Immunotherapy for Malignant Mesothelioma

我们计划的总体目标是利用针对肿瘤分化抗原的单抗为间皮瘤患者开发更有效的治疗方法。我们目前的研究集中于针对肿瘤分化抗原Mesothelin的免疫治疗，该抗原在包括恶性间皮瘤在内的许多癌症中高表达。Mesothelin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，但在几种人类肿瘤中高表达，特别是间皮瘤、卵巢癌、肺癌和胰腺癌。这种不同的表达使其成为肿瘤特异性治疗的候选药物。我们的努力现在集中在使用不同的方法将其用于间皮瘤治疗。这些药物包括嵌合的抗间皮蛋白单抗(MORAb-009)、抗间皮蛋白免疫毒素(SS1P)和抗间皮蛋白药物结合物(BAY 94-9343)。SS1P是一种重组免疫毒素，由抗间硫蛋白FV连接到强效细菌毒素假单胞菌外毒素A的截短形式组成。我们先前已在I期临床试验中确定了SS1P的安全性和最大耐受量(MTD)。我们的实验室研究表明SS1P与化疗具有协同作用，这使得我们正在进行SS1P联合培美曲塞和顺铂治疗胸膜间皮瘤化疗患者的临床试验。这项研究的初步结果显示，在接受最大耐受量(MTD)治疗的13名可评估患者中，有8人有部分反应，有非常高的应答率。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，大多数患者对其产生中和抗体，将治疗限制在1至2个周期。我的实验室与Pastan小组和NCI的Dan Fowler博士合作，已经证明了五肽抑素联合环磷酰胺治疗可以消除免疫能力强的小鼠对SS1P的免疫反应。基于这些结果，我们刚刚开始了一项试验性研究，以观察在化疗难治性间皮瘤患者中，五肽抑素联合环磷酰胺是否可以降低SS1P的免疫原性，并允许重复使用SS1P。到目前为止，已有10名患者参加了这项研究，6名可评估的患者中有2名有显著的肿瘤反应。我们还完成了MORAb-009联合培美曲塞和顺铂治疗胸膜间皮瘤的单臂II期临床试验。这项临床试验已经达到了其应计目标，有89名患者参加，正在等待数据分析。我们还在进行一项I期临床试验，以确定抗间皮蛋白抗体药物结合物Bay 94-9343的安全性和MTD，该药物由人源化抗间皮蛋白单抗连接到Maytansinid dm4组成。到目前为止，NCI已经治疗了9名间皮瘤患者，并且剂量正在增加。在实验室，我们专注于开发人体间皮瘤的体外和体内模型。我们已经建立并鉴定了从间皮瘤患者的腹水和胸水中获得的几种早期传代肿瘤细胞。我们现在计划评估这些早期传代细胞在免疫缺陷小鼠中形成肿瘤的能力。这些模型对于评估LMB正在开发的新型治疗药物是必不可少的。

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 on-going clinical trial of SS1P in combination with pemetrexed and cisplatin in chemo-nave patients with pleural mesothelioma. Preliminary 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 have just started 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.So far 10 patients have been enrolled on the study and 2 out of 6 evaluable patients have had significant tumor response. 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. So far 9 patients with mesothelioma have been treated at the NCI and dose escalation is on-going.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 now plan to evaluate the ability of these early passage cells to form tumors in immunodeficient mice. These models are essential to evaluate novel therapeutic agents being developed in LMB.