Injecting nivolumab (Opdivo) directly into precancerous oral lesions led to a reduction in lesion size, allowing some patients to avoid surgery, according to study results from a phase I clinical trial presented at the American Association for Cancer Research (AACR) Annual Meeting 2026, held April 17-22.
About 5% of the general population has precancerous lesions in the mouth, and the risk of developing oral cancer is 1% to 36%, depending on the degree of dysplasia (i.e., how abnormal the cells in the lesion are) and other factors, explained presenter Moran Amit, M.D., Ph.D., a surgeon and assistant professor at the University of Texas MD Anderson Cancer Center. Because there are no reliable biomarkers to predict the risk of progression, many patients typically undergo surgical removal of the lesions, a procedure that is associated with high morbidity, he said.
“The mouth is the main conduit for so many different functions, including speaking, eating, drinking, and breathing. Think about the last time you felt pain in your mouth. How debilitating it was. Now, the lesion has returned. “Imagine a patient who has to undergo multiple surgeries in many parts of the mouth as the disease progresses,” Amit said, noting that about 60% of patients have multiple lesions and the risk of recurrence after surgery can be as high as 40%.
Each time a patient undergoes surgery, the volume of the oral cavity, most commonly the tongue, decreases. If you lose a certain amount of your tongue, you won’t be able to make sounds or swallow effectively. Due to precancerous lesions, patients may lose the ability to speak or eat. The aim of our research was to find a way to save patients from this often debilitating surgery. ”
Moran Amit, MD, Surgeon and Assistant Professor, University of Texas MD Anderson Cancer Center
Previous studies have shown that treatment with the immune checkpoint inhibitor nivolumab may reduce the size and risk of progression of precancerous oral lesions, but this treatment is administered systemically via intravenous infusion and is associated with severe toxicity, Amit said.
“While effective, systemic administration of nivolumab can cause unacceptable toxicity in patients who do not yet have cancer,” he noted.
Amit et al. reasoned that lower doses (2% to 4% of the intravenous dose) of nivolumab injected directly into oral lesions could effectively treat the lesions without inducing the systemic toxicity associated with intravenous nivolumab.
To test this hypothesis, they conducted a phase I clinical trial to evaluate the safety and efficacy of intralesional nivolumab.
The study enrolled 29 patients who had at least one histologically confirmed untreated precancerous oral lesion and were at high risk of progression to oral cancer due to its size, location, morphology, degree of dysplasia, or patient age or medical history. More than half of the lesions were on the tongue. Fifteen patients had lesions with high-grade (moderate or severe) dysplasia. The remaining 14 patients had low-grade (mild) dysplasia.
Patients received 10 mg or 20 mg of nivolumab injected directly into one of their oral lesions every 3 weeks for a total of 4 cycles. The study protocol allowed treatment of only one lesion per patient to assess whether the effects of intralesional nivolumab were systemic or limited to the injection site. If a patient had multiple lesions, the largest lesion was selected for treatment.
After a median follow-up of 14.5 months after the first injection, 25 of 29 patients (85%) experienced a clinical response, defined as a decrease in lesion size. Lesion area decreased by an average of 60%, with 19 patients experiencing a reduction of 50% or more. Clinical responses were observed in high-grade and low-grade lesions at baseline. Twelve patients (41%) experienced histological downgrade of the treated lesions, and 6 patients had a complete pathological response. This means that there were no signs of dysplasia in the treated lesions at follow-up. Of the 6 patients who had a complete pathological response, 4 had moderate dysplasia before treatment and 2 had mild dysplasia.
Twelve months after treatment, 82.13% of treated lesions were cancer-free. In the six patients whose treated lesions progressed to cancer, progression was detected early and the lesions were surgically removed. None of the patients whose lesions did not progress required or chose surgical resection of the treated lesions during the follow-up period.
Serum levels of nivolumab were consistently 10-fold lower than those typically observed with systemic administration. No dose-limiting toxicities occurred with intralesional treatment. The most common adverse events were fatigue, diarrhea, and rash. Mild injection site reactions occurred in 40% of injections and resolved within 48 hours without intervention. Most adverse events were grade 1 or 2, with one incident each of grade 3 diarrhea, grade 3 hyperglycemia, and grade 4 acidosis.
All but four enrolled patients completed all treatment cycles and monitoring. Patient-reported outcomes showed that patient symptoms, including symptoms related to swallowing, mouth and throat pain, speech, communication, taste, and nutrition, improved or remained stable during treatment and follow-up. Patients reported more enjoyment of life and increased physical activity after treatment compared to baseline.
The researchers also examined tissue samples from 23 patients to determine how intralesional nivolumab affected the immune microenvironment of treated and untreated lesions. They observed immune activation only in the treated lesions, as shown by increased infiltration of CD4+ T cells, CD8+ T cells, activated dendritic cells, and immune cell interactions indicating an adaptive immune response. Amit said no immune changes were seen in untreated lesions from the same patients, suggesting that intralesional delivery effectively limited nivolumab’s ability to reach the target site.
“Our findings show that intralesional delivery of nivolumab is safe, well-tolerated, and provides efficacy rates unmatched by other non-surgical methods. This eliminates the need for surgery for the majority of patients and removes parts of the mouth, such as the tongue, cheeks, floor of the mouth, and roof of the mouth,” said Amit. “Even if patients end up undergoing surgery later on, the average 60% reduction in lesion size with intralesional nivolumab means that the amount of surgery required in the future can be significantly minimized, which is expected to significantly reduce the impact on patients’ quality of life.”
Amit pointed out that this finding could have implications beyond oral lesions. “Many types of cancer are preceded by precursor lesions that develop in areas such as the skin, cervix, and colon. Our results raise the possibility that the administration of topical immunotherapy may be an effective blocking strategy against these precancerous lesions.”
Limitations of this study include the single-arm design, short follow-up period, and the fact that the study did not have statistical power to assess efficacy.
This research was supported by the Cancer Prevention Institute of Texas.
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American Association for Cancer Research
