Immunotherapy for Malignant Mesothelioma

我们项目的总体目标是利用针对肿瘤分化抗原或生长因子的单克隆抗体，为间皮瘤患者开发更有效的治疗方法。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）。a.针对间皮素的单克隆抗体的实验室研究和临床试验。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，但在一些人类肿瘤中，尤其是间皮瘤、卵巢癌、肺癌和胰腺腺癌中，它的表达量很高。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。我们现在的工作重点是利用不同的方法将其用于间皮瘤的治疗。SS1P是一种重组免疫毒素，由抗间皮素Fv与强效细菌毒素假单胞菌外毒素a的截断形式连接而成。我们之前已经在I期临床试验中确定了SS1P的安全性和最大耐受剂量（MTD）。我们的实验室研究显示SS1P与化疗之间的协同作用，因此我们正在进行SS1P与培美曲塞和顺铂联合治疗化疗的胸膜间皮瘤患者的临床试验。这项研究的初步结果显示，在10名可评估的患者中，有8名接受最大耐受剂量（MTD）治疗的患者有部分反应，反应率非常高。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，大多数患者产生针对它的中和抗体，这将治疗限制在1至2个周期。我的实验室与帕斯坦小组和NCI的实验室Dan Fowler博士合作表明，在免疫功能正常的小鼠中，用戊他汀加环磷酰胺治疗可以消除对SS1P的免疫反应。基于这些结果，我们刚刚开始了一项试点研究，以观察戊他汀加环磷酰胺是否可以降低化疗难耐间皮瘤患者SS1P的免疫原性，并允许重复给药SS1P。我们还完成了MORAb-009联合培美曲塞和顺铂一线治疗胸膜间皮瘤的单臂II期临床试验。该临床试验已达到其累积目标，共有89名患者入组，正在等待数据分析。除了SS1P和MORAb-009，我们即将启动一项I期临床试验，以确定抗间皮素抗体药物偶联物BAY 94-9343的安全性和MTD，该偶联物由人源抗间皮素单克隆抗体连接到美坦素DM4。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酪氨酸激酶受体。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。环妥珠单抗（IMC-A12）是一种针对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。我们的研究结果表明，包括抑制IGF-IR下游信号在内的环妥珠单抗的抗肿瘤功效与IGF-IR位点/细胞高度相关。我们目前正在进行一项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。这项研究于2010年7月开始，目前已有20名患者入组。

The overall goal of our program is to develop more effective therapies for patients with mesothelioma using monoclonal antibodies direcetd to tumor differentiation antigens or growth factors. 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. Our efforts are now focused on exploiting it for mesothelioma therapy using different approaches. 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 10 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. 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. In addition to SS1P and MORAb-009 we are about to initiate a phase I clinical 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. 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. Cixutumumab (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. Our results show that the anti-tumor efficacy of cixutumumab including inhibition of IGF-IR downstream signaling is highly correlated with IGF-IR sites/cell. We have currently conducting 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 20 patients have been enrolled.