Abstract 4976: Ricolinostat, a selective HDAC6 inhibitor with immunomodulatory properties, has significant antimelanoma activity in vitro and in vivo
Authors: Cheng Fengdong , Andressa Sodre , Chen Jie , Villagra Alejandro , Woods David , Weber Jeffrey , Quayle Steven , Simon Jones , Sotomayor Eduardo 
Published: July 2017

Melanoma is a less common but the most aggressive type of skin cancer and the rates of melanoma have been rising for the last 30 years. Immunotherapy may represent a new treatment paradigm to benefit melanoma patients. Previous studies have identified HDAC6 playing a central role in the regulating melanoma immunogenicity. We have shown that genetic knockdown (KD) of HDAC6 in murine and human melanoma cells resulted in an increased the expression of MHCI and costimulatory molecules as well as melanoma associated antigens. In vivo studies demonstrated that the growth of melanoma cells lacking HDAC6 was significantly delayed as compared to wild-type cells. This growth was further delayed when HDAC6KD melanoma bearing mice were treated with anti-PD-1 antibodies.

Recently, we have shown that in vitro treatment of murine melanoma cells with Ricolinostat decreases PD-L1 expression and increases the expression of acetyl tubulin. Surprisingly, in vivo treatment of B16 melanoma bearing animals with increasing concentrations of ricolinostat resulted in a dose-dependent inhibition of melanoma growth (p&lt;0.05). No toxicities were observed at the doses studied; however, the antitumor effect exerted by ricolinostat was not observed when melanoma bearing SCID mice were treated with this compound, indicating that an intact host immune system is required for the observed antitumor activity. In lieu of these previously unknown immunomodulatory properties of ricolinostat, we next assessed the effects of this compound upon T-cells and whether ricolinostat could augment the efficacy of checkpoint blockade in vivo. Murine T-cells were activated with anti-CD3 plus anti-CD28 in the presence or absence of ricolinostat. Then, those T-cells were adoptively transferred into B16 melanoma bearing mice. T-cell subpopulations from the lymph nodes were analyzed ex vivo. We show here that treatment of murine T-cells with ricolinostat resulted in a significant increase in central memory T-cells endowed with a strong anti-melanoma activity in vivo as compared to control group (p&lt;0.05). Finally, the addition of ricolinostat treatment to either anti-CTLA4 or anti-PD1 treatment was associated with an enhanced inhibition of melanoma tumor growth.

In summary, our results have identified HDAC6 as a novel target for melanoma immunotherapy and point out ricolinostat as an attractive agent to add to the immuno-oncology armamentarium.

Citation Format: Fengdong Cheng, Sodre Andressa, Jie Chen, Alejandro Villagra, David Woods, Jeffrey Weber, Steven Quayle, Jones Simon, Eduardo Sotomayor. Ricolinostat, a selective HDAC6 inhibitor with immunomodulatory properties, has significant antimelanoma activity in vitro and in vivo [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 4976. doi:10.1158/1538-7445.AM2017-4976