Bronchoscopic Cryo-Immunotherapy of Lung Cancer

项目摘要/摘要 这是人类首次在晚期进行支气管镜冷冻免疫治疗(Bci)的安全性和可行性研究。 非小细胞肺癌(NSCLC)。冷冻免疫疗法包括作为原位冷冻消融术的肿瘤 疫苗接种，产生肿瘤特异性CD8+T细胞的激活和增殖，并已在 无论是在同基因小鼠恶性肿瘤模型中，还是在早期人类临床试验中，L都是如此[1]。 此外，冷冻免疫疗法可能与其他形式的免疫疗法协同作用，例如免疫。 针对PD-1/PD-L1通路的检查点抑制物(CPI)--诱导增强的抗肿瘤免疫 在包括非小细胞肺癌[2-6]在内的各种癌症中的反应和临床结果的改善。这两种技术的结合 脑梗死合并CPI可使CPI治疗无效的患者产生抗肿瘤免疫反应 独自一人。 支气管镜冷冻消融术用于安全有效的姑息治疗已有二十多年的历史。 和清除中央呼吸道的支气管内肿瘤，但尚未应用于治疗 周围型肺肿瘤[7，8]。经皮冷冻消融治疗已经有十多年的历史了。 不能手术切除的周围型原发和继发性肺肿瘤[9]。经皮穿刺术 冷冻消融，坚硬的冷冻治疗探头通过经胸计算机插入靶肿瘤 体层摄影(CT)引导下，横穿胸膜和肺实质，其结果是高发生率。 气胸[9]。在BCI中，周围型肺肿瘤将直接通过呼吸道进入，最大限度地减少 气胸的风险。BCI也可以在标准的支气管镜检查过程中进行 手术，而且可能比经皮冷冻消融的手术时间短得多， 这项研究的主要目标是建立脑机接口的安全性和可行性，以及确定 最大耐受量--即最佳冷冻时间。这项研究的次要目标是 应用多重流式细胞术分析BCI诱导的抗肿瘤免疫应答 脑梗塞后外周血细胞反应，包括脑梗塞后CD8+T细胞表达PD-1和 树突状细胞(DC)激活的标志物。将对外周血淋巴细胞进行额外的分析 利用PanCancer OncoImmuneTM Profile面板(华盛顿州西雅图的NanoString®Technology)评估 淋巴细胞基因表达的变化。。我们将接受BCI前的支气管肺泡灌洗(BAL) 肿瘤部位邻近和远端肺单位的标本与BCI前BAL的结果相关联 淋巴细胞和BCI强度诱导的抗肿瘤免疫反应。最后，接受脑机接口治疗的患者 将使用标准的RECIST对胸部CT扫描的肿瘤大小的变化进行纵向跟踪 测量[10]，并评估无进展和总存活率。

Project Summary/Abstract This is a first-in-human, safety and feasibility study of bronchoscopic cryo-immunotherapy (BCI) in advanced non-small cell lung cancer (NSCLC). Cryo-immunotherapy involves the cryoablation of tumors as an in-situ vaccination, generating tumor-specific CD8+ T cell activation and proliferation, and has been demonstrated in both in syngeneic murine models of malignancy as well as in early-phase human clinical trials l [1]. Additionally, cryo-immunotherapy may synergize with other forms of immunotherapy – such as immune checkpoint inhibitors (CPI) targeting the PD-1/PD-L1 pathway - to elicit enhanced anti-tumor immune responses and improved clinical outcomes in a variety of cancers, including NSCLC [2-6]. The combination of BCI with CPI may enable anti-tumor immune responses in patients who are refractory to therapy with CPI alone. Bronchoscopic cryoablation has been utilized for over twenty years for safe and effective palliative treatment and debulking of endobronchial tumors in the central airways, but has not yet been applied to the treatment of peripheral lung tumors [7, 8]. Percutaneous cryoablation has been utilized for more than a decade to treat peripheral primary and secondary lung tumors that are not amenable to surgical resection [9]. In percutaneous cryoablation, rigid cryotherapy probes are inserted into the target tumor via transthoracic computed tomography (CT) guidance, traversing the pleura and lung parenchyma with a resultant high rate of pneumothoraces [9] . In BCI, peripheral lung tumors will be accessed directly via the airway, minimizing the risk of pneumothoraces. BCI can also be performed during the course of standard of care bronchoscopic procedures, and potentially at much shorter procedure times than percutaneous cryoablation, The primary objectives of this study are to establish the safety and feasibility of BCI, as well as to determine the maximum tolerated dose - i.e. optimal duration of freeze time. The secondary objective of this study is to assess for BCI-induced anti-tumor immune responses by multiplex flow cytometry (FACS) analysis of pre- and post BCI cellular responses in peripheral blood, including post- BCI CD8+ T cell expression of PD-1 and markers of dendritic cell (DC) activation. Additional analysis of peripheral blood lymphocytes will be performed utilizing the PanCancer OncoImmuneTM profile panel (NanoString® Technology, Seattle, WA) to assess for changes in lymphocyte gene expression. . We will be obtaining pre-BCI bronchoalveolar lavage (BAL) specimens from lung units both adjacent and distal to the tumor site to correlate findings in pre-BCI BAL lymphocytes and the strength of BCI induced anti-tumor immune responses. Finally, patients undergoing BCI will be followed longitudinally for changes in tumor size on chest CT scans using standard RECIST measurements[10] and also evaluated for progression-free and overall survival.