Photodynamic therapy with prior inhibition of epidermal growth factor receptor to stimulate antitumor innate immune response

项目概要/摘要 抑制 显著 临床 与 最 预充 治疗， 表皮生长因子受体（EGFR）的表达可 在非小细胞肺癌（NSCLC）动物模型中改善治疗功效。目前， EGFR酪氨酸激酶抑制剂（TKI）用于治疗NSCLC患者仅限于 EGFR突变疾病。EGFR-TKI治疗通常持续至疾病进展，因为 患者最终发展成EGFR-TKI抗性疾病。在这里，我们建议使用EGFR-TKI作为一个简短的， 治疗几天，而不是每天连续治疗。重要的是，作为一个启动 我们假设EGFR-TKI预处理将提高PDT的治疗效果（和电离 放射疗法，XRT）通过先天免疫应答依赖性机制。 的 EGFR EGFR-TKI 预充 涉及 EGFR-TKIs 损害 的确， 证明 TKI/PDT）。 淋巴细胞 单元格） 先天 尽管 探讨 临床 XRT。 血管 垫块 和 证明 值得注意的是， 使用EGFR-TKI作为刺激先天免疫的启动方法与以下患者相关： 野生型疾病。然而，在每日连续给药的情况下，其潜在疗效可能不明显。 由于长期使用EGFR-TKI抑制先天性和适应性免疫而导致的治疗。作为 EGFR-TKI可通过多种机制增强PDT和XRT的反应， EGFR-TKI和PDT或XRT之间的协同作用，以促进肿瘤导向的先天免疫。 可能增加接受PDT或XRT的肿瘤中的中性粒细胞活化， 和/或刺激先天免疫系统的其它细胞，例如先天免疫淋巴细胞。 我们发表的数据显示EGFR-TKI增加PDT的血管损伤，初步数据显示， 当PDT之前是EGFR-TKI（EGFR-TKI）时，肿瘤局部中性粒细胞活化增加， 此外，EGFR-TKI和PDT或XRT可以协同增加先天免疫细胞的数量。 以及靶细胞的免疫可见性（例如，肿瘤细胞或肿瘤相关内皮细胞 这些淋巴细胞。事实上，在初步数据中，EGFR-TKI/PDT的疗效取决于 免疫淋巴细胞NK细胞和NK细胞。我们注意到，在应答EGFR-TKI， 与PDT或XRT的组合是一个新的研究领域。此外，我们独特地 使用质子XRT进行EGFR-TKI预充。从本建议书中获得的知识将指导选择 EGFR-TKI启动放射治疗的方法，无论是PDT、光子XRT还是质子 为了实现这一目标，我们将讨论以下目标：确定中性粒细胞在促进 在PDT之前使用EGFR-TKI时的损伤。确定EGFR-TKI预处理 先天免疫淋巴细胞对PDT治疗的肿瘤的反应。为了确定疗效， EGFR-TKI联合电离辐射治疗（光子和质子）的先天免疫效应， 在控制肺转移中的应用。 目标1。 目标2. 目标3：

PROJECT SUMMARY/ABSTRACT Inhibition remarkably clinical with most priming therapy, of epidermal growth factor receptor (EGFR) prior to the delivery of photodynamic therapy (PDT) can improve treatment efficacy in animal models of non-small cell lung cancer (NSCLC). Currently, use of EGFR tyrosine kinase inhibitors (TKIs) for treatment of patients with NSCLC is limited to those EGFR mutated disease. EGFR-TKI therapy is typically continued until time of disease progression since patients eventually develop EGFR-TKI resistant disease. Here, we propose to use EGFR-TKIs as a brief, therapy for several days rather than as a daily continuous therapeutic. Importantly, as a priming we hypothesize thatEGFR-TKI pretreatment will improve the therapeutic efficacy of PDT (and ionizing radiotherapy, XRT) through an innate immune response-dependent mechanism. the EGFR EGFR-TKI priming involve EGFR-TKIs damage Indeed, demonstrate TKI/PDT). lymphocytes cells) innate notwithstanding investigate clinical XRT. vascular augments and demonstrate Significantly, we posit that use of EGFR-TKIs as a priming approach to stimulate innate immunity is relevant to patients with wild-type disease. However, its potential efficacy may not be apparent in the setting of daily continuous therapy due to suppression of innate and adaptive immunity by prolonged use of EGFR-TKIs. As a therapy, EGFR-TKIs could augment responses to PDT and XRT through multiple mechanisms that cooperation between the EGFR-TKIs and PDT or XRT to promote tumor-directed innate immunity. may increase neutrophil activation in tumors receiving PDT or XRT, serving to increase vascular and/or stimulate other cells of the innate immune system, such as innate immune lymphocytes. our published data show EGFR-TKI to increase vascular damage to PDT, and preliminary data increases in tumor-localized neutrophil activation when PDT is preceded by EGFR-TKI (EGFR- Additionally, EGFR-TKIs and PDT or XRT may cooperatively increase numbers of innate immune and the immunologic visibility of target cells (e.g., tumor cells or tumor-associated endothelial to these lymphocytes. In fact, in preliminary data the efficacy of EGFR-TKI/PDT is dependent on the immune lymphocytes NK and  T cells. We note that the role of  T cells in response to EGFR-TKI, combinations with PDT or XRT, is a novel area of investigation. Moreover, we uniquely EGFR-TKI priming with proton XRT. Knowledge gained from this proposal will guide selection of a approach to EGFR-TKI priming with radiation therapy, whether it be with PDT, photon XRT, or proton Toward this goal, we will address the following aims: To define the role of neutrophils in promoting damage when PDT is preceded by EGFR-TKI. To ascertain how pretreatment with EGFR-TKI the response of innate immune l ymphocytes to PDT-treated tumors. To establish the efficacy innate immune effects of EGFR-TKIs combined with ionizing radiation therapies (photon and proton) and application in control of lung metastasis. Aim 1. Aim 2. Aim 3.