Abstract Oral premalignant lesions affect 5% of the global population with transformation rates of 1-8% in mild-moderate dysplasia and up to 36% in severe dysplasia. Current management via surgical excision yields 30-40% recurrence despite negative margins, with cumulative functional morbidity. While systemic PD-1 blockade demonstrated biological activity in oral dysplasia, immune-related toxicity precludes use in non-cancer populations. We hypothesized intralesional delivery would achieve immune remodeling while eliminating systemic exposure. We conducted a phase 1, open-label, dose-escalation trial of intralesional nivolumab in patients with histologically confirmed oral epithelial dysplasia (NCT05327270). Twenty-nine patients received 10 mg or 20 mg intralesional nivolumab every three weeks for four cycles. Primary endpoints were safety and tolerability; secondary endpoints included lesion response, progression to carcinoma, pharmacokinetics, spatial immune profiling, and, uniquely for this population, prospective patient-reported outcomes (PROs). No dose-limiting toxicities occurred; 94% of adverse events were grade 1-2 with no systemic immune-related toxicities. Plasma nivolumab concentrations remained 10-fold below IV dosing without accumulation. Lesion area decreased 60% across cohorts with 41% histologic downgrading. Twelve-month cancer-free survival was 75. 8%; all progression events were detected early and surgically salvageable. We performed the first prospective longitudinal analysis of PROs in oral premalignancy. High study completion (86%) and adherence, despite significant travel burden, coupled with stable or improved quality-of-life scores (specifically pain and swallowing), indicate that repeated intralesional injections are a feasible, non-toxic approach associated with no functional adversity. Unlike surgical standards that degrade function, this strategy preserved patient quality-of-life. Mechanistic analyses using spatial transcriptomics (Xenium) and multiplexed imaging (CODEX) revealed immune activation exclusively in treated lesions: increased CD4+ and CD8+ T cell infiltration, enriched CCR7+ activated dendritic cells, elevated CD103+ tissue-resident CD8+ T cells, and formation of higher-order immune assemblies. Untreated non-index lesions from the same patients showed no immune changes, definitively demonstrating anatomically restricted immune activation. PBMC profiling confirmed absence of systemic immune perturbation. This first-in-class trial demonstrates intralesional PD-1 blockade safely reprograms premalignant tissue immunity without systemic perturbation, establishing lesion-directed checkpoint inhibition as a viable cancer interception strategy. These findings have established the foundation for a randomized, placebo-controlled Phase 2 trial currently enrolling at MD Anderson Cancer Center (NCT06561087) and support broader applicability to accessible epithelial precancers including cervical, anal, and cutaneous dysplasia. Citation Format: Moran Amit, Robert Saddawi-Konefka, Shorook Naara, Fred Netto, Fred Netto, Chen F Fushun, Yen Vu, Sophie Li, Tongxin Xie, Shamima Akhter, Hinduja Sathishkumar, Tieling Zhou, Sreyashi Basu, Luana Sousa, Neal Akhave, Theresa Hofstede, Ann Gillenwater, Ed Diaz, Kirsten Pytynia, Lorena Gomez, Michelle Williams, Andrew Sikora, Jeffrey Myers, Humam Kadara, James Allison, Sharma Padmaneee, Mark Chambers. Intralesional PD-1 blockade for oral cancer prevention: First-in-class phase 1 trial abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (8Suppl): Abstract nr CT188.
Amit et al. (Fri,) studied this question.