Despite successes in the treatment of melanoma patients with checkpoint inhibitors (CI), majority of patients do not respond to CI alone and a high unmet medical need remains for these patients. One promising approach is to enhance the immunogenicity and alter the tumor microenvironment from an immune-deserted to an inflamed phenotype with combination therapy. Epigenetic modulation has been reported as one key determining factor in shaping the immune microenvironment and compounds altering these processes (e.g. histone deacetylases (HDAC) inhibitors) are particularly promising.
Tumor bearing animals (CT26 & C38 syngenic models) were treated with 4SC-202, an oral clinical stage combined HDAC class I/LSD1 inhibitor, or CIs PD-(L)-1 alone and in combination. Tumor growth was assessed continuously and after approx. 2 weeks of treatment tumors were excised and analyzed by flow cytometry and gene expression profiling. Additionally, animals not intended for these analyses were further monitored and tumor growth/survival was monitored.
4SC-202 treatment led to an increase of MHC molecules and enhanced expression of inflammatory markers like IFN-γ and various chemokines in tumors. Detailed analysis of the tumors revealed that 4SC-202 strongly altered the immune cell composition; particularly the number of cytotoxic T cells (CTL) was markedly increased. Importantly, subsequent combination treatment of 4SC-202 with CIs in syngenic animal models showed a strong synergistic effect resulting in significant longer survival in both models leading to 55% of tumor free animals (C38 model).
In an upcoming study, patients with advanced melanoma who are refractory/non-responding to anti-PD-1 antibodies will be treated with 4SC-202 plus anti-PD1. These patients do not only represent a population with a high unmet medical need but melanoma also represents a model tumor for immunotherapy in general and CI in particular. We hypothesize that addition of 4SC-202 to anti-PD-1 antibody treatment may lead to increased immunogenicity of the tumor, an inflamed tumor microenvironment and ultimately to clinical benefit in anti-PD-1 refractory/non-responding advanced-stage melanoma patients.
Clinical trial identification
Legal entity responsible for the study
F. Hermann: Employee of 4SC AG, Planegg-Martinsried, Germany.