4sc-202 Induces Inflamed Tumor Microenvironment, Strongly Enhances Tumor Infiltration With Cytotoxic T Cells And Primes Tumors For Anti-Pd-1/Pd-L1 Therapy

Various HDAC inhibitors were described as beneficially affecting anti-tumoral immune response. Although different HDAC inhibitors were investigated in syngeneic tumor models, the mode of anti-tumoral action is not yet fully understood. Here, we analyzed the anti-tumoral mode-of-action (MOA) of 4SC-202, an orally available clinical stage epigenetic small molecule inhibitor specifically targeting histone deacetylases HDAC class I as well as the lysine-specific demethylase LSD1. To ensure that the conclusions would be relevant for the clinical situation we used a clinically equivalent dose and schedule. Anti-tumoral efficacy and the impact of 4SC-202 alone or in combination with an anti-PD-L1 antibody on the tumor microenvironment were analyzed in the syngeneic colorectal CT26 model in immunocompetent BALB/c or in nude/irradiated BALB/c mice. A broad spectrum HDAC inhibitor was used for comparison. Transcriptome analysis was performed by RNA-Seq, and the composition of immune cell subpopulations in the tumor was determined by flow cytometry. 4SC-202 treatment at clinically relevant dosage regimen significantly inhibited growth of CT26 tumors. A competent immune system was apparently necessary for the anti-tumoral effect of 4SC-202 since its tumor-reducing effect was lost in immunocompromised mice. 4SC-202 treatment led to an increase of MHC class II molecules and enhanced expression of inflammatory markers like IFN-γ and various chemokines in the tumors. Detailed analysis of the tumor microenvironment revealed that 4SC-202 strongly increased the number of tumoricidal cytotoxic T cells (CTL). In contrast, a broad-spectrum HDAC inhibitor tested in the same model demonstrated anti-tumoral efficacy but did not affect the number of CTLs in tumors demonstrating that HDAC inhibitors employ different MOAs for their anti-tumoral response and that the effect on CTLs is not attributed to HDAC inhibition in general. Since the T cell abundance is pre-requisite for the efficacy of PD1/PD-L1 blockade, we tested the combination of clinically relevant dosage regiment of 4SC-202 with an anti-PD-L1 antibody. The combined treatment was more efficacious than monotherapies and resulted in significantly longer survival. 4SC-202 already demonstrated a favorable safety profile in a phase I clinical trial with relapsed or refractory hematological malignancies with two objective responses (1 CR, 1 PR) and disease stabilizations in several patients. 4SC-202’s immune priming capacity offers further options for clinical development of 4SC-202 in combination with various cancer immunotherapy approaches. Citation Format: Tanja Wulff, Kerstin Kronthaler, Sabine Schrepfer, Ulrike Parnitzke, Anne Catherine Bretz, Roland Baumgartner, Svetlana Hamm. 4SC-202 induces inflamed tumor microenvironment, strongly enhances tumor infiltration with cytotoxic T cells and primes tumors for anti-PD1/PD-L1 therapy [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 2632. doi:10.1158/1538-7445.AM2017-2632