Clinical Trials in Mesothelioma

该项目的总体假设是免疫基因治疗可以成功地用于治疗恶性胸膜间皮瘤（MPM）。该项目将继续将项目2和3的临床前发现转移到尖端临床试验（台架到床旁）;并将临床数据和标本返回到项目2和3，以告知下一轮临床试验（床旁到台架）的改进。 该项目的第一个焦点是继续和扩展使用表达1型干扰素（Ad. IFN）的腺病毒（Ad）的胸膜内注射的成功试验。基于项目2的临床前数据，启动了一项1/2期试验，将两种Ad. IFN-α剂量（间隔3天给药）与塞来昔布联合给药，两周后进行4-6个周期的一线（培美曲塞/顺铂/）或二线（吉西他滨/卡铂）化疗。本提案的目的1是完成II期试验，以确定缓解率是否需要将该疗法转移到行业或合作团体的更大随机II期或III期试验。该项目的第二个重点是过继性T细胞治疗，使用具有嵌合抗原受体（汽车）的T细胞，最初靶向间皮瘤肿瘤表面抗原间皮素。考虑到一些其他汽车的潜在安全性问题，将进行一项使用GMP级mRNA转导的T细胞的试验（目的2A）。由于CAR表达时间有限，

The overall hypothesis of this project is that immuno-gene therapy can be used successfully to treat malignant pleural mesothelioma (MPM). The Project will continue to move the preclinical findings from Projects 2 and 3 into cutting-edge clinical trials (bench-to-bedside); and to provide clinical data and specimens back to Projects 2 and 3 to inform improvements in the next iteration of clinical trials (bedside-to bench). The first focus of this project is to continue and extend successful trials using intrapleural injections of an adenovirus (Ad) expressing type 1 interferon (Ad.lFN). Based on preclinical data from Project 2, a Phase 1/2 trial was initiated combining two Ad.IFN-alpha doses (given 3 days apart) with concomitant Celecoxib administration, followed two weeks later by 4-6 cycles of either front-line (pemetrexed/cisplatin/) or second-line (gemcitabine/carboplatin) chemotherapy. Aim 1 of this proposal is to complete the Phase 2 trial to determine if the response rate warrants moving this therapy to a larger randomized Phase 2 or 3 trial by either industry or cooperative groups. The second focus of the Project is adoptive T cell therapy using T cells with chimeric antigen receptors (CARs) initially targeted to the mesothelioma tumor surface antigen, mesothelin. Given potential safety concerns with some other CARs, a trial using T-cells transduced with GMP grade mRNA will be conducted (Aim 2A). Since CAR expression time is limited, if any