Injectable Nivolumab Shows Promise for Precancerous Oral Lesions in Phase I Trial
Key Insights
A phase I clinical trial demonstrated that intralesional nivolumab injection reduced precancerous oral lesion size by an average of 60% in 85% of patients, allowing many to avoid surgery.
The treatment used only 2-4% of the standard intravenous dose, resulting in 10-fold lower serum levels and minimal systemic toxicity compared to systemic administration.
After 14.5 months median follow-up, 82.13% of treated lesions remained cancer-free, with six patients achieving complete pathologic response.
A novel approach to treating precancerous oral lesions using direct injection of the immune checkpoint inhibitor nivolumab has shown promising results in a phase I clinical trial, potentially offering patients an alternative to debilitating surgery. The research, presented at the American Association for Cancer Research (search) (AACR) Annual Meeting 2026, demonstrated significant lesion reduction while preserving oral function and quality of life.
Clinical Challenge and Unmet Need
Approximately 5% of the general population have precancerous lesions in their mouth that carry a 1% to 36% risk of progression to oral cancer, depending on the extent of dysplasia and other factors. Currently, patients typically undergo surgical resection of these lesions due to the absence of reliable biomarkers to predict progression risk, but this procedure is associated with high morbidity.
"The mouth is the main conduit to so many different functions, including speaking, eating, drinking, and breathing," explained Dr. Moran Amit, a surgeon and assistant professor at The University of Texas MD Anderson Cancer Center and the study's presenter. "Each time a patient has to undergo surgery, they are losing volume of their oral cavity, most commonly on the tongue. Once you lose a certain amount of your tongue, you cannot articulate anymore, you cannot swallow effectively."
The clinical burden is substantial, with about 60% of patients presenting with multiple lesions and recurrence rates after surgery reaching as high as 40%. This creates a cycle of repeated surgeries that progressively impairs patients' ability to speak and eat.
Innovative Treatment Approach
While prior research indicated that systemic nivolumab could reduce the size and progression risk of precancerous oral lesions, intravenous administration comes with severe toxicities that would be unacceptable for patients who do not yet have cancer. To address this limitation, Amit and colleagues developed an intralesional approach using only 2% to 4% of the standard intravenous dose.
The phase I clinical trial enrolled 29 patients with at least one histologically confirmed, untreated premalignant oral lesion at high risk of progression to oral cancer. More than half of the lesions were located on the tongue. Fifteen patients had lesions with high-grade (moderate or severe) dysplasia, while the remaining 14 patients had low-grade (mild) dysplasia.
Treatment Protocol and Results
Patients received either 10 mg or 20 mg of nivolumab injected directly into one oral lesion every three weeks for four cycles. The protocol treated only one lesion per patient to assess whether effects would be systemic or localized to the injection site.
After a median follow-up of 14.5 months, the results were striking: 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 reductions greater than 50%. Clinical responses were observed for both high-grade and low-grade lesions at baseline.
Twelve patients (41%) experienced histologic downgrading of their treated lesion, and six patients achieved complete pathologic response, meaning their treated lesion showed no signs of dysplasia at follow-up. Of these six patients with complete response, four had moderate dysplasia before treatment and two had mild dysplasia.
Safety and Tolerability Profile
The intralesional approach demonstrated a favorable safety profile. Serum levels of nivolumab were consistently 10-fold lower than typically observed with systemic administration, and no dose-limiting toxicities occurred. The most common adverse events were fatigue, diarrhea, and rash. Mild injection-site reactions occurred in 40% of injections but resolved within 48 hours without intervention.
Most adverse events were grade 1 or 2, with only isolated cases of grade 3 diarrhea, grade 3 hyperglycemia, and grade 4 acidosis. All but four enrolled patients completed all treatment cycles and monitoring.
Quality of Life and Functional Outcomes
Patient-reported outcomes showed that symptoms related to swallowing, mouth and throat soreness, voice, communication, taste, and nutrition either improved or remained stable during treatment and follow-up. Patients reported greater enjoyment of life and increased physical activity after treatment compared to baseline.
Importantly, none of the patients whose lesions didn't progress required or opted for surgical resection of their treated lesions during the follow-up period. Twelve months after treatment, 82.13% of treated lesions continued to be cancer-free.
Mechanistic Insights
Tissue analysis from 23 patients revealed that intralesional nivolumab induced immune activation exclusively in treated lesions. Researchers observed greater infiltration of CD4+ T cells, CD8+ T cells, and activated dendritic cells, along with immune-cell interactions indicative of adaptive immune responses. Untreated lesions from the same patients did not exhibit immune changes, confirming that intralesional delivery effectively limited nivolumab's function to target sites.
Clinical Implications and Future Directions
"Our findings demonstrate that intralesional delivery of nivolumab is safe, well tolerated, and results in efficacy rates unparalleled by other nonsurgical methods, which allowed us to spare surgery for the majority of patients," said Amit. "Even if a patient ends up undergoing surgery later, the average 60% reduction in lesion size from intralesional nivolumab means we can substantially minimize the amount of surgery they'll need down the road."
The approach may have broader applications beyond oral lesions. "Many cancer types are preceded by precursor lesions, such as those arising on the skin, cervix, or colon," Amit noted. "Our results raise the possibility that local immunotherapy administration could be an effective interception strategy for those precancerous lesions as well."
Study Limitations
The researchers acknowledged several limitations, including the single-arm design, relatively short follow-up time, and the fact that the study was not statistically powered to assess efficacy. The study was supported by the Cancer Prevention and Research Institute of Texas (search).