Abstract 1059: Enhanced anti-tumor efficacy of a checkpoint inhibitor in combination with the HDAC inhibitor belinostat in a murine hepato-cellular carcinoma preclinical model

Abstract

Abstract Introduction Belinostat is an HDAC inhibitor currently marketed in the US for the treatment of PTCL. A new oral formulation is under development (positive PoC in preclinical PK study) and provides an increase potential to develop new indications of belinostat in combination with other drugs. It has been extensively demonstrated that some anti-tumor agents, besides their direct anti-tumor effect, may induce additional mechanisms involving activation of immune responses. Thus, combination of these drugs with other immunotherapeutic protocols may yield improved therapeutic benefits. The objective of the present study is the characterization of the therapeutic efficacy of a combination of checkpoint inhibitors (anti-CTLA-4 antibodies) with belinostat in a murine HCC model. In addition, immunoprofiling was performed in order to assess the associated immune response. Methods In vivo efficacy was performed in a Hepa 129 murine hepatocellular carcinoma model implanted subcutaneously in immune-competent C3H mice using anti-CTLA4 alone, belinostat alone or in combination. Treatments were optimized to be able to demonstrate positive effect of the combination. Tumor volume was the primary endpoint. Samples from the spleen were taken to analyze immune mechanism mediating the antitumor activity. Percent of CD4, CD8 T cells and regulatory T cells were determined by flow cytometry. Anti-tumor T cell response was measured by IFN-gamma ELISPOT assay. Results Belinostat improved anti-tumor therapeutic response induced by the anti-CTLA4 checkpoint inhibitor with a significant superior tumor growth inhibition compared to control groups. Treatment with the combination resulted in a complete cessation in tumor growth in all mice during the belinostat treatment period which continued for 1 week after the final dose. Mechanistic studies showed that the underlying immune response correlated with the observed therapeutic effect of the combination with enhancement of IFN-gamma production as antitumor T cell response and decrease in regulatory T cells in the spleens of treated animals. Conclusion These results provide a rational for using belinostat in combination with checkpoint inhibitors to reinforce therapeutic response. Currently only approx. 20% of patients respond to check point inhibitors alone. The oral formulation of belinostat will allow greater flexibility in dosing schedule and use in multiple clinical situations. Further studies are ongoing in order to fully characterize this finding and to facilitate its translation into patients. Citation Format: Diana Llopiz, Marta Ruiz, Perrine Pivette, Véronique Trochon-Joseph, Bérangère Vasseur, Caroline Lemarchand, Graham Dixon, Pablo Sarobe, Bruno Sangro. Enhanced anti-tumor efficacy of a checkpoint inhibitor in combination with the HDAC inhibitor belinostat in a murine hepato-cellular carcinoma preclinical model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1059. doi:10.1158/1538-7445.AM2017-1059