Clinical Trials in Mesothelioma

恶性间皮瘤(MPM)的治疗仍然不足。新疗法，如基因疗法 或免疫基因疗法，是迫切需要的。本项目基于之前的一系列第一阶段 使用含单纯疱疹病毒的重组复制缺陷腺病毒载体的临床试验 34例MPM患者胸苷激酶基因检测结果分析显著的瘤内HSVtk基因转移 取得了进展，并注意到一些放射学和临床反应，包括2名患者持久 延迟的完全反应，高度提示抗肿瘤免疫反应。在此基础上， 实验室和临床工作的重点转移到了胸部恶性肿瘤的遗传免疫治疗上。 基于强大的临床前数据，一项新的I期临床试验使用腺病毒单剂胸腔内注射 对MPM和恶性胸腔积液(MPE)患者进行了干扰素-β(Ad.1FN-β)治疗。 该方法是安全的，许多免疫学反应和临床反应都是 观察到的。该项目的目标是继续并扩大这些针对患者的临床试验 间皮瘤。在第一个目标中，将进行第一阶段试验，以评估安全性、毒性分布、免疫力 两种剂量的Ad.1FN-β胸腔内注射治疗MPE/MPM的疗效和临床疗效。特定的 AIMS 2和3将包括在MPM患者中测试方法的第二阶段临床试验，这些方法 从我们的临床前研究发展而来，以增强疗效。目标2将确定疗效和免疫力 联合应用两剂Ad.1FN-β作为新辅助治疗的相关反应 在MPM患者中应用手术去髓鞘和辅助性COX-2抑制剂。目标3将决定 联合应用两种剂量Ad.1FN-β的疗效和免疫应答 MPM患者的化疗和辅助性COX-2抑制剂。在目标4中，调查人员将开始 利用基因工程T淋巴细胞进行过继免疫治疗试验所需的步骤 间皮瘤和其他表达间皮瘤抗原的肿瘤患者对间皮蛋白的反应性 经过临床前优化。

The treatment of malignant mesothelioma (MPM) remains inadequate. New therapies, such as gene therapy or immuno-gene therapy, are desperately needed. This Project is based on a previous series of Phase I clinical trials using recombinant, replication-deficient adenoviral (Ad) vectors containing the Herpes Simplex Thymidine Kinase (HSVtk) gene in 34 MPM patients. Significant intratumoral HSVtk gene transfer was achieved and some radiographic and clinical responses were noted, including 2 patients who had durable complete responses in delayed fashion, highly suggestive of anti-tumor immune responses. On this basis, the focus of laboratory and clinical work was shifted to genetic immunotherapy of thoracic malignancies. Based on strong preclinical data, a new Phase I clinical trial using a single dose of intrapleural adenoviral interferon beta (Ad.lFN-beta) for patients with MPM and malignant pleural effusions (MPE) was conducted. The approach was safe and a number of immunologic responses, as well as clinical responses were observed. The goal of this Project is to continue and extend these clinical trials aimed at patients with mesothelioma. In the first aim, a Phase 1 trial will be conducted to assess the safety, toxicity profile, immune responses, and clinical effect of two intrapleural doses of Ad.lFN-beta for patients with MPE/MPM. Specific Aims 2 and 3 will consist of Phase 2 clinical trials testing approaches in patients with MPM that were developed from our preclinical studies to augment efficacy. Aim 2 will determine the efficacy and immune responses associated with the delivery of two doses of Ad.lFN-beta as neo-adjuvant therapy in combination with surgical debulking and adjuvant COX-2 inhibitors in patients with MPM. Aim 3 will determine the efficacy and immune responses associated with the delivery of two doses of Ad.lFN-beta in combination with chemotherapy and adjuvant COX-2 inhibitors in patients with MPM. In Aim 4, investigators will begin the steps needed to develop an adoptive immunotherapy trial using genetically engineering T-lymphocytes reactive against mesothelin for patients with mesothelioma and other tumors expressing this tumor antigen after preclinical optimization.