Immunotherapy for Malignant Mesothelioma

恶性间皮瘤的免疫治疗

• 批准号: 8763233
• 负责人: RAFFIT HASSAN
• 金额: $ 94.79万
• 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/8763233
• 关键词: Antibodies; Ascites; Bacterial Toxins; Cell Line; Cells; Characteristics; Cisplatin; Clinical Trials; Collaborations; Conduct Clinical Trials; Cyclophosphamide; Data Analyses; Differentiation Antigens; Enrollment; Evaluable Disease; Generations; Goals; Human; Immune response; Immunocompetent; Immunotherapeutic agent; Immunotherapy; Immunotoxins; In Vitro; Laboratories; Laboratory Research; Laboratory Study; Link; Liquid substance; Lung Adenocarcinoma; Malignant Neoplasms; Malignant mesothelioma; Maximum Tolerated Dose; Mesothelial Cell; Mesothelioma; Modeling; Molecular; Monoclonal Antibodies; Mus; Ovarian Adenocarcinoma; Pancreatic Adenocarcinoma; Patients; Pemetrexed; Pentostatin; Peritoneum; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Pilot Projects; Pleura; Pleural; Pleural Mesothelioma; Proteins; Pseudomonas aeruginosa toxA protein; Recombinants; Refractory; Research; Safety; Scientist; Staging; Therapeutic Agents; arm; base; chemotherapy; cohort; effective therapy; immunogenic; immunogenicity; in vivo Model; interest; meetings; mesothelin; neoplastic cell; neutralizing antibody; novel; novel therapeutics; partial response; pericardial sac; programs; response; tumor

The overall goal of our program is to develop more effective therapies for patients with mesothelioma using monoclonal antibodies direcetd to tumor differentiation antigens. Our current studies are focused on using immunotherapy directed against the tumor differentiation antigen mesothelin that is highly expressed in many cancers including malignant mesothelioma. 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. These include a chimeric anti-mesothelin monoclonal antibody (MORAb-009); anti mesothelin immunotoxin (SS1P) and an anti-mesothelin drug conjugate (BAY 94-9343). 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 clinical trial of SS1P in combination with pemetrexed and cisplatin in chemo-nave patients with pleural mesothelioma. Results of this study show a very high response rate with 8 out of the 13 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 are doing 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. We are also conducting a phase I clinical trial 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. This trial is also being conducted at M.D.Anderson and at Sarah Canon Research Center. The MTD has been established and patients are now being treated at the various expansion cohorts. In the laboratory we have focused on developing in-vitro and in-vivo models of human mesothelioma. We have established and characterized several early passage tumor cells obtained from ascites and pleural fluid of patients with mesothelioma. We have fully characterized these cells for morphological and molecular characteristics. These models are essential to evaluate novel therapeutic agents being developed in LMB but should be valuable to other scientists studying mesothelioma.

我们项目的总体目标是利用针对肿瘤分化抗原的单克隆抗体为间皮瘤患者开发更有效的治疗方法。我们目前的研究集中在使用针对肿瘤分化抗原间皮素的免疫疗法，间皮素在许多癌症中高度表达，包括恶性间皮瘤。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，但它在几种人类肿瘤中高度表达，特别是间皮瘤、卵巢癌、肺癌和胰腺腺癌。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。我们的努力现在集中在利用它间皮瘤治疗使用不同的方法。这些包括嵌合抗间皮素单克隆抗体（MORAb-009）;抗间皮素免疫毒素（SS 1 P）和抗间皮素药物缀合物（BAY 94-9343）。SS 1 P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连接组成。我们之前已经在I期临床试验中确定了SS 1 P的安全性和最大耐受剂量（MTD）。我们的实验室研究显示SS 1 P和化疗之间的协同作用，导致我们的临床试验SS 1 P联合培美曲塞和顺铂化疗初治胸膜间皮瘤患者。本研究的结果显示了非常高的缓解率，在接受最大耐受剂量（MTD）治疗的13例可评价患者中有8例出现部分缓解。虽然这项试验的结果令人兴奋，但我们也有兴趣提高SS 1 P的疗效。由于SS 1 P是一种免疫原性蛋白质，大多数患者会产生中和抗体，将治疗限制在1至2个周期。我的实验室与Pastan小组和NCI的实验室Dan Fowler博士合作，已经表明用喷司他丁加环磷酰胺治疗可以消除免疫活性小鼠对SS 1 P的免疫反应。基于这些结果，我们正在进行一项初步研究，以观察喷司他丁加环磷酰胺是否能降低化学难治性间皮瘤患者SS 1 P的免疫原性，并允许重复给予SS 1 P。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。这项临床试验已达到其招募目标，入组了89例患者，正在等待数据分析。我们还正在进行I期临床试验，以确定抗间皮素抗体药物缀合物BAY 94-9343的安全性和MTD，BAY 94-9343由连接至美登木素DM 4的人源化抗间皮素单克隆抗体组成。本试验也在M.D.安德森和Sarah Canon研究中心进行。MTD已经确立，患者目前正在各个扩展队列接受治疗。在实验室中，我们专注于开发人类间皮瘤的体外和体内模型。我们已经建立并鉴定了几个早期传代肿瘤细胞从间皮瘤患者的腹水和胸腔积液。我们已经充分表征了这些细胞的形态学和分子特征。这些模型是必不可少的，以评估新的治疗药物正在开发的LMB，但应该是有价值的其他科学家研究间皮瘤。