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

头颈部鳞状细胞癌（HNSCC）是一种致死性实体恶性肿瘤，生存期仅为5年 估计约为50%，并与全身免疫功能损害的高发生率相关 逃避肿瘤特异性免疫反应。临床前和临床数据表明，PDE 5 抑制剂（他达拉非）可用于通过抑制HNSCC患者的 癌症诱导的髓源性抑制细胞（MDSC）。在HNSCC中进行的单独、独立的临床试验 患者已经证明他达拉非1）可以安全给药; 2）降低MDSC功能和数量; 3)增加整体系统免疫力; 4）增加TIL;和5）与增加免疫力相关。 肿瘤特异性免疫基于这些数据，我们假设PDE 5抑制剂可用于1） 抑制癌症诱导MDSC和2）当与 晚期头颈部鳞状细胞癌（HNSCC）的常规多模态疗法。到 为了验证这一假设，我们将对HNSCC患者同时给予长效PDE 5抑制剂 在治疗期间和治疗完成后持续接受初次放疗+/-化疗。 我们将评估1）MDSC的数量和功能，2）对疫苗的免疫应答，以及3）肿瘤特异性 治疗前、治疗期间和治疗后各时间点的免疫力，以确定PDE 5的最佳时机和设计 免疫疗法与常规疗法联合用于HNSCC。 该项目的长期目标是研究和开发安全、耐受性良好的PDE 5抑制剂。 与常规疗法组合改善肿瘤特异性免疫应答的免疫调节剂。 这种方法也可以进一步发展为其他基于免疫的疗法的潜在辅助手段， 包括HPV阳性HNSCC中基于疫苗的方法（项目4）和新型组合抗体 基础疗法（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).