass General Brigham Health System. “We found that our proposed drug combination prevents cancer through a mechanism not similar to that of current immunotherapies, suggesting that our drug combination may treat and prevent cancer through very different mechanisms.”

Squamous cell carcinoma (SCC) is the second most common type of skin cancer. Precancerous spots, often caused by sun exposure, signal an increased risk of developing SCC, but removing individual spots does not significantly reduce the likelihood of developing this cancer. Recently, researchers found that using a vitamin D analog (calcipotriol) in combination with chemotherapy (5-FU) can eliminate precancerous spots and prevent cancer by activating the patient’s own immune system; however, until this trial, the mechanism remained unclear.

Demehri’s team conducted an open clinical trial to investigate the mechanism of calcipotriol plus 5-FU immunotherapy. Eighteen patients with established precancerous skin lesions participated. Participants applied 0.0025% calcipotriol and 2.5% 5-FU to the affected areas (face, scalp and upper extremities) twice daily for six days. They were examined in the clinic and skin biopsies were taken from them before treatment, one day after completion of treatment, and eight weeks after completion of treatment.

The treatment successfully eliminated 95% of the precancerous spots on the face, with 7 out of 10 patients having all of their facial lesions removed. On the scalp, 82% of spots were removed, and 65% and 68% on the right and left upper extremities, respectively. Side effects included some redness and inflammation around the spots removed with the drug combination, but all skin reactions resolved within four weeks of treatment. Notably, healthy skin did not undergo an immune response to the drug.

The researchers examined skin biopsy specimens under a microscope to understand the mechanism of action of the drug and found high CD4+ T-cell activity at sites where precancerous lesions were removed. They evaluated the long-term success of the drug by continuing to collect skin biopsies from participants for five years after the study ended and found that the effects of the immunotherapy persisted.

To better understand the drug’s mechanism of action, members of Demehri’s lab created a mouse model by inducing tumor development and then treated the mice with the investigational immunotherapy. They found that the treatment significantly delayed tumor appearance and reduced the number of tumors, and that these effects appeared to be dependent on CD4+ T-cell activity.

This study was designed to evaluate the long-term efficacy and mode of action of immunotherapy in patients with healthy immune systems. Demehri is currently working on a multicenter clinical trial to evaluate whether a similar effect would be seen in immunocompromised individuals, such as organ recipients at increased risk of developing skin cancer.

Demehri and colleagues are also studying how the mechanism discovered in this trial could be used for other types of immunotherapy aimed at preventing other forms of cancer, such as oral, breast or anal cancer.

This trial demonstrates that immunology can be a powerful force in cancer prevention, just as it has transformed cancer treatment over the past decade.