1189P - 4SC-202 plus Anti-PD1: Breaking PD1-refractoriness to increase efficacy of checkpoint inhibition in patients with advanced melanoma

Date 10 September 2017
Event ESMO 2017 Congress
Session Poster display session
Topics Cancer in Adolescents
Cancer Immunology and Immunotherapy
Melanoma and other Skin Tumours
Presenter Frank Hermann
Citation Annals of Oncology (2017) 28 (suppl_5): v403-v427. 10.1093/annonc/mdx376
Authors F. Hermann
  • Clinical Development, 4SC AG, 82152 - Planegg-Martinsried/DE

Abstract

Background

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.

Methods

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.

Results

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).

Conclusions

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

Not available.

Legal entity responsible for the study

4SC AG

Funding

4SC AG

Disclosure

F. Hermann: Employee of 4SC AG, Planegg-Martinsried, Germany.