Exploratory clinical trial of topical Imiquimod 5% cream as window-of-opportunity monotherapy for early-stage oral cancer

项目总结/摘要 据估计，全球每年有40万人，其中3万人是美国人，被新诊断出患有 口腔鳞状细胞癌（OSCC）。在新诊断的口腔癌病例中，约80%在肿瘤中- 淋巴结转移（TNM）I/II期，无区域淋巴结受累或远处转移。为这些 早期口腔癌患者的五年生存率估计为60%。目前尚无 为40%的癌症特异性死亡率高风险的早期口腔癌患者提供替代治疗。 由于80%的口腔癌患者在诊断时处于早期阶段， 准确的诊断和随后的正确治疗决定将大大改善5年 这种致命疾病患者的生存率。 为了解决这些关键的差距，我们建议评估5%咪喹莫特乳膏在新辅助治疗中的疗效。 设置，一个窗口的机会研究，管理之间的组织学诊断的口腔鳞癌和最初的 肿瘤手术咪喹莫特是FDA批准的TLR（Toll样受体）激动剂。之前我们已经报道 局部咪喹莫特的口腔内应用导致恶性黑素瘤的完全消退， 不良事件极少，患者5年无复发生存。咪喹莫特可诱导肿瘤细胞 凋亡和坏死，并激活抗肿瘤免疫应答。 在目前的提案中，我们的目标是进行概念验证研究（探索性临床试验），以评估 新辅助咪喹莫特免疫调节局部治疗在减少原发性口腔癌大小方面的疗效 目的1：评价其在早期口腔癌患者中的安全性和毒性。在目标2中，我们将评估 使用定量多重免疫荧光法研究咪喹莫特的抗肿瘤和免疫调节作用。 研究结果将提供增强的治疗方案，提高早期口腔鳞癌的总体生存率 患者

PROJECT SUMMARY / ABSTRACT Each year an estimated 400,000 people globally, among them 30,000 Americans, are newly diagnosed with oral squamous cell carcinoma (OSCC). Of the newly diagnosed oral cancer cases, ~80% are in the tumor- node-metastasis (TNM) Stage I/II without regional lymph node involvement or distant metastasis. For these early-stage oral cancer patients, the five-year survival rate is estimated to be 60%. Currently, there is no alternative therapy for 40% of early-stage oral cancer patients at high risk for cancer-specific mortality. As 80% of oral cancer patients are in early stage at the time of diagnosis, a window of opportunity exists in which accurate prognostication and subsequent decisions for proper treatment will dramatically improve 5-year survival of patients with this deadly disease. To address these critical gaps, we propose to assess efficacy of topical imiquimod 5% cream in a neoadjuvant setting, a window-of-opportunity study, administered between the histologic diagnosis of OSCC and the initial surgery of tumor. Imiquimod is an FDA-approved TLR (Toll-like receptor) agonist. We have previously reported that intra-oral application of topical imiquimod resulted in complete resolution of malignant melanoma with minimal adverse events and the patient had recurrence-free 5-year survival. Imiquimod can induce tumor cell apoptosis and necrosis, and activate anti-tumoral immune response. In the current proposal, we aim to conduct a proof-of-concept study (exploratory clinical trial) to assess the efficacy of neoadjuvant imiquimod immunomodulatory topical therapy in reducing the size of primary oral cancer and evaluate its safety and toxicity in early-stage oral cancer patients (Aim 1). In Aim 2, we will evaluate the anti-tumoral and immunomodulatory effects of imiquimod using quantitative multiplex immunofluorescence. The findings will provide enhanced treatment regimen that increase overall survival rate of early-stage OSCC patients.