Augmentation of Immune Response to Head & Neck Squamous Cell Carcinoma via Phosp

摘要头颈部鳞状细胞癌(HNSCC)是一种生存5年的致命性实体恶性肿瘤。 估计约为50%，并与较高的系统性免疫损害率有关 一种对肿瘤特异性免疫反应的逃避。临床前和临床数据表明，PDE5 抑制剂(他达拉非)可用于增强HNSCC患者的免疫功能，途径是抑制 癌症诱导的髓系衍生抑制细胞(MDSCs)。HNSCC的单独、独立临床试验 患者已经证明，他达拉非1)可以安全地使用；2)减少MDSCs的功能和数量； 3)提高全球系统免疫力；4)增加TLLS；以及5)与 肿瘤特异性免疫。基于这些数据，我们假设PDE5抑制剂可能用于1) 抑制癌症诱导的MDSCs；2)联合应用可增强肿瘤特异性免疫应答 晚期头颈部鳞状细胞癌(HNSCC)的常规多模式治疗。至 验证这一假设，我们将同时对HNSCC患者应用长效PDE5抑制剂 在治疗期间和治疗结束后持续接受初次放射治疗+/-化疗。 我们将评估1)MDSC的数量和功能，2)对疫苗的免疫反应，以及3)肿瘤特异性 在治疗前、治疗中和治疗后的时间点进行免疫以确定PDE5的最佳时机和设计 免疫疗法与常规疗法联合治疗HNSCC。 该项目的长期目标是研究和开发安全、耐受性良好的PDE5抑制剂。 免疫调节剂，可提高肿瘤特异性免疫反应，与传统疗法相结合。 该方法还可以被进一步开发为其他基于免疫的疗法的潜在辅助手段， 包括基于疫苗的HPV阳性HNSCC治疗方法(项目4)和新的组合抗体 以治疗为基础(项目3)。

Head and neck squamous cell carcinoma (HNSCC) is a lethal solid malignancy with 5 year survival estimates of approximately 50%, and is associated with a high rate of systemic immune impairment as well a evasion of a tumor specific immune response. Preclinical and clinical data have shown that PDE5 inhibitors (tadalafil) can be used to augment immune function in HNSCC patients through inhibition of the cancer-induced myeloid derived suppressor cells (MDSCs). Separate, independent clinical trials in HNSCC patients have shown that tadalafil 1) can be safely administered; 2) reduces MDSCs function and numbers; 3) increases global systemic immunity; 4) increases TlLs; and 5) is associated with an increase In tumor-specific immunity. Based on these data we hypothesize that PDE5 inhibitors may be employed to 1) inhibit cancer induced MDSCs and 2) can increase tumor-specific immune response when combined with conventional multi-modality therapies for advanced head and neck squamous cell carcinoma (HNSCC). To test this hypothesis, we will administer long acting PDE5 inhibitors concurrently to HNSCC patients undergoing primary radiation therapy +/-chemotherapy, continuously during and after completion of therapy. We will assess 1) MDSC number and function, 2) immune response to vaccine, and 3) tumor-specific immunity at timepoints before, during, and after therapy to determine optimum timing and design of PDE5 immunotherapy in conjunction with conventional therapy for HNSCC. The long term goal ofthis project is to investigate and develop PDE5 inhibitors as safe, well tolerated immune modulators that improve tumor specific immune response in combination with conventional therapy. This approach may also be further developed as a potential adjunct to other immune based therapies, including vaccine based approaches in HPV positive HNSCC (Project 4) and novel combination antibody based therapies (Project 3).