Intralesional nivolumab reduced the size of precancerous lesions and preserved quality of life in patients with oral epithelial dysplasia, according to results from a first-in-human phase I dose-escalation trial presented in a poster and press briefing during the 2026 American Association for Cancer Research (AACR) Annual Meeting.1 The findings suggest that lesion-directed checkpoint inhibition may represent a viable strategy for cancer interception that could help some patients avoid surgery.
During a press briefing, presenting author Moran Amit, MD, PhD, Surgeon-Scientist and Assistant Professor, The University of Texas (UT) MD Anderson Cancer Center, Houston, noted that there were 36 people in the room and estimated that as many as 5 of them could have an oral premalignant lesion. These lesions affect 5% of the global population, carry a 1% to 36% risk of progression to oral cancer based on the extent of dysplasia, and, once identified, would be managed with surgical resection—the current standard of care.
Moran Amit, MD, PhD
“Each time a patient has to undergo surgery, they are losing volume of their oral cavity, most commonly on the tongue,” said Dr. Amit in an AACR press release, noting that about 60% of patients present with multiple lesions, while recurrence following surgery may reach 40%. “Once you lose a certain amount of your tongue, you cannot articulate anymore, [and] you cannot swallow effectively.”
The investigators thus sought to spare patients from this oftentimes debilitating surgery. Prior research has demonstrated the activity of systemic PD-1 blockade in oral dysplasia, but this “can lead to toxicities that would not be acceptable for patients who do not even have cancer yet,” Dr. Amit noted in the press release.
With intralesional delivery of such therapy, designed to mitigate toxicity, “for the first time, we have a nonsurgical, effective, and safe approach…to treat premalignancies…,” he commented.
Study Details
Thirty-three patients were assessed for eligibility for this open-label trial (ClinicalTrials.gov Identifier NCT05327270). Those with at least one histologically confirmed, untreated premalignant oral lesion at high risk of progression to oral cancer based on size, location, morphology, extent of dysplasia, or patient age or medical history who participated in the study and were randomly assigned to receive 10 mg (n = 13) or 20 mg (n = 16) of nivolumab—approximately 2% to 4% of the intravenous dose—administered via intralesional injection every 3 weeks for a total of four cycles.
Elizabeth M. Jaffee, MD, FAACR
During the question-and-answer session of the press briefing, former AACR President and AACR Academy President Elizabeth M. Jaffee, MD, FAACR, of Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, who served as moderator, noted that the evaluated doses were low and asked what data informed that decision. Dr. Amit responded, “We know that when you give it at full dose [systemically], only a fraction gets to the lesion itself—about 5% when you look at pharmacokinetic data from other studies. On top of that, there were preclinical trials…that showed that local administration using biogels in animals [at an equivalent dose] is effective.”
The protocol limited treatment to one lesion per patient to assess whether intralesional nivolumab produced systemic or localized effects; when multiple lesions were present, the largest was treated. Over half of lesions were located on the tongue; 15 patients had high-grade (moderate or severe) and 14 had low-grade (mild) dysplasia.
Dr. Amit noted that many patients had a history of oral cancer; thus, “we are also moving from the prevention and treatment space to survivorship,” he stated. The development of these precancerous lesions can be especially distressing for those with prior experience of the disease.
Because the trial administered cancer therapy to patients without cancer, “we need to be very mindful of toxicity,” Dr. Amit stated. Accordingly, safety and tolerability were evaluated as the primary endpoints. Secondary endpoints included lesion response, progression to carcinoma, pharmacokinetics, spatial immune profiling, and prospective patient-reported outcomes.
Safety and Patient Experience Profile
No dose-limiting toxicities were observed with intralesional treatment. Adverse events were predominantly grade 1 or 2 (94%), and no systemic immune-related toxicities were observed; however, there was one case each of grade 3 diarrhea, grade 3 hyperglycemia, and grade 4 acidosis. The most frequently reported adverse events were fatigue, diarrhea, and rash—consistent with the known safety profile of immunotherapy in patients with cancer, according to Dr. Amit. These events were self-limited and self-resolving, with no significant difference seen between the 10- and 20-mg groups. Mild injection-site reactions occurred in 40% of patients and resolved within 48 hours without intervention.
Intralesional delivery of nivolumab is safe, well tolerated, and results in efficacy rates unparalleled by other nonsurgical methods….— MORAN AMIT, MD, PhD
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Consistent with the observed safety of the approach, Dr. Amit emphasized the magnitude of patient desire to avoid oral surgeries, noting that study participants traveled a mean of 205 miles each way to receive the treatment at UT MD Anderson. “That tells you how desperate they are,” he remarked.
Patient-reported outcomes showed overall stability or improvement across “almost every dimension” of symptoms during treatment and follow-up, according to Dr. Amit. Improvements in enjoyment of life and physical activity were reported relative to baseline.
“We are not giving them symptoms,” Dr. Amit highlighted, upon presenting these findings from the first prospective longitudinal analysis of patient-reported outcomes in oral premalignancy. “We are not causing them harm.”
Clinical Activity
After a median follow-up of 14.5 months from the first injection, 85% of patients achieved a clinical response (defined as a reduction in lesion size). Mean lesion area decreased by 60%, with 19 patients experiencing reductions greater than 50%.
“Despite many years of research, there are zero biomarkers for oral premalignancies. There are some biomarkers for immunotherapy efficacy in cancer, but we know that at least in the field of head and neck, they are somewhat unreliable, so we decided to use the grade of dysplasia as our sole biomarker,” Dr. Amit explained during the question-and-answer session. “It is a squeaky biomarker, but it is all we have.”
Twelve patients (41%) experienced histologic downgrading of the treated lesion, including six patients (21%) who achieved a complete pathologic response (defined as no evidence of dysplasia at follow-up). Of these, four had moderate and two had mild dysplasia at baseline.
The 12-month cancer-free survival rate was 75.8% among all treated patients, which, according to Dr. Amit, “suggests durable benefit and treatment de-escalation.” He added, during the question-and-answer session, “This was [a] great outcome for us, because the 75% cancer-free survival after a year translated into surgery-free survival. To me, [that rate] is amazing—it is unheard of.” All progression events were identified early and amenable to surgical salvage. No patients whose lesions did not progress required or chose surgical resection of their treated lesions during the follow-up period.
Biologic Signal and ‘Promising’ Pharmacokinetics
According to Dr. Amit, spatial transcriptomic and multiplexed imaging analyses revealed “significant shifts in the immune microenvironment of [the treated] lesions.” In tissue samples from 23 patients, treated lesions demonstrated immune activation, characterized by increased CD4- and CD8-positive T-cell infiltration, enrichment of CCR7-positive activated dendritic cells, elevated CD103-positive tissue-resident CD8-positive T cells, and formation of higher-order immune assemblies.
“Unfortunately, two out of three patients will have [synchronous] lesions, and in those lesions that were noninjected, we didn’t see response,” Dr. Amit noted. He therefore suggested in the press release that intralesional delivery effectively limited nivolumab activity to the targeted sites.
Profiling of peripheral blood mononuclear cells confirmed the absence of systemic immune perturbation, which, Dr. Amit said, “is exactly what we wanted to achieve.” Serum nivolumab levels were consistently found to be about 10-fold lower than those seen with systemic administration, with no evidence of accumulation.
The Path 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,” Dr. Amit remarked in the press release. “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.”
Despite describing the results as “promising,” Dr. Amit acknowledged that they come from an early-phase trial and are therefore preliminary. The study is limited by its single-arm design, short follow-up duration, and insufficient statistical power to assess efficacy. A follow-up phase II randomized, placebo-controlled trial (NCT06561087) is underway at UT MD Anderson.
When asked during the question-and-answer session about management of patients with multiple lesions, Dr. Amit stated, “In the future trials, which we are going to design and launch very soon, we are going to inject all lesions in the mouth. Since the pharmacokinetic data were so promising and we didn’t see any leak to the systemic circulation, we really don’t think there is a problem in increasing the dose to up to 40 [mg], and maybe even 80 [mg], by distributing the volume across different lesions in the oral cavity.”
Further, the findings may extend beyond premalignant lesions of the oral cavity. “Many cancer types are preceded by precursor lesions, such as those arising on the skin, cervix, or colon,” Dr. Amit explained in the press release. “Our results raise the possibility that local immunotherapy administration could be an effective interception strategy for those precancerous lesions as well.”
DISCLOSURE: The study was sponsored by the Cancer Prevention and Research Institute of Texas. Dr. Amit reported no conflicts of interest. Dr. Jaffee reported the following nonrelevant relationships: She serves as Chief Medical Advisor for the Lustgarten Foundation; is co-founder of Abmeta Therapeutics and Adventris; has served on advisory boards for Mestag Therapeutics, SURGE Therapeutics, Break Through Cancer, HDT Bio, NEUVOGEN, Candel Therapeutics, and NeoTx; and has received industry grants from Genentech and Agenus.
REFERENCE
1. Amit M, Saddawi-Konefka R, Naara S, et al: Intralesional PD-1 blockade for oral cancer prevention: First-in-class phase 1 trial. 2026 AACR Annual Meeting. Abstract CT188. Presented April 21, 2026.
