Immunotherapy for Malignant Mesothelioma

由于使用化疗治疗间皮瘤的经典干预措施取得的成功有限，我们选择通过靶向肿瘤分化抗原来治疗间皮瘤。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三种间皮素靶向药物。SS1P是一种重组免疫毒素，由与截短的假单胞菌外毒素A相连的抗间皮蛋白抗体组成。我们最近完成了SS1P在表达间皮蛋白的癌症患者中的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。我们采用的策略是SS1P联合培美曲塞和顺铂作为不能切除的胸膜间皮瘤患者的一线治疗方案。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。这项临床试验目前开放用于治疗胸膜间皮瘤患者，到目前为止已经治疗了这项研究的3名患者。我们正在评估的治疗间皮瘤的第二种间硫蛋白靶向药物是MORAb-009，这是一种嵌合的抗间硫蛋白单抗，是LMB和MorPhotek Inc.合作开发的。在临床前研究中，MORAb-009介导了对表达间硫蛋白的肿瘤细胞的抗体依赖的细胞毒性(ADCC)，抑制了间硫蛋白与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。本实验室的研究表明，MORAb-009与化疗联合应用，抗肿瘤效果显著增强。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期研究即将开始。NCI将是这项研究的主要地点。我们的团队和其他研究人员已经确定间甲硫蛋白是疫苗治疗的靶点，因为它是一种免疫原性蛋白，可以在患者中引起体液和细胞免疫反应。我们还鉴定了间硫蛋白的免疫原性表位，并表明T细胞系来自天然或激动剂间硫蛋白表位，从而裂解表达间硫蛋白的肿瘤细胞系。我们目前正在进行ANZ-207的I期临床试验，ANZ-207是由Anza治疗公司的科学家开发的一种间皮蛋白肿瘤疫苗。ANZ-207(Lm&#916；Acta/&#916；inlB/hMeso)是一种肿瘤疫苗，它以单核细胞增生性李斯特菌活菌株为载体，编码人间皮蛋白。临床前研究表明，ANZ-207能在小鼠和食蟹猴体内诱导人类间皮蛋白特异性的CD4+/CD8+免疫，并对荷瘤小鼠显示出治疗效果。与安扎治疗公司合作，我们在ANZ-207方案的开发中发挥了重要作用，因为它与间皮瘤患者有关。这项临床试验目前正在进行中，到目前为止，我们已经在这项研究中治疗了2名患者。我们小组在将间甲肾上腺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，我们现在正在临床上对这些药物进行评估。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。

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 three 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 pemetrexed and cisplatin as front line therapy for patients with unresectable pleural mesothelioma. 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. This clinical trial is currently open for treatment of patients with pleural mesothelioma and have thus far treated 3 patients on this study. 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. Studies by my laboratory have 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 study of MORAb-009 with pemetrexed and cisplatin for the treatment of pleural mesothelioma is about to open. NCI will be the lead site for this study. Our group and other investigators have identified mesothelin as a target for vaccine therapy since it is an immunogenic protein that elicits both humoral and cellular immune response in patients. We have also identified the immunogenic epitopes of mesothelin and showed that T-cell lines derived from the native or the agonist mesothelin epitope lyse mesothelin expressing tumor cell lines. We are currently conducting a phase I clinical trial of ANZ-207, a mesothelin tumor vaccine developed by scientists at Anza Therapeutics. ANZ-207 (LmΔactA/ΔinlB/hMeso) is a tumor vaccine that utilizes a live-attenuated strain of the bacterium Listeria Monocytogenes (Lm) as the vector and encodes human mesothelin. Pre-clinical studies show that ANZ-207 elicits human mesothelin-specific CD4+/CD8+ immunity in mice and in cynomolgus monkeys and exhibits therapeutic efficacy in tumor bearing mice. Working with Anza Therapeutics we played an important part in protocol development of ANZ-207 as it relates to patients with mesothelioma. This clinical trial is currently open to accrual and we have thus far treated 2 patients on this study. 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.