Immunotherapy for Malignant Mesothelioma

由于使用化疗治疗间皮瘤的经典干预措施收效甚微，我们选择以肿瘤分化抗原为靶点来治疗间皮瘤。我们目前的研究集中在针对LMB中发现的一种肿瘤抗原--间皮蛋白的免疫治疗上。在正常人体组织中，间皮蛋白的表达仅限于胸膜、心包和腹膜内的间皮细胞，而在多种人类肿瘤中，尤其是间皮瘤、卵巢癌、肺癌和胰腺癌中表达较高。这种不同的表达使其成为肿瘤特异性治疗的候选药物。在确认间皮素作为癌症治疗的靶点后，我们现在的努力集中在利用它进行间皮瘤治疗，使用不同作用机制的药物。我们目前正在评估临床上治疗间皮瘤的两种间硫蛋白靶向药物。&lt；/P&gt；&lt；P&gt；SS1P是一种重组免疫毒素，由抗间硫蛋白Fv连接到截短的假单胞菌外毒素A组成。我们最近完成了SS1P在间硫蛋白表达癌症患者中的I期临床试验。我们建立了SS1P的最大耐受量(MTD)、剂量限制毒性(DLT)、药代动力学，并观察了一组接受大量预治疗的患者的抗肿瘤活性。在确定SS1P的安全性和耐受性后，我们现在正在评估其对间皮瘤的疗效。我们采取的策略是将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，这些研究表明SS1P和几种化疗药物在肿瘤异种移植模型中具有显着的协同作用。SS1P联合培美曲塞和顺铂一线治疗间皮瘤患者的临床试验目前正在进行中，到目前为止已有11名患者在这项研究中接受了治疗。SS1P与化疗的结合具有良好的耐受性，并已导致多种抗肿瘤反应。我们正在评估的用于间皮瘤治疗的第二种间皮素靶向药是MORAb-009，这是一种嵌合的抗间皮素单抗，是LMB和MorPhotek Inc.合作开发的。在临床前研究中，MORAb-009介导了对表达间皮素的肿瘤细胞的抗体依赖细胞毒(ADCC)，抑制间皮素与CA-125的结合，并导致肿瘤生长抑制。我们最近完成了MORAb-009的三个机构的I期临床试验，在表达间皮蛋白的癌症患者中，只有间皮瘤患者在NCI参加了这项研究。这项研究确定了MORAb-009的安全性和最大耐受量，并显示了这种抗体对患者中间皮蛋白/CA125相互作用的非常有趣的影响。我的实验室目前正在进行研究，看看MORAb-009是否可以在动物模型中抑制肿瘤转移。我们还发现，MORAb-009与化疗联合应用，其抗肿瘤效果明显增强。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期临床试验于今年早些时候开始。NCI是这项研究的领头羊，到目前为止，已有11名患者在这项试验中接受了治疗。我们的团队在将间甲肾上腺素定义为癌症治疗的靶点以及我们目前正在临床评估的开发疗法方面发挥了重要作用。我的团队结合Pastan实验室的基础实验室研究所做的临床和转化性研究使我们能够将间充质素靶向的概念从替补席上带到临床。除了为间皮瘤患者带来新的治疗选择外，我们的研究还可能对卵巢癌、胰腺癌和肺腺癌等高表达间皮瘤的常见癌症的治疗产生影响。

<P>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 mesothelin, a tumor antigen identified in LMB. Mesothelin expression in normal human tissues is limited to 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.</P><P>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 11 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.</P><P>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 is currently conducting studies to see if MORAb-009 can inhibit tumor metastasis in animal models. We have also 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 earlier this year. NCI is the lead site for this study and so far 11 patients have been treated on this trial.</P><P>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.</P>