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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC010816-05
Application #
8349180
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2011
Total Cost
$798,901
Indirect Cost
Name
National Cancer Institute Division of 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
Alewine, Christine; Hassan, Raffit; Pastan, Ira (2015) Advances in anticancer immunotoxin therapy. Oncologist 20:176-85
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
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
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
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
Hassan, Raffit; Sharon, Elad; Thomas, Anish et al. (2014) Phase 1 study of the antimesothelin immunotoxin SS1P in combination with pemetrexed and cisplatin for front-line therapy of pleural mesothelioma and correlation of tumor response with serum mesothelin, megakaryocyte potentiating factor, and cancer antigen Cancer 120:3311-9
Pastan, Ira; Hassan, Raffit (2014) Discovery of mesothelin and exploiting it as a target for immunotherapy. Cancer Res 74:2907-12
Zhang, Jingli; Bera, Tapan K; Liu, Wenhai et al. (2014) Megakaryocytic potentiating factor and mature mesothelin stimulate the growth of a lung cancer cell line in the peritoneal cavity of mice. PLoS One 9:e104388

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