5,6 Pleural mesothelioma is most common, but mesothelioma can also occur in the peritoneum and pericardium. In the United States, th e majority of mesotheliomas occur in men (approximately 80%). These are most often of pleural origin, and 90% or more of these tumors are caused by asbestos.6-8 1.1.1 Current Therapies for Malignant Mesothelioma The best -documented, potentially curative approach to malignant pleural mesothelioma (MPM) has been extrapleural pneumonectomy, followed by chemotherapy and radiothe rapy in selected patients with earlier stages of disease, 6,9 but the majority of patients present with advanced disease and are not candidates for surgical resection. For patients whose disease is unresectable or who otherwise are not candidates for curative surgery, pemetrexed in combination with cisplatin is the standard of care. In a randomized Phase 3 clinical trial treatment with pemetrexed and cisplatin led to an improvement in overall survival of 12.7 months compared to 9.3 months with cisplatin alone. The objective response rate was 41% . 10,11 It is clear that new therapies are needed, and immunotherapy offers the promise of improving outcomes in these patients by developing specific immune responses against tumor antigens. In support of this notion, the presence of high levels of CD8+ tumor -infiltrating ly mphocytes is associated in better prognosis in patients undergoing extrapleural pneumonectomy for MPM . 12 1.1.2 Mesothelin Mesothelin is a cell surface tumor differentiation antigen present on normal mesothelial cells that is highly expressed in many human tumors including virtually all mesothelioma and pancreatic cancers, 55% to 71% of ovarian cancers and 41% to 55% of lung adenocarcinomas . 13-19 The limited distribution of mesothelin in normal human tissues and high expression in many cancers makes it an attractive candidate for antibody -targeted immunotherapy and clinical trials of anti-mesothelin antibodies are currently ongoing . 20,21 Studies by Dr. Raffit Hassan, the Principal Investigator of the proposed trial, and his colleagues as well Aduro Biotech , Inc. Protocol ADU -CL-02-v8 CRS -207 with Pemetrexed and Cisplatin Version 8, 08 March 2018 Page 2 as other groups have shown mesothelin to be also an attractive antigen for active cancer immunotherapy. Dr. Hassan and colleagues have previously shown that a mesothelin -specific IgG antibody response is present in 39% and 42% of patients with mesothelioma and ovarian cancer respectively, suggesting that immune tolerance to mesothelin can be overcome . 22 In addition, studies by Dr. Elizabeth Jaffee and colleagues have demonstrated that in patients with pancreatic carcinoma, positive clinical outcomes following vaccination with an irradiated allogeneic whole cell vaccine encoding granulocyte/macrophage-colony stimulating factor ( GM-CSF; GVAX) correlated with induction of mesothelin - specific cellular immunity . 23,24 In a Phase 1 study, a vaccine with two allogeneic, GM-CSF-secreting pancreatic cell lines induced a dose-dependent delayed type hypersensitivity ( DTH ) response and CD8+ T cell response to multiple human leukocyte antigen ( HLA )-A2, - A3, and –A24 restricted mesothelin epitopes exclusively in 3 of 14 patients. Patients with DTH and CD8+ T cell responses had increased disease -free survival, remaining disease- free at least 25 months after diagnosis. Additionally, Dr.