Abstract
11546 Background: 4SC-202 is an orally available, small molecule clinical stage epigenetic modulator. Epigenetic modifiers are known to bear the potency to enhance response rates of checkpoint inhibitors and broaden the number of indications by combination treatment. Methods: 4SC-202 was tested in cellular assays and in a syngenic mouse model to investigate its capacity for immune modulation and combination treatment with checkpoint inhibitors. Results: Preclinical data demonstrate that 4SC-202 has immune priming potency by up-regulation of i) tumor associated antigens, ii) ligands for NK cell recognition, iii) MHC and costimulatory molecules, and iv) down-regulation of immunosuppression via the suppression of IDO and arginase in tumor cells as well as in myeloid-derived suppressor cells. In contrast to Entinostat and SAHA, 4SC-202 is not toxic for immune cells. By sparing the immune cells and enhancing the immunogenicity of tumor cells, 4SC-202 enables the immune system to attack tumor cells and provides a rationale for the combination with checkpoint inhibitors. To translate these effects from in vitro to in vivo, 4SC-202 was tested in a syngenic colon carcinoma CT26 mouse model in monotherapy and in combination with anti-PD1 antibody. 4SC-202 inhibited the growth of CT26 tumors at clinically relevant doses and therefore confirmed the relevance of the immunomodulating capacity of 4SC-202 for the anti-tumoral effect. The combination treatment with anti-PD1 antibody demonstrated that 4SC-202 is able to sensitize tumors for treatment with checkpoint inhibitors in indications where checkpoint inhibitors alone are not active. Conclusions: As demonstrated in a phase I clinical trial in 24 patients with relapsed or refractory hematological malignancies, 4SC-202 was well tolerated and objective responses (1 CR, 1 PR) and disease stabilizations were observed in several patients. 4SC-202 is an ideal combination partner for checkpoint inhibitors due to its immune priming capacity, the excellent safety profile and the oral formulation which allows convenient application and flexible dosing schedules.
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