Intralesional Nivolumab Shows Promise for Treating Precancerous Oral Lesions

Injecting low-dose nivolumab (Opdivo®; Bristol-Myers Squibb) directly into high-risk, precancerous oral lesions may offer a safe and effective alternative to surgery, according to encouraging phase 1 trial (NCT05327270) data presented at the annual meeting og thr American Association for Cancer Research (AACR), held April 17 – 22, 2026, in San Diego, CA.

Background and Need
Precancerous oral lesions affect about 5% of the population and can progress to oral cancer, carrying risks as high as 36% depending on the degree of dysplasia. Surgery, the current standard of care, often results in significant morbidity—especially when lesions recur on the tongue or other vital oral structures. Repeated surgeries can impair speaking, swallowing, and overall health-related Quality of Life (hrQoL).

“The mouth is the main conduit to so many different functions, including speaking, eating, drinking, and breathing. Think about the last time you had a sore spot in your mouth; how debilitating that was. Now imagine a patient who has to undergo surgery at many locations in their mouth, over and over again, as the lesions recur,”  Moran Amit, MD, PhD, a surgeon and assistant professor at The University of Texas MD Anderson Cancer Center, noting that about 60% of patients present with multiple lesions and that the risk of recurrence after surgery can be as high as 40%.

“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,” Amit explained.

“Because of precancerous lesions, patients can lose their ability to speak and eat. The objective of our study was to find a way to spare patients from this oftentimes debilitating surgery,” he added.

A New Approach
Prior studies have shown that systemic immune checkpoint inhibitors like nivolumab have biological activity against these high-risk, precancerous oral lesions, but can cause unacceptable toxicities in patients without cancer.

Now, researchers at MD Anderson Cancer Center, led by Amit, hypothesized that direct, intralesional injection of nivolumab at a fraction of the systemic dose (2% to 4% of the intravenous dose) would reduce lesion size and risk of progression while minimizing side effects, including the systemic toxicities associated with intravenous nivolumab.

Study Design and Results
In a phase 1, open-label trial, 29 patients with confirmed, untreated high-risk oral premalignant lesions received either 10 mg or 20 mg of nivolumab, injected into the largest lesion, every 3 weeks for 4 cycles.

• 85% (25/29) experienced a clinical response (decrease in lesion size, with an average reduction of 60%).
• 41% of patients had their lesion downgraded histologically, and 6 patients had a complete pathologic response.
• One year after treatment, 82.13% of treated lesions continued to be cancer-free.
• For the six patients whose treated lesions progressed to cancer, the progressions were detected early, and the lesions were surgically removed.
• Serum levels of nivolumab were consistently 10-fold lower than 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 but resolved within 48 hours without intervention. Most adverse events were grade 1 or 2, but there was one case each of grade 3 diarrhea, grade 3 hyperglycemia, and grade 4 acidosis.
• All but four enrolled patients completed all treatment cycles and monitoring. Patients’ symptoms, including swallowing, mouth and throat soreness, voice, communication, taste, and nutrition, either improved or remained stable during treatment and follow-up, according to patient-reported outcomes. Patients reported greater enjoyment of life and increased physical activity after treatment as compared with baseline.

Mechanistic Insights
The researchers also examined tissue samples from 23 patients to determine how intralesional nivolumab impacted the immune microenvironment of treated and untreated lesions.  Tissue analysis showed that immune activation (increases in CD4+ and CD8+ T cells and dendritic cells) was limited to the treated lesion, confirming that intralesional delivery achieved a local immune response without systemic toxicity. Untreated lesions from the same patients did not exhibit immune changes, which, according to Amit, suggests that intralesional delivery effectively limited nivolumab’s function to target sites.

Looking Forward
“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—spare removal of pieces of their mouth, whether it’s the tongue, the cheek, the floor of their mouth, or their palate,” Amit said.

“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, which would hopefully translate to a much lower impact on their health-related quality of life,” he added

These findings suggest that intralesional nivolumab could become a non-surgical option for managing high-risk oral premalignancy. A phase 2 randomized, placebo-controlled trial is now underway to further evaluate this approach (NCT06561087).

Implications
Intralesional nivolumab offers a promising, minimally invasive strategy to prevent oral cancer, reduce surgical morbidity, and preserve oral function and quality of life. This targeted immunotherapy approach may be broadly applicable to other precancerous conditions in accessible tissues.

“Many cancer types are preceded by precursor lesions, such as those arising on the skin, cervix, or colon. Our results raise the possibility that local immunotherapy administration could be an effective interception strategy for those precancerous lesions as well,” Amit concluded.

Study limitation
Limitations of the study include the single-arm design, short follow-up, and lack of statistical power to assess efficacy.
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Clinical trials
Non-randomized, Open-label Study of Intralesional Nivolumab for High Risk Oral Premalignant Lesions – ClinicalTrials.gov ID NCT05327270
Phase II Randomized, Placebo- Controlled Study of Intralesional Nivolumab for High-risk Oral Premalignant Lesions – ClinicalTrials.gov ID NCT06561087

Highlights of Prescribing Information
Nivolumab (Opdivo®; Bristol-Myers Squibb)[Prescribing Information]

Reference
[1] Amit M, Saddawi-Konefka R, Naara S, Netto F, Netto F, Fushun CF, Vu Y, Li S, Xie T, Akhter S, Sathishkumar H, Zhou T, Basu S, Sousa L, Akhave N, Hofstede T, Gillenwater A, Diaz E, Pytynia K, Gomez L, Williams M, Sikora A, Myers J, Kadara H, Allison J, Padmaneee S, Chambers M. Intralesional PD-1 blockade for oral cancer prevention: First-in-class phase 1 trial. In: Proceedings of the 117th Annual Meeting of the American Association for Cancer Research; 2026 April 17-22; San Diego, CA.: AACR; 2026. Abstract nr CT188 / 10.

Featured image photo courtesy © 2016 – 2026 Fotolia/Adobe. Used with permission.

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