Immunotherapy for Malignant Mesothelioma

由于使用化疗治疗间皮瘤的经典干预措施取得了有限的成功，我们选择了通过靶向肿瘤分化抗原来治疗间皮瘤。我们目前的研究重点是利用免疫疗法直接针对两个肿瘤靶点间皮素和胰岛素生长因子1受体（IGF-1R）。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，但在几种人类肿瘤中，尤其是间皮瘤、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。在证实间皮素是癌症治疗的靶点后，我们现在的工作重点是利用不同机制的药物将其用于间皮瘤治疗。我们目前正在临床评估两种间皮瘤靶向药物治疗间皮瘤。SS1P是一种重组免疫毒素，由与截断假单胞菌外毒素a连接的抗间皮素Fv组成。我们最近完成了SS1P在表达间皮素的癌症患者中的I期临床试验。我们确定了SS1P的最大耐受剂量（MTD）、剂量限制性毒性（DLT）、药代动力学，并在一组接受了大量预处理的患者中观察了其抗肿瘤活性。在确定了SS1P的安全性和耐受性之后，我们现在正在评估其在间皮瘤中的疗效。我们采用的策略是将SS1P与标准化疗相结合。这项研究的基本原理是基于我们的实验室研究表明，在肿瘤异种移植模型中，SS1P和几种化疗药物之间存在显著的协同作用。SS1P联合培美曲塞、顺铂一线治疗间皮瘤的临床试验目前正在开放进行中，目前已有15例患者接受了该研究。SS1P联合化疗耐受性良好，并产生了几种抗肿瘤反应。在这项研究中治疗的11例可评估患者中，5例部分缓解，2例病情稳定。我们还表明，接受SS1P和化疗的患者血清间皮素水平的变化与放射反应相关，可能是跟踪患者的有用测试。我们正在评估的用于间皮瘤治疗的第二种间皮瘤靶向药物是MORAb-009，这是LMB和Morphotek公司合作开发的一种嵌合抗间皮瘤单克隆抗体。在临床前研究中，MORAb-009介导对表达间皮素的肿瘤细胞的抗体依赖性细胞毒性（ADCC），抑制间皮素与CA-125的结合，导致肿瘤生长抑制。我们最近完成了一项MORAb-009在表达间皮素的癌症患者中的三机构I期临床试验，只有间皮瘤患者被纳入NCI的这项研究。本研究确定了MORAb-009的安全性和最大耐受剂量，并显示了该抗体对患者间皮素/CA125相互作用的非常有趣的影响。我的实验室研究表明，MORAb-009联合化疗抗肿瘤效果明显提高。基于这些结果，MORAb-009联合培美曲塞和顺铂治疗胸膜间皮瘤的多机构II期临床试验于2009年1月启动，NCI作为该研究的牵头单位。迄今为止，全球已有73名患者接受了该研究的治疗，其中包括NCI的4名患者。关于MORAb-009治疗间皮瘤疗效的初步数据预计将于今年晚些时候公布。我们的团队在将间皮素定义为癌症治疗的靶点以及开发的治疗方法方面发挥了重要作用，我们现在正在临床评估这些治疗方法。我的团队所做的临床和转化研究与帕斯坦实验室的基础实验室研究相结合，使我们能够将间皮素靶向的概念从实验室带到临床。除了为间皮瘤患者提供新的治疗选择外，我们的研究还可能对高表达间皮素的卵巢癌、胰腺癌和肺腺癌等常见癌症的治疗产生影响。b.针对IGF-1R的单克隆抗体的实验室研究和临床试验胰岛素样生长因子-1受体（IGF-1R）是一种具有增殖和抗凋亡作用的受体酪氨酸激酶。IGF-1信号级联表达的改变和IGF-1R活性的增加导致几种肿瘤类型的增殖，也可能有助于对抗癌治疗（包括细胞毒性化疗和生物治疗）的耐药性。IGF-1R通路在恶性间皮瘤细胞系和组织中被激活。IMC-A12是IGF-1R的全人源单克隆抗体，可阻断其与配体IGF-1和IGF-2的相互作用。这导致IGF-1R的内化和降解。我的实验室目前正在研究IGF-1R作为使用IMC-A12治疗间皮瘤的靶点。我们已经建立了从患者身上获得的几种早期传代间皮瘤细胞系，并详细描述了它们的IGF-1R表达，包括每个细胞的位点。IMC-A12的抗肿瘤活性正在利用这些间皮瘤细胞系和已建立的间皮瘤细胞系以及对间皮瘤异种移植物的体内研究进行评估。我们刚刚启动了一项II期临床试验，以测试IMC-A12在标准化疗失败的恶性间皮瘤患者中的疗效。本研究的探索性终点包括肿瘤IGF-1R表达的评估、肿瘤反应与FDG-PET成像的相关性以及使用血清间皮素作为肿瘤反应的标志物。该研究于2010年7月开始，目前已招募了5名患者。

Since classical interventions using chemotherapy for the treatment of mesothelioma have met with limited success we have elected to approach mesothelioma therapy by targeting tumor differentiation antigens. Our current studies are focused on using immunotherapy directed against two tumor targets mesothelin and Insulin Growth Factor 1 Receptor (IGF-1R). a. Laboratory studies and clinical trials of monoclonal antibodies targeting mesothelin 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. Having validated mesothelin as a target for cancer therapy our efforts are now focused on exploiting it for mesothelioma therapy using drugs that act by different mechanisms. We are presently evaluating two mesothelin targeted agents in the clinic for the treatment of mesothelioma. SS1P is a recombinant immunotoxin consisting of an anti-mesothelin Fv linked to a truncated Pseudomonas exotoxin A. We recently completed a phase I clinical trial of SS1P in patients with mesothelin expressing cancers. We established the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics of SS1P and observed anti-tumor activity in a group of heavily pre-treated patients enrolled on this study. Having established the safety and tolerability of SS1P we are now evaluating its efficacy in mesothelioma. The strategy we have adopted is to combine SS1P with standard chemotherapy. The rationale for this study is based on our laboratory studies that show marked synergy between SS1P and several chemotherapeutic agents in tumor xenograft models. The clinical trial of SS1P in combination with pemetrexed and cisplatin for front line treatment of patients with mesothelioma is currently open for accrual, and thus far 15 patients have been treated on this study. The combination of SS1P with chemotherapy has been well tolerated and has resulted in several anti-tumor responses. Out of the 11 evaluable patients treated on this study 5 had partial response and 2 stable disease. We have also shown that changes in serum mesothelin levels in patients treated with SS1P and chemotherapy correlate with radiological responses and may be a useful test to follow patients. The second mesothelin targeted agent we are evaluating for mesothelioma therapy is MORAb-009, a chimeric anti-mesothelin monoclonal antibody that was developed as collaboration between LMB and Morphotek Inc. In pre-clinical studies MORAb-009 mediates antibody-dependent cellular cytotoxicity (ADCC) against mesothelin-expressing tumor cells, inhibits mesothelin binding to CA-125 and leads to tumor growth inhibition. We recently completed a three institution phase I clinical trial of MORAb-009 in patients with mesothelin-expressing cancers and only patients with mesothelioma have been enrolled on this study at the NCI. This study established the safety and maximum tolerated dose of MORAb-009 and showed a very interesting effect of this antibody on mesothelin/CA125 interactions in patients. My laboratory has shown that the anti-tumor efficacy of MORAb-009 is markedly increased in combination with chemotherapy. Based on these results a multi-institutional phase II clinical trial of MORAb-009 with pemetrexed and cisplatin for the treatment of pleural mesothelioma was opened in January 2009 with NCI as the lead site for this study. Seventy three patients have thus far been treated on this study worldwide including 4 patients at NCI. Preliminary data regarding the efficacy of MORAb-009 in mesothelioma are expected to be available latter this year. Our group has been instrumental in defining mesothelin as a target for cancer therapy as well as developed therapies that we are now evaluating in the clinic. The clinical and translational research done by my group in conjunction with basic laboratory research of the Pastan laboratory has allowed us to take the concept of mesothelin targeting from the bench to the clinic. Besides leading to new treatment options for patients with mesothelioma our research could have implications for the treatment of common cancers such as ovarian, pancreatic and lung adenocarcinomas that highly express mesothelin. b. Laboratory studies and clinical trial of a monoclonal antibody targeting IGF-1R Insulin-like growth factor-1 receptor (IGF-1R) is a receptor tyrosine kinase that has proliferative and anti-apoptotic effects. Altered expression of the IGF-1 signaling cascade and increased activity of IGF-1R results in proliferation of several tumor types and may also contribute to resistance to anticancer therapies including cytotoxic chemotherapy and biologic therapies. The IGF-1R pathway is activated in malignant mesothelioma cell lines and tissues. IMC-A12 is a fully human monoclonal antibody to IGF-1R and blocks its interaction with its ligands IGF-1 and IGF-2. This leads to internalization and degradation of IGF-1R. My laboratory is currently studying IGF-1R as target for mesothelioma therapy using IMC-A12. We have established several early passage mesothelioma cell lines obtained from patients and are characterizing them for IGF-1R expression in detail including sites per cell. The anti-tumor activity of IMC-A12 is being evaluated using these and established mesothelioma cell lines as well as in-vivo studies against mesothelioma tumor xenografts. We have just opened a phase II clinical trial to test the efficacy of IMC-A12 in patients with malignant mesothelioma who have failed standard chemotherapy. Exploratory endpoints of this study include evaluation of tumor IGF-1R expression, correlation of tumor response with FDG-PET imaging and use of serum mesothelin as a marker of tumor response. This study opened in July 2010 has thus far enrolled 5 patients.