Immunotherapy for Malignant Mesothelioma, Lung Cancer and Thymic Malignancies

我们项目的总体目标是为胸部癌症患者开发更有效的治疗方法。这项工作主要分为两大类：1。利用间皮素治疗癌症。2. 免疫疗法和其他治疗肺癌、间皮瘤和胸腺癌的方法。1. 利用间皮素治疗癌症，重点是间皮瘤和肺癌。我们目前的研究重点是针对肿瘤分化抗原间皮素（mesothelin）的免疫治疗，该抗原在胸膜、心包和腹膜的正常间皮细胞上表达，但在几种人类肿瘤中，特别是间皮瘤、卵巢癌、肺癌和胰腺腺癌中高度表达。这种间皮素的差异表达使其成为肿瘤特异性治疗的有吸引力的候选者。我们现在的工作重点是利用不同的方法将其用于间皮瘤的治疗。其中包括嵌合抗间皮素单克隆抗体（MORAb-009）；抗间皮素免疫毒素（SS1P）和抗间皮素药物偶联物（BAY 94-9343）。SS1P是一种重组免疫毒素，由抗间皮素Fv与强效细菌毒素假单胞菌外毒素a的截断形式连接而成。我们之前已经在I期临床试验中确定了SS1P的安全性和最大耐受剂量（MTD）。我们的实验室研究显示了SS1P与化疗之间的协同作用，这促使我们在未接受化疗的胸膜间皮瘤患者中进行了SS1P与培美曲塞和顺铂联合治疗的临床试验。这项研究的结果显示，在13名可评估的患者中，有8名接受最大耐受剂量（MTD）治疗的患者有部分反应，反应率很高。虽然这项试验的结果令人兴奋，但我们也对提高SS1P的疗效感兴趣。由于SS1P是一种免疫原性蛋白，大多数患者产生针对它的中和抗体，这将治疗限制在1至2个周期。我的实验室与帕斯坦小组和NCI的实验室Dan Fowler博士合作表明，在免疫功能正常的小鼠中，用戊他汀加环磷酰胺治疗可以消除对SS1P的免疫反应。我们最近在使用抗间皮素免疫毒素SS1P联合戊他汀+环磷酰胺治疗难治性间皮瘤患者中显示了主要和持久的肿瘤消退，目前正在对胸膜和腹膜间皮瘤患者进行II期临床试验。我们也正在进行一项I期临床试验，以确定抗间皮素抗体药物偶联物BAY 94-9343的安全性和MTD，该偶联物由人源抗间皮素单克隆抗体连接到美坦素类DM4。在实验室中，我们专注于开发人类间皮瘤的体外和体内模型。我们已经从间皮瘤患者的腹水和胸膜液中获得了几种早期传代肿瘤细胞，并对其进行了鉴定。我们对这些细胞的形态和分子特征进行了充分的表征。这些模型对于评估间皮瘤的新型治疗药物至关重要。其他正在进行的实验室研究主要集中在了解间皮瘤肿瘤免疫微环境和抗间皮瘤靶向药物治疗后的变化。2. 免疫疗法治疗肺癌和胸腺癌。胸腺癌：胸腺瘤是一种罕见的肿瘤，其特征是淋巴细胞的浸润，使它们特别适合免疫检查点抑制。胸腺瘤患者目前正在接受抗pd - l1单克隆抗体MSB0010718C的I期临床试验治疗。我们已经在这些患者中看到了显著的抗肿瘤活性，并且伴随着胸腺瘤患者特有的副作用。此外，我们正在进行舒尼替尼治疗胸腺癌的II期研究。肺癌：我们目前正在对先前治疗失败的肺腺癌患者进行抗pd - l1单克隆抗体MSB0010718C的临床试验。我们的实验室最近发现约25%的转移性肺腺癌患者高表达间皮素。这些肿瘤中的间皮素表达与KRAS突变和野生型EGFR状态高度相关，并且独立地与不良预后相关。我们的假设是，K-RAS突变肺癌患者可以从间皮素定向治疗中获益。间皮素导向疗法治疗肺癌的临床试验即将开启。

The overall goal of our program is to develop more effective therapies for patients with thoracic cancers. This work falls under two main categories: 1. Exploiting mesothelin for cancer therapy. 2. Immunotherapy and other approaches to treat lung cancer, mesothelioma and thymic cancers. 1. Exploiting mesothelin for cancer therapy with a focus on mesothelioma and lung cancer. Our current studies are focused on using immunotherapy directed against the tumor differentiation antigen mesothelin, which is expressed on normal mesothelial cells lining the pleura, pericardium and peritoneum but is highly expressed in several human tumors especially mesothelioma, ovarian, lung and pancreatic adenocarcinomas. This differential expression of mesothelin makes it an attractive candidate for tumor specific therapy. Our efforts are now focused on exploiting it for mesothelioma therapy using different approaches. These include a chimeric anti-mesothelin monoclonal antibody (MORAb-009); anti mesothelin immunotoxin (SS1P) and an anti-mesothelin drug conjugate (BAY 94-9343). SS1P is a recombinant immunotoxin consisting of the anti-mesothelin Fv linked to a truncated form of the potent bacterial toxin, Pseudomonas exotoxin A. We have previously established the safety and maximum tolerated dose (MTD) of SS1P in phase I clinical trials. Our laboratory studies showing synergy between SS1P and chemotherapy has led to our clinical trial of SS1P in combination with pemetrexed and cisplatin in chemo-nave patients with pleural mesothelioma. Results of this study show a very high response rate with 8 out of the 13 evaluable patients treated at the maximum tolerated dose (MTD) having partial responses. While the results of this trial are exciting we are also interested in increasing the efficacy of SS1P. Since SS1P is an immunogenic protein majority of patients develop neutralizing antibodies to it that limits treatment to 1 to 2 cycles. My laboratory in collaboration with the Pastan group and the laboratory Dr. Dan Fowler at the NCI have shown that treatment with pentostatin plus cyclophosphamide abrogates the generation of immune response to SS1P in immunocompetent mice. We have recently shown major and durable tumor regressions in treatment refractory mesothelioma patients using the anti-mesothelin immunotoxin SS1P combined with pentostatin plus cyclophosphamide and are now doing a phase II clinical trial in patients with pleural and peritoneal mesothelioma. We are also conducting a phase I clinical trial to determine the safety and MTD of the anti-mesothelin antibody drug conjugate BAY 94-9343, which consists of a humanized anti-mesothelin monoclonal antibody linked to the maytansinoid DM4. In the laboratory we have focused on developing in-vitro and in-vivo models of human mesothelioma. We have established and characterized several early passage tumor cells obtained from ascites and pleural fluid of patients with mesothelioma. We have fully characterized these cells for morphological and molecular characteristics. These models are essential to evaluate novel therapeutic agents for mesothelioma. Other ongoing laboratory studies are focused on understanding the mesothelioma tumor immune micro-environmnet and changes following treatment with anti-meosthelin targeted agents. 2. Immunotherapy to treat lung cancer and thymic cancers. Thymic Cancers: Thymoma is a rare tumor characterized by infiltration of lymphocytes making them uniquely suitable for immune-checkpoint inhibition.Thymoma patients are currently being treated on a phase I clinical trial of the anti-PD-L1 monoclonal antibody MSB0010718C. We have seen remarkable anti-tumor activity in these patients that has been accompanied by side-effect profile unique to thymoma patients. In addition, we are conducting a Phase II study of sunitinib in thymic carcinomas. Lung Cancer: We are currently conducting clinical trial of the anti-PD-L1 monoclonal antibody MSB0010718C in patients with lung adenocarcinoma who have failed prior therapies. Our laboratory has recently shown that about 25% of patients with metastatic lung adenocarcinoma highly express mesothelin. Mesothelin expression in these tumors is highly associated with KRAS mutations and wild type EGFR status and is, independently, associated with poor prognosis. Our hypothesis is that patients with K-RAS mutant lung cancer can benefit from mesothelin directed therapies. Clinical trials of mesothelin directed therapies for treating lung cancer are about to open.