title: Efficacy of Anti-mesothelin Immunotoxin RG7787 plus Nab-Paclitaxel against Mesothelioma Patient-Derived Xenografts and Mesothelin as a Biomarker of Tumor Response.
abstract: Purpose:The purpose of this study was to evaluate the antitumor efficacy of the reduced immunogenicity anti-mesothelin immunotoxin RG7787 plus nab-paclitaxel against primary mesothelioma cell lines and tumor xenografts and the utility of mesothelin as a biomarker of tumor response.Experimental Design:Early-passage human malignant mesothelioma cell lines NCI-Meso16, NCI-Meso19, NCI-Meso21, and NCI-Meso29 were evaluated for sensitivity to RG7787 or nab-paclitaxel alone or in combination. In addition, the antitumor activity of RG7787 plus nab-paclitaxel was evaluated using NCI-Meso16, NCI-Meso21, and NCI-Meso29 tumor xenografts in immunodeficient mice. Serum mesothelin was measured at different time points to determine whether its levels correlated with tumor response.Results:All four primary mesothelioma cell lines highly expressed mesothelin with 41 × 103to 346 × 103mesothelin sites per cell and were sensitive to RG7787, with IC50ranging from 0.3 to 10 ng/mL. Except for NCI-Meso19, these cells were also sensitive to nab-paclitaxel, with IC50of 10 to 25 ng/mL.In vitro, RG7787 plus nab-paclitaxel led to decreased cell viability compared with either agent alone. In NCI-Meso16 tumor xenografts, treatment with RG7787 plus nab-paclitaxel led to sustained complete tumor regressions. Similar antitumor efficacy was observed against NCI-Meso21 and NCI-Meso29 tumor xenografts. In all three tumor xenograft models, changes in human serum mesothelin correlated with response to therapy and were undetectable in mice with complete tumor regression with RG7787 and nab-paclitaxel.Conclusions:RG7787 plus nab-paclitaxel is very active against primary human mesothelioma cellsin vitroas well asin vivo, with serum mesothelin levels correlating with tumor response. These results indicate that this combination could be useful for treating patients with mesothelioma.Clin Cancer Res; 23(6); 1564-74. ©2016 AACR.
authors.affiliation: Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.
authors.forename: Jingli
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.
authors.forename: Swati
authors.initials: S
authors.lastname: Khanna
authors.affiliation: Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.
authors.forename: Qun
authors.initials: Q
authors.lastname: Jiang
authors.affiliation: Laboratory of Molecular Biology, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.
authors.forename: Christine
authors.initials: C
authors.lastname: Alewine
authors.affiliation: Laboratory of Pathology, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.
authors.forename: Markku
authors.initials: M
authors.lastname: Miettinen
authors.affiliation: Laboratory of Molecular Biology, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.
authors.forename: Ira
authors.initials: I
authors.lastname: Pastan
authors.affiliation: Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland. hassanr@mail.nih.gov.
authors.forename: Raffit
authors.initials: R
authors.lastname: Hassan
mesh_terms: D000418:Albumins / Q000008:administration & dosage*; D000818:Animals; D014408:Biomarkers, Tumor / Q000097:blood; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D058851:GPI-Linked Proteins / Q000037:antagonists & inhibitors / Q000097:blood*; D006801:Humans; D018796:Immunoconjugates / Q000008:administration & dosage*; D000922:Immunotoxins / Q000008:administration & dosage; D000090204:Mesothelin; D008654:Mesothelioma / Q000097:blood / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D051379:Mice; D017239:Paclitaxel / Q000008:administration & dosage*; D023041:Xenograft Model Antitumor Assays
chemical_list: C520255:130-nm albumin-bound paclitaxel; D000418:Albumins; D014408:Biomarkers, Tumor; D058851:GPI-Linked Proteins; D018796:Immunoconjugates; D000922:Immunotoxins; C000715528:Msln protein, mouse; C000597116:LMB-100; D000090204:Mesothelin; D017239:Paclitaxel