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 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. 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. 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 15 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. Out of the 11 evaluable patients treated on this study 5 had partial response and 2 stable disease. We have also shown that changes in serum mesothelin levels in patients treated with SS1P and chemotherapy correlate with radiological responses and may be a useful test to follow patients. 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 has 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 in January 2009 with NCI as the lead site for this study. Seventy three patients have thus far been treated on this study worldwide including 4 patients at NCI. Preliminary data regarding the efficacy of MORAb-009 in mesothelioma are expected to be available latter this year. 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. 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. 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. We have just opened 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 enrolled 5 patients.