Project 2: Evaluation and Augmentation of Anti-tumoral Immune Responses Induced b

项目2摘要：该计划项目产生的最新结果表明， 术后/PDT超过任何先前报告的系列。这些数据提出的一个假设是， pPDT诱导针对复发肿瘤的免疫应答，并且该应答抑制肿瘤细胞的生长。 肿瘤导致生存期延长。有大量的PDT（无手术）动物数据显示， 除了其直接的细胞毒性作用外，PDT还诱导能够 影响远处肿瘤。也有少数临床报道提示光动力疗法可以诱导抗肿瘤作用 免疫反应。到目前为止，我们还没有来自患者的直接证据来证实或反驳这种免疫。 假说.新的随机临床试验设计，患者将接受pPDT手术， 手术本身提供了一个独特的机会来测试免疫反应假设，并确定这些 免疫反应。为此，我们将与项目1合作，并将评估产生的免疫反应 恶性间皮瘤患者的手术/pPDT对比手术（具体目标1）。这将是 A）与单独手术相比，评估血液白细胞对手术/pPDT的反应 以及与抗肿瘤功效的关系，B）评价对已知的和 与单独手术相比，由手术/pPDT诱导的未知间皮瘤抗原，c）评估抗- 与单独手术相比，手术/pPDT诱导的肿瘤细胞免疫应答，和d）评估 细胞因子对手术/pPDT的反应与抗肿瘤疗效的关系。除了评估我们的 临床科目，我们提出了一个临床前，翻译的目标，发展的目标是改善 基于令人兴奋的初步数据的方法。结合动物核心和项目3和4，我们 将使用新的手术/PDT动物模型来评估抗肿瘤免疫应答的假设， 通过抑制炎症（考克斯-2抑制剂或IL-6抑制剂）可增强手术/PDT产生的 （具体目标2）。如果得到这些目标的支持，我们的目标将是启动未来的临床试验， 将联合收割机手术/pPDT与考克斯-2抑制或抗IL-6抗体相结合。

Project 2 Abstract: Recent results generated by the Program Project have shown that the overall survival after surgery/PDT exceeds any previous reported series. One hypothesis suggested by these data is that pPDT is inducing an immune response against the recurrent tumor and this response is inhibiting the growth of the tumor leading to prolonged survival. There is extensive animal data with PDT (without surgery) showing that, in addition to its direct cytotoxic effects, PDT also induces anti-tumor immune responses capable of affecting distant tumor. There are also a few clinical reports suggesting that PDT alone can induce anti-tumor immune responses. To date, we have no direct evidence from our patients to confirm or refute this immune hypothesis. The new randomized clinical trial design where patients will either receive surgery with pPDT or surgery alone provides a unique opportunity to test the immune response hypothesis and to define these immune responses. To do so, we will work with Project 1 and will evaluate the immune responses generated by surgery/pPDT versus surgery in patients with malignant mesothelioma (Specific Aim 1). This will be accomplished by: A) evaluating the blood leukocyte response to surgery/pPDT in comparison to surgery alone and in relationship to anti-tumor efficacy, B) evaluating anti-tumor humoral immune responses to known and unknown mesothelioma antigens induced by surgery/pPDT in comparison to surgery alone, c) evaluating anti- tumor cellular immune responses induced by surgery/pPDT in comparison to surgery alone, and d) evaluating the cytokine response to surgery/pPDT in relationship to anti-tumor efficacy. In addition to evaluating our clinical subjects, we propose one preclinical, translational aim with the goal of developing improved approaches based on exciting preliminary data. In conjunction with the Animal Core and Projects 3 and 4, we will use novel animal models of surgery/PDT to evaluate the hypothesis that the anti-tumor immune response generated by surgery/PDT can be augmented by inhibition of inflammation (COX-2 inhibitor or IL-6 inhibition) (Specific Aim 2). If supported by these aims, our goal would be to initiate a future clinical trial in which we will combine surgery/pPDT with COX-2 inhibition or anti-IL-6 antibodies.