Clinical development of 4SC-202, a combined epigenetic inhibitor of HDAC class I and LSD1, to overcome anti-PD-1 refractoriness and increase efficacy of checkpoint inhibition.

Abstract

e14096 Background: Checkpoint inhibitor (CI) like anti-PD(L)-1 antibodies are a breakthrough innovation, but a high unmet medical need remains for a large proportion of patients not responding. Low mutational load, microsatellite stability and a non-inflamed tumor microenvironment have been described as negative predictive factors. A promising approach to increase the benefit from anti-PD(L)-1 treatment is to alter the tumor microenvironment to a more immune-inflamed phenotype by combination assets. Epigenetic modulation has been reported as one key determining factor in shaping the immune microenvironment and compounds altering these processes, like histone deacetylases (HDAC) inhibitor in particular offer a promising approach. Methods: We report preclinical results from the small molecule compound 4SC-202, an orally available clinical stage epigenetic inhibitor, specifically targeting HDAC class I and lysine-specific demethylase LSD1. Results: 4SC-202 has shown the ability to elicit a variety of immune modulating effects on tumors and their microenvironment by enhancing the expression of tumor associated antigens as well as MHC and co-stimulatory molecules. Combination treatment of 4SC-202 with CI in syngenic mouse models showed a strong synergistic effect leading to enhanced tumor reduction when compared to 4SC-202 or checkpoint inhibitor treatment alone. Importantly, 4SC-202 strongly increased the number of tumoricidal cytotoxic T cells (CTL) without affecting the viability of activated T cells. Conclusions: Anti-PD(L)-1 refractory/non-responding patients remain a population with a high unmet medical need, increasing in number over time. Advanced melanoma is the model tumor for immunotherapy in general and CI in particular. Based on the strong preclinical rationale, we hypothesize that the addition of 4SC-202 to anti-PD-1 treatment may lead to increased immunogenicity of the tumor, an inflamed tumor microenvironment and subsequent clinical benefit in anti-PD-1 refractory/non-responding melanoma patients. The “SENSITIZE” study is intended to proof this concept in a phase Ib/II clinical trial.