Clinical Trials in Mesothelioma

这个项目的总体假设是，免疫基因疗法可以成功地用于治疗 恶性胸膜间皮瘤。该项目将继续将临床前研究结果从 项目2和3进入尖端临床试验(从病床到床边)；并提供临床数据和 将样本送回项目2和项目3，以便在下一轮临床试验(床边试验)中提供改进信息。 该项目的第一个重点是继续和延长成功的胸腔内注射试验。 表达1型干扰素(Ad.1FN)的腺病毒(Ad.1Fn)。基于项目2的临床前数据，a 启动1/2期试验，将两次Ad.IFN-α剂量(相隔3天)与伴随剂量相结合 塞来昔布，两周后进行4-6个一线疗程(培美曲塞/顺铂/)或 二线(吉西他滨/卡铂)化疗。该提案的第一个目标是完成第二阶段试验 为了确定应答率是否保证将该疗法转移到更大规模的随机2期或3期试验，方法是 无论是行业还是合作团体。该项目的第二个重点是采用T细胞疗法。 具有嵌合抗原受体(CARS)的细胞最初以间皮瘤肿瘤表面抗原为靶点， 间苯妥英林。考虑到其他一些汽车的潜在安全问题，一项使用T细胞转导的试验 将进行GMP级信使核糖核酸(目标2A)。由于CAR的表达时间是有限的，如果有任何“无肿瘤” 影响发生时，它们将是非常短暂的。一旦确定了这种方法的安全性，就会进行更大规模的试验 将使用慢病毒转导的CAR T细胞结合淋巴清除法(目标2B)。 新建立的宾夕法尼亚大学间皮瘤和胸膜疾病计划(PMPDP)将发挥重要作用 在协调多项试验、增加应计利润和支持患者差旅费用方面发挥作用。 这些目标的完成将产生关于人类肿瘤免疫学的新知识，并提供新的 关于过继T细胞转移的潜在用途的数据，特别是使用信使核糖核酸转导的T细胞。这个 最终目标是改变间皮瘤和其他类似癌症的治疗模式，通过展示 免疫疗法应该是多种治疗方式的一部分。

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-tobench). 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 "off tumor" effects occur, they will be very short lived. Once the safety of this approach is established, a larger trial using lentiviral-transduced CAR T cells in combination with lymphodepletion will be conducted (Aim 2B). The newly established Penn Mesothelioma and Pleural Disease Program (PMPDP) will play an important role in coordination of the multiple trials, in augmenting accrual, and in supporting patient travel expenses. Completion of these aims will generate new knowledge about human tumor immunology and provide novel data on the potential use of adoptive T cell transfer, especially the use of mRNA-transduced T cells. The ultimate goal is to change the treatment paradigm for mesothelioma and other similar cancers by showing that immunotherapy should be part of a multi-modality treatment armamentarium.