Immunotherapy is a cutting-edge medical treatment that empowers the body’s immune system to combat diseases like cancer. A groundbreaking clinical trial by researchers at Mass General Brigham has unveiled a new way to prevent squamous cell carcinoma (SCC), the second most common type of skin cancer, by activating the adaptive immune system. The study, published in the Journal of Clinical Investigation, details how combining calcipotriol (a vitamin D analog) and 5-fluorouracil (5-FU, a chemotherapy drug) eliminates precancerous lesions and provides long-term cancer prevention through a unique immune response.
Immunotherapy A New Approach to Prevention
One of the persistent challenges with SCC is the recurrence of precancerous lesions over time, which increases the risk of developing multiple new skin cancers. According to Shawn Demehri, MD, PhD, lead author of the study and a dermatologist at Massachusetts General Hospital, prevention is critical in combating this cancer.
“We found that this drug combination prevents cancer through a mechanism distinct from those used by current immunotheraphy, suggesting that these drugs may treat and prevent cancer via distinct mechanisms,” Demehri explained.
Unlike other treatments, this combination therapy activates CD4+ T helper cells—key components of the adaptive immune system. This novel approach differs from existing immunotherapy, which primarily target cancerous cells directly without engaging the broader immune response.
Immunotherapy Clinical Trial Success: Clearing Precancerous Lesions
The open-label clinical trial enrolled 18 patients with precancerous skin lesions primarily caused by sun damage. Participants applied calcipotriol and 5-FU cream twice daily to the face, scalp, and upper extremities for six days. The results were remarkable:
- 95% of precancerous spots on the face were eliminated, with seven out of ten patients achieving complete clearance of facial lesions.
- The scalp saw an 82% reduction in lesions, while the upper extremities showed 65% and 68% reductions on the right and left sides, respectively.
Patients experienced temporary redness and inflammation around the treated areas, but these side effects resolved within four weeks, leaving healthy skin unaffected. Follow-up biopsies revealed a significant increase in CD4+ T cell activity at lesion sites, confirming the immunotherapy response’s critical role in clearing the spots.
Five Years of Lasting Protection
What sets this therapy apart is its long-lasting effect. The research team conducted skin biopsies on participants for up to five years post-treatment, finding that the immune response continued to protect against new precancerous lesions. In a parallel study on mice, the treatment delayed tumor onset and reduced tumor counts, further validating the therapy’s ability to prevent cancer recurrence.
Demehri is now leading a multi-center clinical trial to evaluate whether this immunotherapy benefits immunocompromised individuals, such as organ transplant recipients who are at a higher risk of skin cancer. The team is also exploring whether this mechanism can be adapted to prevent other cancers, including oral, breast, and anal cancers.
“This trial demonstrates that immunology can be a powerful force in cancer prevention, much like it transformed cancer treatment over the last decade,” Demehri said.
This promising research paves the way for innovative cancer prevention strategies that could transform care for millions at risk of SCC and potentially other cancers.
References: Tomonori Oka, Sabrina S. Smith, Heehwa G. Son, Truelian Lee, Valeria S. Oliver-Garcia, Mahsa Mortaja, Kathryn E. Trerice, Lily S. Isakoff, Danielle N. Conrad, Marjan Azin, Neel S. Raval, Mary Tabacchi, Luni Emdad, Swadesh K. Das, Paul B. Fisher, Lynn A. Cornelius, Shadmehr Demehri. T helper 2 cell–directed immunotherapy eliminates precancerous skin lesions. Journal of Clinical Investigation, 2025
