Immunotherapy for Malignant Mesothelioma, Lung Cancer and Thymic Malignancies

恶性间皮瘤、肺癌和胸腺恶性肿瘤的免疫治疗

• 批准号: 9343710
• 负责人: RAFFIT HASSAN
• 金额: $ 99.51万
• 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/9343710
• 关键词: Adverse effects; Antibody-drug conjugates; Ascites; Bacterial Toxins; Categories; Cell Line; Cells; Characteristics; Cisplatin; Clinic; Clinical Trials; Collaborations; Conduct Clinical Trials; Cyclophosphamide; Differentiation Antigens; Drug Targeting; Epidermal Growth Factor Receptor; Evaluable Disease; Generations; Goals; Human; Immune; Immune response; Immunocompetent; Immunotherapeutic agent; Immunotherapy; Immunotoxins; In Vitro; Infiltration; KRAS2 gene; Laboratories; Laboratory Research; Laboratory Study; Link; Liquid substance; Lung Adenocarcinoma; Lymphocyte; Malignant Neoplasms; Malignant mesothelioma; Malignant neoplasm of lung; Malignant neoplasm of thorax; Malignant neoplasm of thymus; Maximum Tolerated Dose; Mesothelial Cell; Mesothelioma; Modeling; Molecular; Monoclonal Antibodies; Mus; Mutation; Non-Small-Cell Lung Carcinoma; Ovarian Adenocarcinoma; PDCD1LG1 gene; Pancreatic Adenocarcinoma; Pathway interactions; Patients; Pemetrexed; Pentostatin; Peritoneal Mesothelioma; Peritoneum; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Pleura; Pleural; Pleural Mesothelioma; Prior Therapy; Proteins; Pseudomonas aeruginosa toxA protein; Recombinants; Refractory; Research; Role; Safety; Staging; Therapeutic Agents; Thymic Carcinoma; Thymoma; Vaccines; Work; cancer therapy; chemotherapy; differential expression; effective therapy; falls; immunogenic; in vivo Model; interest; lung small cell carcinoma; mesothelin; mutant; neoplastic cell; neutralizing antibody; novel; novel therapeutics; outcome forecast; partial response; pericardial sac; phase 2 study; programs; response; targeted agent; tumor

The overall goal of our program is to develop more effective therapies for patients with thoracic cancers. This work falls under two main categories: 1. Exploiting mesothelin for cancer therapy. 2. Immunotherapy and other approaches to treat lung cancer, mesothelioma and thymic cancers. 1. Exploiting mesothelin for cancer therapy with a focus on mesothelioma and lung cancer. Our current studies are focused on using immunotherapy directed against the tumor differentiation antigen mesothelin, which is expressed on normal mesothelial cells lining the pleura, pericardium and peritoneum but 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 immunotoxins (SS1P and RG7787), an anti-mesothelin drug conjugate (BAY 94-9343) and a mesothelin vaccine (CRS-207). 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. We have recently shown major and durable tumor regressions in treatment refractory mesothelioma patients using the anti-mesothelin immunotoxin SS1P combined with pentostatin plus cyclophosphamide and are now doing a phase II clinical trial in patients with pleural and peritoneal mesothelioma. A newer de-immunized immunotoxin, RG7787 has just entered the clinic for treatment of patients with mesothelin expressing cancers that have failed standard therapies. 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. 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 for mesothelioma. Other ongoing laboratory studies are focused on understanding the mesothelioma tumor immune micro-environmnet and changes following treatment with anti-mesothelin targeted agents. 2. Immunotherapy to treat lung cancer and thymic cancers. Thymic Cancers: Thymoma is a rare tumor characterized by infiltration of lymphocytes making them uniquely suitable for immune-checkpoint inhibition.Thymoma patients are currently being treated on a phase I clinical trial of the anti-PD-L1 monoclonal antibody MSB0010718C. We have seen remarkable anti-tumor activity in these patients that has been accompanied by side-effect profile unique to thymoma patients. In addition, we are conducting a Phase II study of sunitinib in thymic carcinomas. Lung Cancer: We are currently conducting clinical trial of the anti-PD-L1 monoclonal antibody MSB0010718C in patients with lung adenocarcinoma who have failed prior therapies. Our laboratory has recently shown that about 25% of patients with metastatic lung adenocarcinoma highly express mesothelin. Mesothelin expression in these tumors is highly associated with KRAS mutations and wild type EGFR status and is, independently, associated with poor prognosis. Our hypothesis is that patients with K-RAS mutant lung cancer can benefit from mesothelin directed therapies. Clinical trials of mesothelin directed therapies for treating lung cancer are about to open. Our laboratory is also studying the role of immune checkpoints in malignant mesothelioma so that drugs targeting this pathway can be exploited for treating mesothelioma.

我们计划的总体目标是为胸癌患者开发更有效的治疗方法。这项工作主要分为两大类：1.开发间皮脂素用于癌症治疗。2.免疫疗法和其他治疗肺癌、间皮瘤和胸腺癌的方法。1.开发间皮素用于癌症治疗，重点是间皮瘤和肺癌。我们目前的研究主要集中在针对肿瘤分化抗原间皮蛋白的免疫治疗，它在胸膜、心包和腹膜衬里的正常间皮细胞上表达，但在一些人类肿瘤中高表达，特别是间皮瘤、卵巢癌、肺癌和胰腺癌。这种不同的表达使其成为肿瘤特异性治疗的候选药物。我们的努力现在集中在使用不同的方法将其用于间皮瘤治疗。其中包括嵌合的抗间皮蛋白单抗(MORAb-009)、抗间皮脂蛋白免疫毒素(SS1P和RG7787)、抗间皮脂蛋白药物结合物(BAY 94-9343)和间硫蛋白疫苗(CRS-207)。SS1P是一种重组免疫毒素，由抗间皮细胞毒素Fv与强效细菌毒素假单胞菌外毒素A的截短型连接而成。我们先前已在I期临床试验中确定了SS1P的安全性和最大耐受量(MTD)。我们的实验室研究表明SS1P与化疗具有协同作用，这使得我们对SS1P联合培美曲塞和顺铂治疗胸膜间皮瘤的化疗方案进行了临床试验。这项研究的结果显示，在接受最大耐受量(MTD)治疗的13名可评估患者中，有8人有部分反应，有非常高的应答率。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，大多数患者对其产生中和抗体，将治疗限制在1至2个周期。我的实验室与Pastan小组和NCI的Dan Fowler博士合作，已经证明了五肽抑素联合环磷酰胺治疗可以消除免疫能力强的小鼠对SS1P的免疫反应。我们最近发现，在使用抗间皮质素免疫毒素SS1P联合五肽抑素和环磷酰胺治疗难治性间皮瘤患者时，肿瘤有显著和持久的消退，目前正在对胸膜和腹膜间皮瘤患者进行II期临床试验。RG7787是一种较新的去免疫免疫毒素，刚刚进入临床，用于治疗标准治疗失败的间硫蛋白表达癌症患者。我们还在进行一项I期临床试验，以确定抗间皮蛋白抗体药物结合物Bay 94-9343的安全性和MTD，该药物由人源化抗间皮蛋白单抗连接到Maytansinid dm4组成。在实验室中，我们一直致力于开发人间皮瘤的体外和体内模型。我们已经建立并鉴定了从间皮瘤患者的腹水和胸水中获得的几种早期传代肿瘤细胞。我们已经对这些细胞的形态和分子特征进行了充分的表征。这些模型对于评估间皮瘤的新型治疗药物是必不可少的。其他正在进行的实验室研究侧重于了解间皮瘤的肿瘤免疫微环境以及抗间皮素靶向药物治疗后的变化。2.治疗肺癌和胸腺癌的免疫疗法。胸腺癌：胸腺瘤是一种罕见的肿瘤，其特征是淋巴细胞的渗透，使其特别适合于免疫检查点抑制。胸腺瘤患者目前正在接受抗PD-L1单抗MSB0010718C的I期临床试验。我们已经在这些患者中看到了显著的抗肿瘤活性，并伴随着胸腺瘤患者特有的副作用。此外，我们正在进行一项关于舒尼替尼治疗胸腺癌的II期研究。肺癌：我们目前正在对先前治疗失败的肺腺癌患者进行抗PD-L1单抗MSB0010718C的临床试验。我们的实验室最近发现，大约25%的转移性肺腺癌患者高表达间硫蛋白。在这些肿瘤中，间鞘蛋白的表达与KRAS突变和野生型EGFR状态高度相关，并且独立地与不良预后相关。我们的假设是，K-RAS突变肺癌患者可以受益于间充质素类药物的治疗。间充质素类药物治疗肺癌的临床试验即将开始。我们的实验室还在研究免疫检查点在恶性间皮瘤中的作用，以便开发针对这一途径的药物来治疗间皮瘤。