Bronchoscopic Cryo-Immunotherapy of Lung Cancer

肺癌的支气管镜冷冻免疫治疗

基本信息

批准号：
9973153
负责人：
DANIEL STERMAN
金额：
$ 18.43万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-05 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9973153
关键词：
Admission activity Adverse event BCL2 gene Bronchoalveolar Lavage Bronchoscopy CD3 Antigens CD8-Positive T-Lymphocytes Cell Compartmentation Cells Cellular immunotherapy Clinical Clinical Trials Cold Therapy Color Common Terminology Criteria for Adverse Events Complication Cryosurgery Dendritic Cells Dendritic cell activation Development Distal Distant Dose Dose-Limiting Enrollment Environment Epinephrine Excision Feasibility Studies Fine needle aspiration biopsy Flow Cytometry Freezing Future Gene Expression Genes HLA-DR Antigens Hemorrhage Human Ice Immune Immune checkpoint inhibitor Immunosuppression Immunotherapy Interferon Type I Interventional radiology Investigation Lung Lung Neoplasms Lymphocyte Malignant Neoplasms Malignant neoplasm of lung Maximum Tolerated Dose Measurement Methods Non-Small-Cell Lung Carcinoma Operative Surgical Procedures Outcome PD-1/PD-L1 PDL1 pathway Palliative Care Patients Performance Peripheral Peripheral Blood Lymphocyte Peripheral Blood Mononuclear Cell Phase Phenotype Pilot Projects Pleura Pneumothorax Primary Neoplasm Procedures RNA Sequence Analysis Radial Refractory Saline Scanning Sentinel Site Specimen Structure of parenchyma of lung T-Cell Activation T-Lymphocyte Technology Thoracostomy Time Toxic effect Tube Tumor Debulking Ultrasonography Work X-Ray Computed Tomography anti-tumor immune response base chest computed tomography design first-in-human follow-up hemodynamics human study improved in situ vaccination innovation mouse model multiple omics nano-string novel peripheral blood programmed cell death protein 1 respiratory response risk minimization safety and feasibility safety study single-cell RNA sequencing standard of care tumor tumor microenvironment

项目摘要

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.

项目概要/摘要这是一项先进的支气管镜冷冻免疫疗法 (BCI) 的人体首次安全性和可行性研究非小细胞肺癌 (NSCLC) 冷冻免疫疗法涉及原位冷冻消融肿瘤。疫苗接种可产生肿瘤特异性 CD8+ T 细胞激活和增殖，并已在在同基因小鼠恶性肿瘤模型以及早期人体临床试验中均如此[1]。此外，冷冻免疫疗法可能与其他形式的免疫疗法（例如免疫疗法）产生协同作用。针对 PD-1/PD-L1 通路的检查点抑制剂 (CPI) - 引发增强的抗肿瘤免疫包括 NSCLC 在内的多种癌症的缓解和临床结果的改善[2-6]。 BCI 联合 CPI 可以使对 CPI 治疗难治的患者产生抗肿瘤免疫反应独自的。支气管镜冷冻消融术已用于安全有效的姑息治疗已有二十多年和中央气道支气管内肿瘤减灭术，但尚未应用于以下疾病的治疗：经皮冷冻消融术用于治疗周围型肺肿瘤已有十多年的历史。不适合经皮切除的周围原发性和继发性肺部肿瘤[9]。冷冻消融，通过经胸腔计算机将刚性冷冻治疗探针插入目标肿瘤断层扫描 (CT) 引导，穿过胸膜和肺实质，从而获得高成功率气胸 [9] 在 BCI 中，将通过气道直接接触周围肺肿瘤，从而最大限度地减少气胸。气胸的风险也可以在标准支气管镜护理过程中进行。手术，并且手术时间可能比经皮冷冻消融术短得多，本研究的主要目标是确定 BCI 的安全性和可行性，并确定最大耐受剂量 - 即最佳冷冻时间本研究的次要目标是。通过多重流式细胞术 (FACS) 分析前和后的结果来评估 BCI 诱导的抗肿瘤免疫反应 BCI 后外周血细胞反应，包括 BCI 后 CD8+ T 细胞 PD-1 和将对外周血淋巴细胞进行额外的树突状细胞 (DC) 激活标记物分析。利用 PanCancer OncoImmuneTM 配置面板（NanoString® Technology，西雅图，华盛顿州）来评估我们将获得 BCI 前的支气管肺泡灌洗液 (BAL)。来自肿瘤部位附近和远端肺单位的样本，以将 BCI 前 BAL 中的发现关联起来淋巴细胞和 BCI 的强度诱导抗肿瘤免疫反应最后，接受 BCI 的患者。将使用标准 RECIST 纵向跟踪胸部 CT 扫描中肿瘤大小的变化测量[10]，并评估无进展生存期和总生存期。