Intralesional nivolumab in oral potentially malignant disorders: A phase 1 pilot study on safety, tolerability, and preliminary efficacy.
Authors: Naara Shorook , Yaniv Dan , Andrews Clara , Sathishkumar Hinduja , Guimaraes de Sousa Luana , Akhave Neal , Williams Michelle D. , Myers Jeffrey , Chambers Mark Steven , Amit Moran 
Published: June 2024

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Background: Oral Potentially Malignant Disorders (OPMD) encompass a diverse group of oral mucosal diseases, including the prevalent oral leukoplakia (OL), serving as precursors to invasive oral squamous cell carcinoma. OPMD exhibits an annual malignant transformation rate up to 36%. Despite the breadth of research on OPMD the standard-of-care remains surgery or observation. We aim to evaluate the safety and tolerability of intralesional injections of Nivolumab in patients with OPMD. Secondary objectives include assessing objective response rate and pathologic complete response rate. We describe the results of an immune prevention trial designed to avoid systemic toxicities of immunotherapy in patient with pre-malignancy by administrating aPD1 intralesionaly. Methods: Phase 1, single-arm, open-label, dose-escalation pilot study that involves intralesional injections of Nivolumab (index lesion) in patients with high-risk OPMD lesions every 3 weeks (total of 4 doses, 12 weeks). Non-index, non-injected, oral lesion(s) were also documented and monitored. The study includes two dose cohorts (10 mg and 20 mg) to assess maximally tolerated dose with a 3 + 6 dose-escalation design. Adverse events were reported according to NCI CTCAE Version 5.0. Serial biopsies at baseline and up to 8 weeks after treatment were taken to assess efficacy using a composite score (i.e., size and degree of dysplasia) in index lesion. Major response was defined as >80% decrease in score; partial response as 40%-80% decrease. Freshly frozen tumors were subjected to RNA sequencing and gene pathway analysis to identify biomarkers of response or progression. Results: At the time of data analysis, 13 patients have completed treatment (61.5% males), both dose levels were well tolerated. The adverse event grades ranged from grade 1 (i.e. diarrhea, elevated LFT and skin rash) constituting the majority at 80.5% of reported adverse events, grade 2 (i.e. skin rash, cellulitis) at 13.9%, and grade 3 (i.e. hypertension) at 5.6%. Ten patients had multifocal disease. Major response was observed in 22.5% and partial response in 50% of the patients. One patient progressed to invasive SCC in a non-index lesion. RNA sequencing based immune phenotyping revealed increased infiltration of CD8 cytotoxic T cells in index lesions after treatment. Pathway analysis revealed significant alterations in immune pathways including Th1 and Th2 pathways, Natural killer and immunoregulatory pathways. Spatial transcriptome analysis and pharmacokinetics data are pending. Conclusions: Intralesional nivolumab is well tolerated in OPMD with suggested potential biological and clinical activity. A randomized phase II trial to assess cancer free survival is recommended to determine the efficacy in preventing cancer progression. We recommend dose of 20mg for phase II as it was well tolerated. Clinical trial information: NCT05327270 .