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使用针对间皮素的免疫疗法，这是一种在LMB中发现的肿瘤抗原。间皮素在正常人体组织中的表达仅限于胸膜、心包和腹膜的间皮细胞，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，间皮素的表达量很高。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。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。我们目前正在评估三种间皮瘤的间皮素靶向药物。其中两种药物CAT-5001 （SS1P）和MORAb-009已进入临床阶段，第三种药物CRS-207即将进入I期试验。CAT-5001是一种重组免疫毒素，由抗间皮素Fv组成，与截断的假单胞菌外毒素a相连。我们最近完成了CAT-5001在表达间皮素的癌症患者中的I期临床试验。我们确定了CAT-5001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CAT-5001的安全性和耐受性之后，我们现在计划评估其在间皮瘤中的疗效。我们采用的策略是CAT-5001联合培美曲塞和顺铂作为不可切除胸膜间皮瘤患者的一线治疗。这项研究的基本原理是基于我们的实验室研究，表明CAT-5001和几种化疗药物在异种肿瘤移植模型中具有显著的协同作用。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。我们目前正在NCI进行一项针对表达间皮素的癌症患者的MORAb-009的三家机构I期临床试验，只有间皮瘤患者被纳入该研究。我实验室的研究表明，MORAb-009与吉西他滨和紫杉醇联合使用，抗肿瘤效果明显提高。基于这些结果，MORAb-009联合吉西他滨与单独吉西他滨的多机构II期随机研究即将在晚期胰腺癌中展开。此外，在完成正在进行的I期剂量递增研究后，我们正在启动一项MORAb-009联合化疗治疗恶性间皮瘤的II期研究。我们的研究小组和其他研究人员已经确定间皮素作为疫苗治疗的靶点，因为它是一种免疫原性蛋白，可引起患者的体液和细胞免疫反应。我们还鉴定了间皮素的免疫原性表位，并表明源自天然或激动剂间皮素表位的t细胞系可以裂解表达间皮素的肿瘤细胞系。CRS-207是Cerus Corp.的科学家开发的一种间皮素肿瘤疫苗，目前正在启动CRS-207的I期临床试验。CRS-207 （LmΔactA/ΔinlB/hMeso）是一种肿瘤疫苗，利用单核细胞增生李斯特菌（Lm）的减毒活菌株作为载体，编码人间皮素。临床前研究表明，CRS-207在小鼠和食蟹猴中引发人间皮素特异性CD4+/CD8+免疫，并在荷瘤小鼠中显示出治疗效果。与Cerus公司合作，我们在CRS-207的方案开发中发挥了重要作用，因为它与间皮瘤患者有关。该临床试验将是2-3个机构的I期研究，目前正在NCI进行科学审查。NCI站点将招募间皮瘤患者，目的是获得安全性和有效性信号，随后可能导致间皮瘤的II期临床试验。本研究的一个翻译终点是测量CRS-207治疗前后对间皮素的体液免疫反应，并将使用我们实验室开发的ELISA进行评估。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

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 mesothelioma. Two of these agents, CAT-5001 (SS1P) and MORAb-009 are in the clinic and the third agent CRS-207 is about to enter phase I testing. CAT-5001 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 CAT-5001 in patients with mesothelin expressing cancers. We established the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics of CAT-5001 and observed anti-tumor activity in a group of heavily pre-treated patients enrolled on this study. Having established the safety and tolerability of CAT-5001 we now plan to evaluate its efficacy in mesothelioma. The strategy we have adopted is to combine CAT-5001 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 CAT-5001 and several chemotherapeutic agents in tumor xenograft models. 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 are currently conducting 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. Studies by my laboratory have shown that the anti-tumor efficacy of MORAb-009 is markedly increased in combination with gemcitabine and taxol. Based on these results a multi-institutional phase II randomized study of MORAb-009 with gemcitabine versus gemcitabine alone is about to open in advanced pancreatic cancer. In addition, we are in the process of initiating a phase II study of MORAb-009 with chemotherapy in malignant mesothelioma after the completion of the ongoing phase I dose-escalation 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 initiating a phase I clinical trial of CRS-207, a mesothelin tumor vaccine developed by scientists at Cerus Corp. CRS-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 CRS-207 elicits human mesothelin-specific CD4+/CD8+ immunity in mice and in cynomolgus monkeys and exhibits therapeutic efficacy in tumor bearing mice. Working with Cerus Corp. we played an important part in protocol development of CRS-207 as it relates to patients with mesothelioma. This clinical trial which will be a 2-3 institution phase I study is currently undergoing scientific review at the NCI. The NCI site will enroll patients with mesothelioma, with the goal of getting safety and efficacy signals that could subsequently lead to a phase II clinical trial in mesothelioma. A translational endpoint of this study is measurement of humoral immune response to mesothelin before and after CRS-207 treatment and will be evaluated using an ELISA developed in our laboratory. 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