PDT Optimization and Mechanisms

描述（由申请人提供）：头颈部鳞状细胞癌（HNSCC）是全球第六大最常见的癌症，在美国男性中排名第八。早期疾病的治疗是有效的，但会导致生活质量的显著下降。筛查HNSCC是不常规的，患者往往表现为晚期或转移性疾病。晚期、复发或转移性HNSCC患者的中位生存期不到一年。因此，在HNSCC的治疗中有一个明显的未满足的需求。单位点研究表明，光动力疗法（PDT）对早期和晚期HNSCC的疗效都很好，功能保持良好。尽管有这些研究，PDT仍然是一个未充分利用的“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，并且导致更少的治疗相关发病率。本项目的总体假设是，PDT是一种有效的治疗HNSCC的方法，与目前的治疗方式相比，PDT会导致长期的肿瘤反应，但会导致更少的生活质量问题。当前应用的总体目标是将PDT从小众治疗转移到HNSCC的标准治疗（SoC），从而为HNSCC提供一种新的治疗选择，其相关发病率低于当前恶性肿瘤的SoC。为了实现这一目标，提出了一个由三个项目组成的紧密集中的计划。项目1提出了三项临床试验：两项多中心随机II期试验，研究PDT对早期和晚期复发性疾病SoC的有效性；一项I期试验，研究PDT产生的疫苗作为HNSCC手术治疗辅助的安全性。研究项目旨在提高PDT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。在项目2中，将选择和测试具有更好肿瘤保留特性的HNSCC靶向光敏剂。HNSCC患者经常表现出抑制的免疫反应；PDT增强抗肿瘤免疫。PDT或接种PDT产生的肿瘤细胞裂解物将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。该项目将由4个核心提供支持，包括生物分析和光学核心。生物分析核心将测试先前确定的PDT临床反应预测因子。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。这个PPG是引人注目的，因为高度整合的拟议研究具有强大的潜力，证明PDT作为HNSCC的治疗方式的有效性，可以保持患者的生活质量，同时探索新的机制，以提高目前使用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.