Intralesional Nivolumab for Oral Epithelial Dysplasia: What an Early Trial Tells Us

Could injecting an immune checkpoint inhibitor directly into a dysplastic oral lesion reduce the need for extensive surgery? A first-in-class phase I trial offers encouraging early findings—but important questions about cancer prevention remain unanswered.

Managing OPMDs beyond surgery

The clinical management of oral potentially malignant disorders (OPMDs) remains challenging. Although surgical excision is a primary management option, the complex anatomy of the oral cavity can make treatment difficult.

Recurrence may occur even after clear surgical margins, while repeated interventions can contribute to functional morbidity. These challenges highlight the need for alternative treatment approaches.

Could targeting the local immune environment offer a new way forward?

This compelling research question was explored by Dr Moran Amit, MD, PhD, and colleagues at The University of Texas MD Anderson Cancer Center. They presented preliminary findings from a phase I clinical trial investigating intralesional PD-1 blockade with nivolumab at the 2026 American Association for Cancer Research (AACR) Annual Meeting. The findings were also published as conference abstracts in Cancer Research and the Journal of Clinical Oncology (JCO). [1–3]

Key details of the phase I clinical trial

What did the study examine?

• The study enrolled 29 patients with histologically confirmed oral epithelial dysplasia and at least one lesion considered at high risk of progression.

• It was an open-label, single-arm, dose-escalation phase I trial, without a comparison group.

• The primary endpoints were safety and tolerability.

• Secondary endpoints included lesion response, progression to carcinoma, drug exposure, immune changes and patient-reported quality of life. [1,2]

Why target PD-1 with nivolumab?

• Programmed death-1 (PD-1) is an immune checkpoint receptor on T cells that regulates their activity. When PD-1 binds to its ligand, PD-L1, it suppresses T-cell activation. This can allow abnormal cells to evade immune surveillance.

• Under normal conditions, the PD-1/PD-L1 pathway maintains peripheral immune tolerance. However, tumours can exploit this pathway to suppress antitumour immune responses. [4]

• Nivolumab is a human IgG4 monoclonal antibody that binds to PD-1 and blocks its interaction with PD-L1, helping to restore antitumour immune activity. [5]

• Intralesional administration aims to reduce systemic exposure and associated toxicity by delivering low doses directly into dysplastic lesions, potentially activating local immune responses while limiting systemic drug exposure.

Whether this approach can provide sustained clinical benefit with an acceptable safety profile remains an important question for ongoing research.

What prompted the researchers to explore a new approach?

• OPMDs are estimated to affect approximately 5% of the global population, although prevalence estimates depend on how conditions are defined and studied. [3]

• The risk of malignant transformation varies according to the degree of dysplasia and other clinical and patient factors.

• The investigators hypothesised that delivering nivolumab directly into selected lesions could remodel the local immune environment while minimising systemic drug exposure and potentially avoiding extensive surgical procedures.

What did the researchers report?

The 29 enrolled patients received either 10 mg or 20 mg of nivolumab injected into one selected lesion every three weeks for four cycles. In patients with multiple lesions, only one lesion was treated, allowing the researchers to compare local and untreated sites. [1–3]

Clinical response and histological changes

Lesion area decreased by an average of 60% across study cohorts, and histological downgrading was observed in 12 of 29 patients (41%). The AACR press release additionally reported that six patients had no detectable dysplasia in their treated lesions at follow-up. [1–3]

Safety and systemic exposure

• No dose-limiting toxicities were reported in the conference abstracts.

• The JCO and AACR abstracts report that 94% of adverse events were grade 1–2 and describe no systemic immune-related toxicities. [1,2]

• The AACR press release additionally lists one grade 3 diarrhoea event, one grade 3 hyperglycaemia event and one grade 4 acidosis event. The release does not clearly state whether these particular events were treatment-related. [3]

• Plasma nivolumab concentrations remained approximately tenfold lower than levels associated with intravenous administration, without reported accumulation. [1,2]

Cancer-free outcomes and quality of life

• The published JCO and AACR conference abstracts report an estimated 12-month cancer-free survival of 75.8%. [1,2]

• The AACR press release instead reports 82.13% of treated lesions remaining cancer-free at 12 months. [3]

• Six treated lesions progressed to cancer according to the press release; progression was detected early and the lesions were surgically removed. [3]

• Study completion and treatment adherence were encouraging despite travel-related challenges.

• Patient-reported quality-of-life scores remained stable or improved, particularly for pain and swallowing. [1–3]

What do the immune findings add?

• Immune profiling revealed increased CD4+ and CD8+ T-cell infiltration, enrichment of CCR7+ activated dendritic cells, increased CD103+ tissue-resident CD8+ T cells and higher-order immune assemblies within treated lesions. [1,2]

• Untreated lesions in the same patients did not demonstrate comparable immune changes.

• Peripheral blood mononuclear cell profiling showed no detectable systemic immune response in the assays reported.

Together, these findings provide preliminary evidence that intralesional nivolumab can modify the local immune environment. They are consistent with the proposed mechanism but do not, on their own, prove elimination of malignant potential.

What are the limitations?

• This was a small, single-arm study without a control group, with relatively short follow-up.

• As a phase I trial, it was primarily designed to assess safety and tolerability, not powered to establish efficacy. Without a comparison group, it is difficult to determine how much of the observed change can be attributed to treatment.

• Most importantly, lesion shrinkage and histological improvement do not, by themselves, demonstrate a reduction in malignant transformation.

What do these results mean for clinical practice?

For clinicians managing oral epithelial dysplasia, the most meaningful future outcome is not simply a smaller lesion. It is fewer malignant transformations, fewer extensive procedures and better long-term oral function—without unacceptable adverse effects.

The results should therefore not change routine management, surveillance or shared decision-making for patients with oral epithelial dysplasia at present. This is a promising investigational strategy, not an established alternative to surgery or follow-up.

What lies ahead?

The findings have provided a rationale for a randomised, placebo-controlled phase II trial (NCT06561087). This next stage should help establish whether preliminary clinical and immune responses translate into meaningful clinical benefit. [2]

Conclusion

Intralesional PD-1 blockade with nivolumab offers an intriguing approach to oral cancer prevention by targeting the immune environment within dysplastic lesions.

The early findings are promising, but larger controlled trials and longer follow-up are essential before its place in routine clinical practice can be determined. This approach currently remains investigational.

The key question is whether the observed responses can be sustained and ultimately translate into a reduced risk of malignant transformation and a reduced need for extensive surgical intervention.

Researchers also hope to explore the potential of this approach in other epithelial precancers, including cervical and anal precancerous lesions.

References

1. Amit M, et al. Intralesional PD-1 blockade for oral cancer prevention: First-in-class phase 1 trial. J Clin Oncol. 2026;44(16_suppl):10517 (conference abstract). https://doi.org/10.1200/JCO.2026.44.16_suppl.10517

2. Amit M, et al. Abstract CT188: Intralesional PD-1 blockade for oral cancer prevention: First-in-class phase 1 trial. Cancer Res. 2026;86(8 Suppl):CT188 (conference abstract). https://aacrjournals.org/cancerres/article/86/8_Supplement/CT188/785179/

3. American Association for Cancer Research. Intralesional Nivolumab May Be Effective Against Precancerous Oral Lesions. April 21, 2026 (press release). https://www.aacr.org/about-the-aacr/newsroom/news-releases/intralesional-nivolumab-may-be-effective-against-precancerous-oral-lesions/

4. Jiang Y, Chen M, Nie H, Yuan Y. PD-1 and PD-L1 in cancer immunotherapy: clinical implications and future considerations. Hum Vaccin Immunother. 2019;15(5):1111–1122. https://doi.org/10.1080/21645515.2019.1571892

5. Kumar S, Chatterjee M, Ghosh P, et al. Targeting PD-1/PD-L1 in cancer immunotherapy: An effective strategy for treatment of triple-negative breast cancer (TNBC) patients. Genes Dis. 2023;10(4):1318–1350. https://doi.org/10.1016/j.gendis.2022.07.024

6. National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_8.5×11.pdf