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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC010816-10
Application #
9343710
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
10
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
Zhang, Jingli; Khanna, Swati; Jiang, Qun et al. (2017) Efficacy of Anti-mesothelin Immunotoxin RG7787 plus Nab-Paclitaxel against Mesothelioma Patient-Derived Xenografts and Mesothelin as a Biomarker of Tumor Response. Clin Cancer Res 23:1564-1574
Khanna, Swati; Thomas, Anish; Abate-Daga, Daniel et al. (2016) Malignant Mesothelioma Effusions Are Infiltrated by CD3+T Cells Highly Expressing PD-L1 and the PD-L1+Tumor Cells within These Effusions Are Susceptible to ADCC by the Anti-PD-L1 Antibody Avelumab. J Thorac Oncol 11:1993-2005
Zhang, Yi-Fan; Phung, Yen; Gao, Wei et al. (2015) New high affinity monoclonal antibodies recognize non-overlapping epitopes on mesothelin for monitoring and treating mesothelioma. Sci Rep 5:9928
Thomas, Anish; Chen, Yuanbin; Steinberg, Seth M et al. (2015) High mesothelin expression in advanced lung adenocarcinoma is associated with KRAS mutations and a poor prognosis. Oncotarget 6:11694-703
Alewine, Christine; Hassan, Raffit; Pastan, Ira (2015) Advances in anticancer immunotoxin therapy. Oncologist 20:176-85
Kalra, Neetu; Zhang, Jingli; Thomas, Anish et al. (2015) Mesothelioma patient derived tumor xenografts with defined BAP1 mutations that mimic the molecular characteristics of human malignant mesothelioma. BMC Cancer 15:376
Lindenberg, Liza; Thomas, Anish; Adler, Stephen et al. (2015) Safety and biodistribution of 111In-amatuximab in patients with mesothelin expressing cancers using single photon emission computed tomography-computed tomography (SPECT-CT) imaging. Oncotarget 6:4496-504
Keenan, Bridget P; Saenger, Yvonne; Kafrouni, Michel I et al. (2014) A Listeria vaccine and depletion of T-regulatory cells activate immunity against early stage pancreatic intraepithelial neoplasms and prolong survival of mice. Gastroenterology 146:1784-94.e6
Miller, Andrew C; Miettinen, Markku; Schrump, David S et al. (2014) Malignant mesothelioma and central nervous system metastases. Report of two cases, pooled analysis, and systematic review. Ann Am Thorac Soc 11:1075-81
Pastan, Ira; Hassan, Raffit (2014) Discovery of mesothelin and exploiting it as a target for immunotherapy. Cancer Res 74:2907-12

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