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

增强头部的免疫反应

• 批准号: 8395740
• 负责人: Ivan M. Borrello
• 金额: $ 31.96万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-17 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8395740
• 关键词: Adjuvant; Aftercare; Antibodies; Antigens; Autologous; Biological Assay; Cell Count; Cell Line; Cell physiology; Childhood; Clinical Data; Clinical Trials; Data; Development; Diphtheria Toxoid; Endpoint Determination; Goals; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Head and neck structure; Human Papillomavirus; Immune; Immune response; Immunity; Immunosuppression; Immunotherapy; Impairment; Implant; Individual; Institution; Malignant Epithelial Cell; Malignant Neoplasms; Measures; Modality; Mus; Myelogenous; Neoadjuvant Therapy; Operative Surgical Procedures; Patients; Peripheral; Phenotype; Placebos; Pneumococcal vaccine; Prevnar; Radiation therapy; Regulatory T-Lymphocyte; Reproduction spores; Solid; Suppressor-Effector T-Lymphocytes; T cell response; T-Lymphocyte; Testing; Time; Tumor Immunity; Tumor-Infiltrating Lymphocytes; Universities; Vaccines; Xenograft procedure; base; chemotherapy; conventional therapy; cross reacting material 197; cytotoxic; design; immune function; improved; inhibitor/antagonist; novel; novel vaccines; pre-clinical; response; tadalafil; therapy development; tumor

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).

头部和颈部鳞状细胞癌（HNSCC）是一种致命的固体恶性肿瘤，生存5年 估计约为50％，并且与全身免疫损伤率高有关 逃避肿瘤特异性免疫反应。临床前和临床数据表明PDE5 抑制剂（Tadalafil）可用于通过抑制HNSCC患者的免疫功能 癌症诱导的髓样衍生的抑制细胞（MDSC）。在HNSCC中进行独立的独立临床试验 患者表明他达拉非1）可以安全地给药； 2）降低MDSC的功能和数字； 3）增加全球系统性免疫； 4）增加TLL； 5）与增加有关 肿瘤特异性免疫。基于这些数据，我们假设PDE5抑制剂可以使用为1） 抑制癌症诱导的MDSC和2）与 晚期头颈鳞状细胞癌（HNSCC）的常规多模式疗法。到 检验该假设，我们将同时对HNSCC患者同时管理长作用PDE5抑制剂 在治疗完成期间和之后，接受初级放射疗法+/-化学疗法。 我们将评估1）MDSC数量和功能，2）对疫苗的免疫反应，3）肿瘤特异性 在治疗之前，期间和之后的时间点的免疫力确定PDE5的最佳时序和设计 免疫疗法与HNSCC的常规疗法结合使用。 这个项目的长期目标是调查和开发PDE5抑制剂作为安全，耐受性良好的抑制剂 与常规疗法结合使用改善肿瘤特异性免疫反应的免疫调节剂。 该方法也可以作为其他基于免疫疗法的潜在辅助方法进一步开发 包括HPV阳性HNSCC（项目4）和新型组合抗体的基于疫苗的方法 基于疗法（项目3）。