RG7787 for Mesothelioma Therapy

Purpose: Evaluate anti-tumor efficacy of the reduced immunogenicity anti-mesothelin immunotoxin RG7787 plus nab-Paclitaxel against primary mesothelioma cell lines and tumor xenografts and 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 anti-tumor 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 if its levels correlated with tumor response. Results: All four primary mesothelioma cell lines highly expressed mesothelin with 41x103 to 346x103 mesothelin sites/cell and were sensitive to RG7787 with IC50 ranging from 0.3 to 10 ng/ml. Except for NCI-M-19, 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 to either agent alone. In NCI-Meso16 tumor xenografts, treatment with RG7787 plus nab-paclitaxel led to sustained complete tumor regressions. Similar anti-tumor 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.

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