Work

483 Intralesional PD-1 blockade induces localized immune mobilization and coordinated lymphatic niche assembly in high-risk oral premalignant lesions

Year: 2026

Type: conference-paper

Abstract: Background Oral premalignant lesions (OPLs) represent a clinically accessible precursor to oral squamous cell carcinoma and provide a unique opportunity for cancer interception. 1–4 Although systemic PD-1 blockade has transformed the treatment of advanced malignancies, its application in premalignancy remains limited by concerns regarding toxicity, treatment burden, and the risk-benefit balance in patients without invasive cancer. We hypothesized that direct intralesional administration of nivolumab would induce localized immune activation while minimizing systemic exposure, resulting in lesion regression and prevention of malignant progression.Methods We conducted a phase I open-label dose-escalation trial evaluating intralesional nivolumab in patients with high-risk OPLs. Twenty-nine patients received intralesional nivolumab (10 mg or 20 mg) every three weeks for four doses. Primary endpoints were safety and tolerability; secondary endpoints included lesion response, histologic response, cancer-free survival, pharmacokinetics, patient-reported outcomes, and immune correlatives.Results Intralesional nivolumab was well tolerated, with no dose-limiting toxicities observed. Systemic nivolumab exposure remained low and non-accumulating, and peripheral immune populations demonstrated minimal treatment-associated changes. Clinically, 85% of patients experienced lesion regression, 65% achieved greater than 50% reduction in lesion size, and 12-month cancer-free survival was 75.8% ( figure 1).To define mechanisms of response, we integrated spatial transcriptomics and multiplexed tissue imaging across paired treated and synchronous untreated lesions. Intralesional nivolumab induced localized immune remodeling restricted to treated lesions, characterized by expansion of T-cell and dendritic-cell populations and acquisition of IFNγ-responsive and T-cell-inflamed transcriptional programs. Clinical response was associated with coordinated dendritic cell:T-cell organization, enrichment of higher-order immune assemblies, and emergence of specialized lymphatic-associated immune niches. In contrast, non-responding lesions exhibited persistent immunosuppressive macrophage-dominant epithelial interactions and failed to establish coordinated immune architecture (figure 2).Conclusions Intralesional nivolumab is safe, well tolerated, and demonstrates encouraging clinical activity in patients with high-risk oral premalignant lesions. Local PD-1 blockade induces spatially restricted immune mobilization characterized by coordinated dendritic cell:T-cell organization and assembly of lymphatic-associated immune niches linked to favorable clinical outcomes. These findings support localized checkpoint blockade as a promising strategy for cancer interception and identify coordinated immune organization as a potential mechanistic determinant of effective premalignant lesion regression.Acknowledgements We thank the patients and their families for participating in this study. We acknowledge the clinical research staff, research coordinators, and multidisciplinary teams at The University of Texas MD Anderson Cancer Center for their contributions to study conduct and patient care. This study was supported by the Cancer Prevention and Research Institute of Texas (CPRIT; RP210176).Trial Registration ClinicalTrials.gov: NCT05327270.References Hanna GJ, Kacew AJ, Chau NG, et al. Neoadjuvant pembrolizumab for oral cavity premalignancy demonstrates clinical activity and immune modulation. Clin Cancer Res. 2023;29:1994–2005.Han S, et al. Immune profiling of oral premalignant lesions identifies immune determinants of malignant progression. Cancer Discov. 2023;13:2110–2127.Warnakulasuriya S, Kujan O, Aguirre-Urizar JM, et al. Oral potentially malignant disorders: a consensus report from an international seminar on nomenclature and classification, convened by the WHO collaborating centre for oral cancer. Oral Dis. 2021;27:1862–1880.William WN Jr, Papadimitrakopoulou V, Lee JJ, et al. Erlotinib and the risk of oral cancer: the Erlotinib Prevention of Oral Cancer (EPOC) randomized clinical trial. JAMA Oncol. 2016;2:209–216.Ethics Approval The study was approved by the Institutional Review Board of The University of Texas MD Anderson Cancer Center. All participants provided written informed consent before enrollment. The study was conducted in accordance with the Declaration of Helsinki and was registered at ClinicalTrials.gov ( NCT05327270).Consent Written informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.Abstract 483 Figure 1 Safety, tolerability and clinical activity of intralesional nivolumab in high-risk oral premalignant lesions. (A) Phase I open-label dose-escalation study schema evaluating intralesional nivolumab (10 mg or 20 mg) administered every three weeks for four doses; (B) Patient-level treatment exposure, adverse events, and anti-nivolumab antibody status; (C) Summary of clinical outcomes demonstrating favorable safety, lesion regression, histologic improvement, and 12-month cancer-free survival. Intralesional nivolumab was well tolerated with no dose-limiting toxicities and induced clinical responses in the majority of treated lesionsAbstract 483 Figure 2Intralesional PD-1 blockade induces localized immune mobilization and coordinated lymphatic niche assembly. (A) Spatial transcriptomic atlas of oral premalignant lesions identifying epithelial, immune, stromal, vascular, and lymphatic cell populations; (B) Differential expression and pathway enrichment analyses demonstrating acquisition of IFNγ-responsive, T-cell-inflamed, and inflammatory transcriptional programs following intralesional nivolumab treatment; (C) Multiplex spatial imaging and cell-interaction analyses demonstrating increased coordination between activated dendritic cells and effector T-cell populations within treated lesions following therapy; (D) Emergence of specialized perilymphatic immune niches following treatment. Representative multiplex imaging and spatial interaction analyses demonstrating enrichment of coordinated dendritic cell-T-cell assemblies within lymphatic-associated regions of responding lesions

Source: Journal for ImmunoTherapy of Cancer

DOI: 10.1136/jitc-2026-sitc2026.0483