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

项目摘要/摘要 抑制 值得注意的是 临床 使用 多数 引爆 治疗， 在给予光动力疗法(PDT)之前表皮生长因子受体(EGFR)的表达可以 提高非小细胞肺癌(NSCLC)动物模型的治疗效果。目前， EGFR酪氨酸激酶抑制剂(TKIs)治疗非小细胞肺癌的患者仅限于 EGFR基因突变的疾病。EGFR-TKI治疗通常持续到疾病进展时间，因为 患者最终会患上对EGFR-TKI具有抵抗力的疾病。在这里，我们建议使用EGFR-TKIs作为简短的， 治疗几天，而不是每天持续治疗。重要的是，作为引爆 我们假设EGFR-TKI预处理将提高PDT(和电离)的治疗效果 放射治疗，XRT)通过先天免疫反应依赖的机制。 这个 EGFR EGFR-TKI 引爆 涉及到 EGFR-TKIs 毁伤 的确， 示范 TKI/PDT)。 淋巴细胞 单元格) 与生俱来 尽管如此 调查 临床 XRT。 血管 增强功能 和 示范 值得注意的是，我们假设 使用EGFR-TKIs作为激发天然免疫的一种方法与慢性阻塞性肺疾病患者相关 野生型疾病。然而，它的潜在效果在日常连续的设置中可能并不明显 长期使用EGFR-TKIs抑制先天免疫和获得性免疫的治疗。作为一名 治疗方面，EGFR-TKIs可通过多种机制增强对PDT和XRT的反应 EGFR-TKIs与PDT或XRT协同促进肿瘤先天免疫。 可能增加接受PDT或XRT的肿瘤中性粒细胞的激活，从而增加血管 和/或刺激先天免疫系统的其他细胞，例如先天免疫淋巴细胞。 我们公布的数据显示，EGFR-TKI增加了PDT的血管损伤，初步数据 当PDT前应用EGFR-TKI(EGFR-TKI)时，肿瘤局部的中性粒细胞活化增加。 此外，EGFR-TKIs和PDT或XRT可能协同增加先天免疫的数量 以及目标细胞(例如，肿瘤细胞或肿瘤相关内皮细胞)的免疫可见性 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T细胞。我们注意到T细胞在EGFR-TKI应答中的作用， 与PDT或XRT相结合，是一个新的研究领域。此外，我们独特的 用质子XRT启动EGFR-TKI。从这项建议中获得的知识将指导选择 无论是光动力疗法、光子XRT还是质子放射治疗，EGFR-TKI启动放射治疗的探讨 为了实现这一目标，我们将解决以下目标：确定中性粒细胞在促进 当PDT之前有EGFR-TKI时的损害。确定使用EGFR-TKI进行预处理 先天免疫L淋巴细胞对光动力疗法治疗肿瘤的反应为了确立疗效 EGFR-TKIs联合电离放射治疗(光子和质子)和 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.