Immunotherapy for Malignant Mesothelioma

恶性间皮瘤的免疫治疗

• 批准号: 8349180
• 负责人: RAFFIT HASSAN
• 金额: $ 79.89万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8349180
• 关键词: Antibodies; Apoptotic; Bacterial Toxins; Biological Response Modifier Therapy; Cell Line; Cells; Cisplatin; Clinical; Clinical Trials; Collaborations; Conduct Clinical Trials; Cyclophosphamide; Cytotoxic Chemotherapy; Data Analyses; Differentiation Antigens; Differentiation and Growth; Enrollment; Evaluable Disease; Evaluation; Generations; Goals; Growth Factor; Human; Immune response; Immunocompetent; Immunotherapy; Immunotoxins; Insulin; Insulin-Like Growth Factor I; Insulin-Like Growth Factor II; Insulin-Like-Growth Factor I Receptor; Laboratories; Laboratory Study; Ligands; Link; Lung Adenocarcinoma; Malignant Neoplasms; Malignant mesothelioma; Maximum Tolerated Dose; Mesothelial Cell; Mesothelioma; Monoclonal Antibodies; Mus; Outcome; Ovarian Adenocarcinoma; Pancreatic Adenocarcinoma; Pathway interactions; Patients; Pemetrexed; Pentostatin; Peritoneum; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Pilot Projects; Pleura; Pleural Mesothelioma; Positron-Emission Tomography; Proteins; Pseudomonas aeruginosa toxA protein; Receptor Protein-Tyrosine Kinases; Recombinants; Refractory; Research; Resistance; Safety; Serum; Signal Transduction; Site; Staging; Tissues; Translational Research; Tumor Markers; arm; base; cancer therapy; chemotherapy; effective therapy; efficacy testing; human monoclonal antibodies; immunogenic; immunogenicity; improved; in vivo; interest; meetings; mesothelin; neutralizing antibody; novel; partial response; pericardial sac; programs; receptor; receptor expression; response; tumor; tumor xenograft

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.

我们计划的总体目标是使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疗法。我们目前的研究重点是使用针对间皮素和胰岛素生长因子 1 受体 (IGF-1R) 两个肿瘤靶标的免疫疗法。 一个。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、心包和腹膜内衬的正常间皮细胞上表达，但在多种人类肿瘤中高度表达，特别是间皮瘤、卵巢癌、肺癌和胰腺癌。间皮素的这种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使用不同的方法将其用于间皮瘤治疗。 SS1P 是一种重组免疫毒素，由抗间皮素 Fv 与截短形式的强效细菌毒素假单胞菌外毒素 A 组成。我们之前已在 I 期临床试验中确定了 SS1P 的安全性和最大耐受剂量 (MTD)。我们的实验室研究表明 SS1P 和化疗之间具有协同作用，因此我们正在进行 SS1P 联合培美曲塞和顺铂治疗胸膜间皮瘤初治患者的临床试验。这项研究的初步结果显示，缓解率非常高，在最大耐受剂量 (MTD) 治疗的 10 名可评估患者中，有 8 名出现部分缓解。虽然这项试验的结果令人兴奋，但我们也对提高 SS1P 的功效感兴趣。由于 SS1P 是一种免疫原性蛋白，大多数患者会产生针对它的中和抗体，从而将治疗限制为 1 至 2 个周期。我的实验室与 Pastan 小组和 NCI 的 Dan Fowler 博士实验室合作表明，使用喷司他丁加环磷酰胺治疗可以消除免疫功能正常的小鼠对 SS1P 的免疫反应的产生。基于这些结果，我们刚刚开始一项试点研究，以观察喷司他丁加环磷酰胺是否可以降低化疗难治性间皮瘤患者中 SS1P 的免疫原性，并允许重复施用 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。该临床试验已入组 89 名患者，已达到其累积目标，正在等待数据分析。除了 SS1P 和 MORAb-009 之外，我们还将启动 I 期临床，以确定抗间皮素抗体药物偶联物 BAY 94-9343 的安全性和 MTD，该药物偶联物由与美登木素生物碱 DM4 连接的人源化抗间皮素单克隆抗体组成。 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) 是一种受体酪氨酸激酶，具有增殖和抗凋亡作用。 IGF-1 信号级联表达的改变和 IGF-1R 活性的增加会导致多种肿瘤类型的增殖，并且还可能导致对包括细胞毒性化疗和生物疗法在内的抗癌疗法产生耐药性。 IGF-1R 通路在恶性间皮瘤细胞系和组织中被激活。 Cixutumumab (IMC-A12) 是一种针对 IGF-1R 的全人源单克隆抗体，可阻断其与其配体 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。我们已经建立了几种从患者身上获得的早期传代间皮瘤细胞系，并详细表征了它们的 IGF-1R 表达，包括每个细胞的位点。正在使用这些和已建立的间皮瘤细胞系以及针对间皮瘤异种移植物的体内研究来评估 IMC-A12 的抗肿瘤活性。我们的结果表明，cixutumumab 的抗肿瘤功效（包括抑制 IGF-IR 下游信号传导）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对标准化疗失败的恶性间皮瘤患者的疗效。本研究的探索性终点包括评估肿瘤 IGF-1R 表达、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，迄今为止已招募了 20 名患者。