Immunotherapy for Malignant Mesothelioma

我们项目的总体目标是利用针对肿瘤分化抗原的单克隆抗体，为间皮瘤患者开发更有效的治疗方法。我们目前的研究重点是针对肿瘤分化抗原间皮素（mesothelin）进行免疫治疗，该抗原在包括恶性间皮瘤在内的许多癌症中高度表达。间皮素是一种肿瘤分化抗原，在胸膜、心包和腹膜的正常间皮细胞上表达，但在一些人类肿瘤中，尤其是间皮瘤、卵巢癌、肺癌和胰腺腺癌中，它的表达量很高。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。基于这些结果，我们正在进行一项初步研究，以观察戊他汀加环磷酰胺是否能降低化疗难耐间皮瘤患者SS1P的免疫原性，并允许重复给药SS1P。我们还完成了MORAb-009联合培美曲塞和顺铂一线治疗胸膜间皮瘤的单臂II期临床试验。该临床试验已达到其累积目标，共有89名患者入组，正在等待数据分析。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。这项试验也在安德森医学中心和莎拉·佳能研究中心进行。MTD已经建立，患者现在正在各个扩展队列中接受治疗。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。这些模型对于评估正在开发的LMB新治疗药物至关重要，但对其他研究间皮瘤的科学家也有价值。

The overall goal of our program is to develop more effective therapies for patients with mesothelioma using monoclonal antibodies direcetd to tumor differentiation antigens. Our current studies are focused on using immunotherapy directed against the tumor differentiation antigen mesothelin that is highly expressed in many cancers including malignant mesothelioma. Mesothelin, a tumor differentiation antigen is expressed on normal mesothelial cells lining the pleura, pericardium and peritoneum but it 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. Based on these results we are doing a pilot study to see in patients if pentostatin plus cyclophosphamide can decrease the immunogenicity of SS1P in patients with chemo-refractory mesothelioma and allow repeated administration of SS1P. We have also completed the single arm phase II clinical trial of MORAb-009 with pemetrexed and cisplatin for front-line therapy of pleural mesothelioma. This clinical trial has met its accrual goal with 89 patients enrolled and is awaiting data analysis. 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. This trial is also being conducted at M.D.Anderson and at Sarah Canon Research Center. The MTD has been established and patients are now being treated at the various expansion cohorts. 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 being developed in LMB but should be valuable to other scientists studying mesothelioma.