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

项目2摘要：方案项目产生的最新结果表明，总体存活率 手术后/光动力疗法超过任何以前报道的系列。这些数据提出的一个假设是 PPDT正在诱导一种针对复发肿瘤的免疫反应，这种反应抑制了肿瘤的生长 这种肿瘤会延长患者的生存时间。有大量的动物数据显示PDT(未做手术) 除了直接的细胞毒作用外，PDT还能诱导抗肿瘤免疫反应 影响到远处的肿瘤。也有一些临床报告表明，光动力疗法可以诱导抗肿瘤。 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驳斥这种免疫力。 假设。新的随机临床试验设计，患者将接受pPDT或 仅外科手术就提供了一个独特的机会来检验免疫反应假说并定义这些 免疫反应。为此，我们将与项目1合作，并将评估生成的免疫响应 恶性间皮瘤患者的手术/pPDT与手术对照(特定目标1)。这将是 通过以下方式完成：a)与单纯手术相比，评估血液白细胞对手术/光动力疗法的反应 在与抗肿瘤疗效的关系中，B)评估已知和 手术/pPDT诱导的未知间皮瘤抗原与单独手术的比较，c)评估抗 与单纯手术相比，手术/pPDT诱导的肿瘤细胞免疫反应，以及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 临床学科，我们提出了一个临床前的、翻译的目标，目标是开发改进的 基于令人兴奋的初步数据的方法。与动物核心和项目3和4合作，我们 将使用新的手术/光动力疗法动物模型来评估抗肿瘤免疫反应的假说 可以通过抑制炎症(COX-2抑制剂或IL-6抑制)来增加手术/PDT产生的量 (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，在该试验中，我们将 手术/pPDT联合COX-2抑制或抗IL-6抗体。

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.