Immunotherapy for Malignant Mesothelioma

恶性间皮瘤的免疫治疗

• 批准号: 7965714
• 负责人: RAFFIT HASSAN
• 金额: $ 72.51万
• 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/7965714
• 关键词: Adopted; Animal Model; Antibodies; Binding; CA-125 Antigen; Cell Line; Cisplatin; Clinic; Clinical; Clinical Trials; Collaborations; Conduct Clinical Trials; Differentiation Antigens; Dose-Limiting; Drug Kinetics; Drug usage; Enrollment; Goals; Human; Immunotherapy; Immunotoxins; Institution; Intervention; Laboratories; Laboratory Research; Laboratory Study; Lead; Link; Lung; Lung Adenocarcinoma; Malignant Neoplasms; Malignant mesothelioma; Maximum Tolerated Dose; Mediating; Mesothelial Cell; Mesothelioma; Monoclonal Antibodies; Neoplasm Metastasis; Outcome; Ovarian; Pancreas; Pancreatic Adenocarcinoma; Patients; Pemetrexed; Peritoneum; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Pleura; Pleural Mesothelioma; Pseudomonas aeruginosa toxA protein; Recombinants; Research; Safety; Site; Staging; Toxic effect; Translational Research; Tumor Antigens; Xenograft Model; antibody-dependent cell cytotoxicity; base; cancer therapy; chemotherapeutic agent; chemotherapy; common treatment; effective therapy; human tissue; improved; interest; meetings; mesothelin; neoplastic cell; novel; pericardial sac; preclinical study; programs; response; success; therapy development; tumor; tumor growth; tumor xenograft

<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>

<P自从使用化疗进行经典干预以来， 间皮瘤的治疗遇到了有限的成功，我们选择的方法 通过靶向肿瘤分化抗原治疗间皮瘤。我们目前的研究是 专注于使用针对间皮素的免疫疗法，间皮素是在LMB中鉴定的肿瘤抗原。 间皮素在正常人体组织中的表达仅限于间皮细胞， 胸膜、心包和腹膜，但它在几种人类肿瘤中高度表达 尤其是间皮瘤、卵巢癌、肺癌和胰腺腺癌。此差分 间皮素的表达使其成为肿瘤特异性治疗的有吸引力的候选物。具有 经验证的间皮素作为癌症治疗的靶点，我们的努力现在集中在利用 它用于间皮瘤治疗使用药物，通过不同的机制。我们目前正在 评估两种间皮素靶向药物在临床上治疗 间皮瘤。lt;/P P SS 1 P是一种重组体， 免疫毒素，其由连接至截短的假单胞菌外毒素A的抗间皮素Fv组成。 我们最近完成了SS 1 P在间皮素表达的患者中的I期临床试验， 癌的我们建立了最大耐受剂量（MTD），剂量限制性毒性（DLT）， SS 1 P的药代动力学和观察到的抗肿瘤活性在一组重度预处理的 参与本研究的患者。在确定SS 1 P的安全性和耐受性后，我们 目前正在评估其在间皮瘤中的疗效。我们采取的策略是将联合收割机SS 1 P 进行标准化疗这项研究的基本原理是基于我们的实验室研究 其在肿瘤异种移植物中显示SS 1 P和几种化疗剂之间显著协同作用 模型SS 1 P联合培美曲塞和顺铂一线治疗的临床试验 间皮瘤患者的治疗目前是开放的积累，迄今为止11 患者在本研究中接受了治疗。SS 1 P与化疗的组合已经被证实是有效的。 耐受性良好，并已导致几种抗肿瘤 回应。& lt;/P P第二间皮素靶向 我们正在评估的间皮瘤治疗剂是MORAb-009，一种嵌合抗间皮素 LMB和Morphotek Inc.合作开发的单克隆抗体。在 临床前研究MORAb-009介导抗体依赖性细胞毒性（ADCC） 针对表达间皮素的肿瘤细胞，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一项三个机构的I期临床试验， M0 RAb-009用于表达间皮素的癌症患者和仅间皮瘤患者 已经在NCI参加了这项研究。这项研究确定了安全性和最大 M0 RAb-009的耐受剂量，并显示出该抗体对 间皮素/CA 125相互作用。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。我们还表明， MORAb-009的抗肿瘤功效在与化学疗法组合时显著增加。基于 基于这些结果，一项MORAb-009与培美曲塞的多机构II期临床试验 和顺铂治疗胸膜间皮瘤已于今年早些时候开放。NCI是 该研究的主要研究中心，到目前为止，已有11名患者接受了治疗 审判。& lt;/P P我们的团队一直在 将间皮素定义为癌症治疗的靶点以及我们正在开发的治疗方法， 目前正在临床评估。我的团队在1999年完成的临床和转化研究 与Pastan实验室的基础实验室研究相结合， 间皮素靶向概念从实验室走向临床。除了导致新的治疗方法 间皮瘤患者的选择我们的研究可能对治疗有影响 常见的癌症，如卵巢癌、胰腺癌和肺腺癌， 间皮素。lt;/P>