Novel epigenetic targets Educational session

9IN - HDAC inhibitors and check point inhibitors

Presentation Number
9IN
Lecture Time
12:15 - 12:35
Speakers
  • René Bartz (Planegg, DE)
Location
Room Scene AB, Paris Marriott Rive Gauche, Paris, France
Date
05.03.2018
Time
11:05 - 12:45
Authors
  • René Bartz (Planegg, DE)

Abstract

Background

Despite successes in the treatment of melanoma patients with checkpoint inhibitors (CI), most 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 a more immune-deserted to an immune-inflamed phenotype by means of 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 and C38 syngenic models) were treated with 4SC-202, an orally available clinical stage combined HDAC class I/LSD1 inhibitor, or CIs PD-(L)-1 alone as well as 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. Furthermore, detailed analysis of the tumor revealed that 4SC-202 strongly altered the immune cell composition and 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).

Clinical trial identification

ClinicalTrials.gov Identifier:
NCT03278665

Conclusions

NCT03278665

Clinical trial identification

NCT03278665

Legal entity responsible for the study

4SC AG

Funding

Has not received any funding

Disclosure

R. Bartz: I do not conduct activities that would involve a conflict of interest with CME-accreditable training, but that in the past 2 (two) years I have been a paid employee of 4SC AG.

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