Bronchoscopic Cryo-Immunotherapy of Lung Cancer

项目总结/摘要 这是支气管镜冷冻免疫疗法（BCI）在晚期肺癌患者中的首次人体安全性和可行性研究。 非小细胞肺癌（NSCLC）。冷冻免疫疗法涉及肿瘤的冷冻消融作为原位免疫治疗。 疫苗接种，产生肿瘤特异性CD 8 + T细胞活化和增殖，并已在 在恶性肿瘤的同系小鼠模型中以及在早期人类临床试验中均如此[1]。 此外，冷冻免疫疗法可以与其他形式的免疫疗法协同作用，例如免疫疗法。 靶向PD-1/PD-L1通路的检查点抑制剂（CPI）-引发增强的抗肿瘤免疫 缓解和改善各种癌症（包括NSCLC）的临床结局[2-6]。的组合 BCI与CPI联合使用可能使CPI治疗难治性患者产生抗肿瘤免疫应答 一个人 支气管镜冷冻消融术已被用于超过二十年的安全和有效的姑息治疗 和中央气道内支气管肿瘤的减积，但尚未应用于治疗 周围性肺肿瘤[7，8]。经皮冷冻消融术已用于治疗超过十年 不适合手术切除的外周原发性和继发性肺肿瘤[9]。在经皮 冷冻消融，通过经胸计算机将刚性冷冻治疗探针插入靶肿瘤中， 断层扫描（CT）引导，穿过胸膜和肺实质，导致高的 气胸[9]。在BCI中，周围肺肿瘤将通过气道直接进入，最大限度地减少了 气胸的风险。BCI也可以在支气管镜检查标准护理过程中进行。 手术，并且可能比经皮冷冻消融术的手术时间短得多， 本研究的主要目的是确定BCI的安全性和可行性，以及确定 最大耐受剂量-即最佳冷冻时间。本研究的次要目的是 通过多重流式细胞术（FACS）分析预处理和预处理的Bcl-2蛋白， 外周血中的BCI后细胞应答，包括PD-1的BCI后CD 8 + T细胞表达和 树突状细胞（DC）活化的标志物。将对外周血淋巴细胞进行额外分析 利用PanCancer OncoImmuneTM谱板（NanoString® Technology，西雅图，WA）评估 淋巴细胞基因表达的变化。.我们将获得BCI前支气管肺泡灌洗（BAL） 来自肿瘤部位附近和远端肺单位的标本，以关联BCI前BAL中的发现 淋巴细胞和BCI诱导的抗肿瘤免疫应答的强度。最后，接受脑机接口的患者 将使用标准RECIST对胸部CT扫描的肿瘤大小变化进行纵向随访 测量[10]，并评估无进展生存期和总生存期。

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.