Injecting immunotherapy directly into precancerous oral lesions may be an effective way to prevent progression to cancer without the need for an oftentimes debilitating surgery.
Jessica Lutterman’s oral cancer was discovered entirely by chance. When an earache prompted her to visit an ear-nose-throat physician, she underwent a full oral exam to rule out any issues in her mouth that could lead to ear pain. It was then that the physician noticed a lesion underneath her tongue. The lesion was not the cause of her ear pain, but it was confirmed to be cancer.
She underwent two surgeries, first to remove the original lesion and then to remove recurrences. With a cumulative 15% loss of her tongue, she continues to experience discomfort with eating or prolonged speaking to this day.
When more tongue lesions arose—precancerous this time—she was confronted with the prospect of a third surgery, which would have meant losing even more of her tongue and potentially suffering greater difficulty speaking and eating. Knowing that she didn’t want to go through yet another surgery, Lutterman enrolled in a phase I clinical trial that was testing a different approach: injecting an immunotherapy drug called nivolumab (Opdivo) directly into a precancerous lesion. Three months after the final immunotherapy injection, her treated lesion was gone, and she no longer required surgery.
“When my newer lesions were discovered, the standard of care would have been another major surgery, one that … would have significantly impacted my ability to eat and speak the way I do now,” she said. “[This] trial has given me the opportunity to delay that surgery and maintain a higher quality of life for as long as possible.”
Lutterman is just one of the many patients enrolled in this trial who experienced positive outcomes. New results from the trial reported at the AACR Annual Meeting 2026 highlight the promise of this innovative approach that may help patients avoid surgery, prevent oral cancer, and maintain their quality of life.
A Debilitating Standard of Care
Approximately 5% of the general population have precancerous lesions in their mouth that can carry a 1% to 36% risk of progression to oral cancer, depending on the extent of dysplasia (i.e., how abnormal the cells of the lesion are) and other factors, explained Moran Amit, MD, PhD, a surgeon and assistant professor at The University of Texas MD Anderson Cancer Center who led the clinical trial and reported its results.
Since there are no reliable biomarkers to predict the risk of progression, patients often undergo surgery to remove these lesions before they progress to oral cancer, but this procedure can have lasting impacts.
“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,” said Amit, 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,” he added. “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.”
The Rationale for Intralesional Delivery of Nivolumab
The immunotherapy drug nivolumab is approved by the U.S. Food and Drug Administration to treat advanced head and neck cancers, including oral cancer, but not currently for early stages or precancerous lesions. Prior research had indicated that treatment with this drug could reduce the size and progression risk of precancerous oral lesions, but this treatment, which is delivered into the bloodstream through intravenous (IV) infusion, comes with severe toxicities, said Amit.
“While effective, systemic nivolumab can lead to toxicities that would not be acceptable for patients who do not even have cancer yet,” he noted.
Amit and colleagues reasoned that injecting a much lower dose of nivolumab directly into the oral lesion could effectively treat the lesion without inducing the systemic toxicities associated with IV nivolumab. They opened a phase I clinical trial to test this idea and enrolled 29 patients, including Lutterman.
All patients in the trial had at least one histologically confirmed, untreated premalignant oral lesion that carried a high risk of progression to oral cancer due to its size, location, morphology, or extent of dysplasia, or due to the patient’s age or medical history.
Patients received either 10 mg or 20 mg of nivolumab injected directly into one of their oral lesions every three weeks for a total of four cycles. The trial protocol allowed treatment of only one lesion per patient in order to assess whether intralesional nivolumab’s effects would be systemic or restricted to the site of injection. In instances where patients had more than one lesion, the largest lesion was chosen for treatment.
The Outcomes: Significant Lesion Shrinkage, Histological Downgrading, and Immune Activity
After a median follow-up of 14.5 months after the first injection, 25 of 29 patients had experienced lesion shrinkage, with an average reduction in area of 60% across low-grade and high-grade lesions. In 12 patients, the treated lesion was histologically downgraded, meaning that the cells of the lesion became less abnormal looking. Six patients’ lesions had no signs of dysplasia at the time of follow-up.
Twelve months after treatment, 82.13% of treated lesions continued to be cancer free. None of the patients whose lesions didn’t progress required or opted for surgical resection of their treated lesions during the follow-up time.
The researchers observed immune activation exclusively in the treated lesions but not in untreated lesions from the same patient—an observation that, according to Amit, suggests that intralesional delivery effectively limited nivolumab’s function to target sites.
The Impacts on Quality of Life
With a dose that was 2% to 4% of the typical IV dose, serum levels of nivolumab were consistently 10-fold lower with intralesional delivery than usually observed with IV administration. No dose-limiting toxicities occurred, and 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.
“The injections themselves can be painful in the moment and for a short time afterward, but overall, the treatment has been very manageable and absolutely worth it,” said Lutterman. “I truly feel like the clinical trial has helped preserve my quality of life.”
Other patients also reported preserved quality of life, according to Amit. He shared patient-reported outcomes showing that symptoms related to swallowing, mouth and throat soreness, voice, communication, taste, and nutrition either improved or remained stable during treatment and follow-up, and that patients experienced greater enjoyment of life and increased physical activity after treatment as compared with baseline.
‘Unparalleled’ Efficacy With Implications Beyond the Mouth
“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,” 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, which would hopefully translate to a much lower impact on their quality of life,” he added.
Amit noted that the findings may also have implications beyond oral lesions. “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.”
Using Her Voice (And Tongue) to Spread the Word
Grateful for her outcome and her continued ability to speak with ease, Lutterman is using her voice to raise awareness of oral cancer and quality-of-life concerns through her foundation, The Speak Easy Foundation.
“I became increasingly aware of how little people talk about oral cancer. It can feel almost taboo, and when I was first diagnosed, I struggled to find others who looked like me or were sharing similar experiences. That sense of isolation made me want to help change the conversation, to raise awareness, make it more visible, and create connection so others don’t feel alone,” she said.
Lutterman is also passionate about advocating for other patients and helping them live with dignity, something that participating in this trial has allowed her to do.
“Will I need surgery in the future? Possibly. But being able to buy time and live that time with more normalcy has meant everything to me. … That’s why continued research and advocacy matter so much, not just to help people survive, but to help them truly live well after treatment.”
