PDT Optimization and Mechanisms

描述(申请人提供)：头颈部鳞状细胞癌(HNSCC)是全球第六大常见癌症，美国男性第八大常见癌症。早期疾病的治疗是有效的，但会导致生活质量显著下降。HNSCC的筛查并不是常规的，患者经常出现晚期或转移性疾病。晚期、复发或转移的HNSCC患者的中位生存期不到一年。因此，HNSCC的治疗存在明显的未得到满足的需求。单部位研究表明，早期和晚期HNSCC的光动力疗法(PDT)均可获得良好的预后和良好的功能保留。尽管有这些研究，PDT仍然是一种未得到充分利用的“利基”疗法，因为缺乏研究表明PDT在治疗结果上与传统疗法相当，并导致较少的治疗相关发病率。这项计划项目拨款的总体假设是，光动力疗法是治疗HNSCC的有效疗法，与目前的治疗方式相比，它将导致长期的肿瘤反应，但将导致显著减少的生活质量问题。目前应用的总体目标是将光动力疗法从利基疗法转变为HNSCC的标准护理(SOC)，从而为HNSCC提供一种新的治疗方案，与目前针对这种恶性肿瘤的标准护理(SOC)相比，相关发病率更低。为了实现这一目标，提出了一个由三个项目组成的高度集中的方案。在项目1中提议了三项临床试验：两项多中心随机第二阶段试验，检验PDT对早期和晚期复发疾病的SOC的有效性；以及一项第一阶段试验，检验PDT产生的疫苗作为手术治疗HNSCC的辅助药物的安全性。这些研究项目旨在提高光动力疗法治疗HNSCC的疗效。肿瘤对PDT的不完全反应可能是由于光敏剂保留不足所致。在项目2中，HNSCC将选择和测试具有更好的肿瘤保留性能的靶向光敏剂。HNSCC患者的免疫反应经常受到抑制；PDT增强了抗肿瘤免疫。PDT或接种PDT产生的肿瘤细胞裂解物将在患者和小鼠模型系统中将HNSCC诱导的免疫抑制微环境转化为免疫刺激环境的能力将在项目3中进行测试；该项目还将继续确定PDT增强抗肿瘤免疫的机制。这些项目将得到4个核心的支持，包括生物分析和光学核心。Bioanalysis核心将测试先前确定的PDT临床反应的预测因素。光学核心将分析剂量学，并提供与临床反应相关的组织和血液光学测量。这项PPG令人信服，因为高度整合的拟议研究具有很强的潜力，可以证明PDT作为HNSCC的一种治疗模式的有效性，保持患者的生活质量，同时探索新的机制，以提高治疗结果，超越目前使用SOC模式的治疗结果。

DESCRIPTION (provided by applicant): Head and neck squamous cell carcinoma (HNSCC) is the 6th most common cancer worldwide and the 8th most common cancer occurring in men in the US. Treatment of early stage disease is efficacious, but results in significant reduction in quality of life. Screening for HNSCC is not routine and patients often present with late stage or metastatic disease. Median survival for patients with late stage, recurrent or metastatic HNSCC is less than one year. Thus there is a clear unmet need in the treatment of HNSCC. Single site studies have shown that photodynamic therapy (PDT) of both early and late stage HNSCC results in excellent outcome with good retention of function. In spite of these studies PDT remains an underutilized "niche" therapy due to the lack of studies demonstrating that PDT is comparable to conventional therapy in treatment outcome and results in fewer treatment associated morbidities. The overall hypothesis of this program project grant is that PDT is an effective therapy for HNSCC, which will result in long-term tumor responses that compare to the current treatment modalities, but will result in significantly fewer quality of life issues. The ovrall goal of the current application is to move PDT from a niche therapy to the standard of care (SoC) for HNSCC, thus providing a novel treatment option for HNSCC with lower associated morbidities than the current SoC for this malignancy. To accomplish this goal a tightly focused program consisting of three projects is proposed. Three clinical trials are proposed in Project 1: two multi-center randomized Phase II trials examining the effectiveness of PDT against the SoC for early stage and advanced recurrent disease and a Phase I trial examining the safety of PDT-generated vaccines as an adjuvant to surgical treatment of HNSCC. The research projects are designed to enhance the efficacy of PDT in the treatment of HNSCC. Incomplete tumor response to PDT can be due to inadequate photosensitizer retention. In Project 2 HNSCC targeted photosensitizers with better tumor retention properties will be selected and tested. HNSCC patients frequently exhibit suppressed immune responses; PDT enhances anti-tumor immunity. The ability of PDT or vaccination with PDT generated tumor cell lysates to convert the HNSCC induced immunosuppressive microenvironment to an immune stimulatory environment in patients and murine model systems will be tested in Project 3; this project will also continue t determine the mechanisms behind PDT enhancement of anti-tumor immunity. The Projects will be supported by 4 cores, including Bioanalysis and Optics Cores. The Bioanalysis core will test previously identified predictors of the clinical response to PDT. The Optics Core will analyze dosimetry and provide tissue and blood optical measurements that will be correlated to the clinical response. This PPG is compelling in that the highly integrated proposed studies have a strong potential of demonstrating the effectiveness of PDT as a treatment modality for HNSCC that preserves patient quality of life while simultaneously exploring novel mechanisms to enhance treatment outcomes beyond those currently seen with SoC modalities.