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4SC AG Discuss "Epigenetic Regulation of Immunogenicity" at 10th Scientific Symposium

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4SC AG hosted its 10th Scientific Symposium on Wednesday, 30 September 2015. Joining the event were more than 50 distinguished participants from the international scientific, clinical and industry community involved in the development of novel cancer treatment modalities. The Symposium, held at 4SC's site in Martinsried/Munich, discussed recent advances in epigenetic drug discovery and the clinical impact of epigenetic and immune therapeutic approaches on personalized medicine.

Epigenetic alterations as well as tumour immunity represent key mechanisms in the development of cancer and are therefore considered relevant therapeutic targets. The challenge of treating, and ultimately curing, cancer and as well as the potential of combining immunotherapy with epigenetic approaches was highlighted by Prof. Andreas Mackensen, Director at the Department of Haematology & Internal Oncology at the Erlangen University Hospital, who chaired the conference and paved the way for three scientific talks around epigenetic alterations, their role in health and disease and as modulators of tumour immunity.

Prof. Thomas Jenuwein, keynote lecturer from the Max Planck Institute of Immunobiology & Epigenetics in Freiburg and the first scientist to identify a histone methylating enzyme, opened the event by highlighting that epigenetic malfunction is key to the development of cancer, as it significantly influences the timing and aggressiveness of the disease. For example, an aberrant chromatin marking of a tumour suppressor gene, which is then silenced, leads to uncontrolled proliferation of the cancer cell.

This is where epigenetic therapy comes into play: inhibitors for chromatin-changing enzymes, one prominent example being histone deacetylase, short HDAC inhibitors, possess the ability to reprogram aberrant transcription, i.e. turn on tumour suppression. Epigenetic regulators can also help break the tumour's tolerance towards the immune system, for example by triggering "anti-tumour" immune responses via the presentation of neo-antigens or maintenance of T-lymphocyte activation.

Furthermore, Prof. Jenuwein presented an Agouti mouse model demonstrating the importance of epigenetic mechanisms for the prevention of cancer. In this Agouti mouse a change in the mother's diet had a significant corresponding influence on the offspring, indicating that epigenetic changes can also propagate to the next generations. The underlying mechanisms are not yet fully understood but most likely involve non-coding RNAs that bind their respective (complimentary) DNA sequence in order to transport epigenetic signals.

Prof. Angela Risch, Head of the Cancer Genetics/Epigenetics Division at the University of Salzburg, showcased how epigenetic characterization of cancer is already used in the clinic. For instance, epigenetic profiles (e.g. DNA methylation) can be used to predict a patient's therapeutic outcome, which in certain tumours already outperforms standard histopathological classification. She also expanded on the clinical potential for epigenetic profiling to identify risk groups, epigenetic biomarkers for early detection or response to treatment and the inhibition of key epigenetic regulators.

Interestingly, 4SC has been able to detect a new biomarker in the blood of patients, called ZFP64, during their clinical studies with its epigenetic agent resminostat in advanced liver cancer and Hodgkin's lymphoma. The biomarker's expression prior to resminostat treatment has been shown to correlate with patients' overall survival in both indications. The predictive value of the ZFP64 biomarker, however, needs to be further validated. It is currently under evaluation in ongoing clinical studies.

Translating research findings into the clinic remains a challenge. As Prof. em. Roland Mertelsmann, University Medical Center, Albert Ludwigs University Freiburg, pointed out: epigenetic regulation produces a highly variable cancer phenotype that can rapidly adapt to a changing environment and also to treatment. Cancer can only be cured if you kill the last tumour cell. In order to succeed in the fight against cancer, a patient's own defense system must be activated; the inhibition of so-called immune checkpoints (molecules that can turn immunological signals on or off) is thought to be one way to liberate the endogenous immune system (so called "releasing the break").

"Two hands will better grab a target than one finger", Prof. Jenuwein noted. In fact, all three speakers agreed that the most powerful approach would certainly be a combination of checkpoint inhibition and the expression of neo-antigens on cancer cells via epigenetic therapies. In other words, strengthen the immune system and weaken the tumour, thereby rendering it more vulnerable to immune system attack.

Things had come full circle when Dr. Daniel Vitt and Dr. Susanne Danhauser-Riedl; Chief Scientic Officer and Chief Medical Officer, respectively, of 4SC elaborated on the epigenetic drug candidates in 4SC's pipeline and how these drugs address cancer therapies. The company identified multiple features of their two clinical stage cancer drugs, i.e. resminostat and 4SC-202, which would prime cancer cells for subsequent immunotherapy. As an example and as shown in preclinical tests, resminostat enhances the immunogenicity of cancer cells as it restores the expression of ligands important for lymphocyte binding (i.e. natural killer cells and cytotoxic T cells) and tumour-associated antigens, at the same time reducing unspecific immunosuppressive mechanisms.

Enno Spillner, Chief Executive Officer of 4SC AG commented: "This symposium confirmed 4SC is on a good path in the development of its epigenetic regulators, resminostat as well as 4SC-202. In the US, HDAC inhibitors have already been approved and successfully used in the clinic. 4SC and its partners have been and/or are currently developing resminostat in a number of indications including liver, lung, pancreatic and biliary tract cancer and soon in cutaneous T-cell lymphoma (CTCL). We welcome the participation of so many international experts as well as our Asian development partners for resminostat from Yakult Honsha and Menarini AP in our Symposium."

Summing up 4SC's work in the field, Prof. Jenuwein concluded: "I am very happy to see the development of smart epigenetic inhibitors has been brought to such a high quality by 4SC. This biotech company is at the forefront in Germany for the successful translation of epigenetic therapy to the clinic and for the patient."

Combination approaches provide ways toward improving existing therapies and developing new ones with the aim to provide survival benefit for larger numbers of patients. To further investigate the properties of resminostat and 4SC-202 as immunomodulators and their potential combination with immunotherapy agents, such as checkpoint inhibitors, 4SC has recently been awarded a grant from the German Federal Ministry of Education and Research of up to EUR 450,000 as part of the European Eurostars programme.