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 × 103 to 346 × 103 mesothelin sites per cell and were sensitive to RG7787, with IC50 ranging from 0.3 to 10 ng/mL. Except for NCI-Meso19, these cells were also sensitive to nab-paclitaxel, with IC50 of 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 cells in vitro as well as in 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: Jingli Zhang, Swati Khanna, Qun Jiang, Christine Alewine, Markku Miettinen, Ira Pastan, Raffit Hassan
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 23 Issue 6 Pg. 1564-1574 (Mar 15 2017) ISSN: 1557-3265 [Electronic] United States
• PMID: 27635089 (Publication Type: Journal Article)
• Copyright: ©2016 American Association for Cancer Research.

Chemical References

• 130-nm albumin-bound paclitaxel
• Albumins
• Biomarkers, Tumor
• GPI-Linked Proteins
• Immunoconjugates
• Immunotoxins
• Msln protein, mouse
• LMB-100
• Mesothelin
• Paclitaxel

Topics

• Albumins (administration & dosage)
• Animals
• Biomarkers, Tumor (blood)
• Cell Line, Tumor
• Cell Survival (drug effects)
• GPI-Linked Proteins (antagonists & inhibitors, blood)
• Humans
• Immunoconjugates (administration & dosage)
• Immunotoxins (administration & dosage)
• Mesothelin
• Mesothelioma (blood, drug therapy, immunology, pathology)
• Mice
• Paclitaxel (administration & dosage)
• Xenograft Model Antitumor Assays