Abstract 4906: The selective class I HDAC inhibitor entinostat enhances the antitumor effect of PD-1 inhibition in a syngeneic orthotopic murine model of renal cell carcinoma

2016 
Background: Recent advances in immunotherapy have highlighted the antitumor effects of immune checkpoint inhibition. Novel anti-PD-1/PD-L1 immunotherapies have been shown to effectively overcome tumor avoidance of immune surveillance in several tumor types including renal cell carcinoma. Our group has recently shown that the selective class I HDAC inhibitor entinostat is effective in suppressing regulatory T cells and enhancing immunotherapies in murine renal and prostate models, RENCA and Myc-Cap respectively. In this study we have evaluated the combination of entinostat with an anti-PD-1 antibody in the RENCA renal cell carcinoma model. Methods: 32 BALB/c female mice were implanted with the syngenic, orthotopic, renal cell carcinoma mouse model, RENCA - luciferase tagged - at day -8. Treatment (8 mice /group) with anti-mouse-PD-1 (aPD-1; 10mg/kg twice a week, I.P.), entinostat (5mg/kg 5 days a week), or combination of the two was begun at day 1. Bioluminescence imaging was performed at days -1, 9 and 19 to assess the orthotopic tumor growth. End point tumor weights were taken to assess the effect of combination treatment. Results: Analysis of tumor growth showed a reduction of bioluminescence across the three time points in the combination group as compared to the vehicle and single agent treatments. Additionally, end point analysis of tumor weights revealed an overall reduction in the size of the tumors in the entinostat/anti-mPD-1 combination group (88% inhibition) as compared to the vehicle (p = 0.0002), aPD-1 alone (25% inhibition)(p = 0.0181), and entinostat alone (63% inhibition)(p = 0.0481) groups. Examination of the status of the infiltrating immune cells of the tumor microenvironment via flow cytometry, qRT-PCR, immunohistochemistry, and/or immunofluorescence analysis is ongoing. Conclusions: Our preliminary results suggest that the immunomodulatory activity of the selective class I HDAC inhibitor entinostat may enhance the antitumor effect of PD-1/PD-L1 inhibition and provide the rationale for the clinical testing of this novel combination in patients with RCC. Citation Format: Ashley R. Orillion, Li Shen, Remi Adelaiye-Ogala, May Elbanna, Sreenivasulu Chintala, Sreevani Arisa, Roberto Pili. The selective class I HDAC inhibitor entinostat enhances the antitumor effect of PD-1 inhibition in a syngeneic orthotopic murine model of renal cell carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4906.
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