Dynavax’s SD-101 and 4SC’s Domatinostat Demonstrate Synergy and Induce a Systemic Anti-tumor Response in Preclinical Models
Combination of SD-101 with domatinostat showed better results than combinations of SD-101 with competing HDAC inhibitors. The triple combination of both compounds with PD-1 blockade (checkpoint inhibition) demonstrated even higher efficacy.
Émilie Degagné, PhD, scientist at
Combined mode of actions of SD-101 plus checkpoint inhibitor plus domatinostat
SD-101 is a TLR9 agonist, which was specifically developed for cancer based upon its ability to stimulate both IFN-α production and the maturation of plasmacytoid dendritic cells into tumor antigen presenting cells. This results in increased activation and proliferation of tumor-specific CD8+ T cells which attack distant site non-injected tumors. Domatinostat, acting via epigenetic regulation, renders tumor cells more visible to the immune system and promotes a general immune response against tumor tissue as well as infiltration of T cells into the tumor tissue.
Preclinical data demonstrate that the combination of intra-tumoral SD-101 and systemic domatinostat strongly synergize to induce substantial regression of the primary (injected) tumor, as well as distant site non-injected tumors, including lung metastases. Checkpoint inhibitors, such as anti-PD-1 antibodies further boost the anti-tumor T-cell response, leading to rejection in mice with high metastatic burden. These data indicate that the combination of these three different treatment classes result in induction of a more potent tumor-specific immune response and better recognition and elimination of tumors by immune cells, especially in cancer patients refractory to anti-PD-1 treatment.
“We believe the induction of innate immunity will be instrumental in the future treatment of cancer and are pleased to work with 4SC as they develop differentiated drug candidates to modulate the immune system,” said
Abstract ID 2259: Tumor abscopal responses induced by the TLR9 agonist, SD-101, are strongly potentiated by a HDAC class I inhibitor, domatinostat.
|Date:||1 April 2019|
|Time:||1:00 PM – 5:00 PM EDT|
|Session:||PO.CL06.05 - Combination Immunotherapies 1|
|Location:||Exhibit Hall B, Section 19, Poster Board Number 18|
SD-101, the Company's lead clinical candidate, is a proprietary, second-generation, Toll-like receptor 9 (TLR9) agonist CpG-C class oligodeoxynucleotide.
About domatinostat (4SC-202)
Domatinostat is an orally administered small molecule Class I selective HDAC inhibitor with a unique mode of action that was designed to strengthen the body’s own anti-tumor immune response. Domatinostat also influences the tumor microenvironment facilitating infiltration of immune cells into the tumor and making it more visible to the immune system.
Domatinostat has been investigated in a Phase I study with 24 heavily pretreated patients with several types of advanced hematologic cancers and was well tolerated. Positive signs of anti-tumor efficacy were also observed; with one complete remission (28 months) and one partial responder (8 months).
In addition to its therapeutic potential in cancer monotherapy, 4SC is evaluating domatinostat’s capacity as a partner in combination therapies, specifically in the immuno-oncology area. In this respect, 4SC initiated a Phase Ib/II study of domatinostat in combination with the anti-PD-1 checkpoint inhibitor pembrolizumab in patients with advanced-stage melanoma. A second Phase II study of domatinostat in combination with the anti-PD-L1 checkpoint inhibitor avelumab in patients with advanced-stage microsatellite-stable gastrointestinal cancer is conducted by Prof.
As soon as results from the aforementioned trials will be available, 4SC plans to advance domatinostat into a potentially pivotal study in combination with a checkpoint inhibitor in PD-(L)1 refractory patients with advanced Merkel-cell carcinoma (MCC).
4SC aims to generate future growth and enhance its enterprise value by entering into partnerships with pharmaceutical and biotech companies and/or the eventual marketing and sales of approved drugs in select territories by 4SC itself.
4SC is headquartered in Planegg-Martinsried near
This press release contains "forward-looking" statements. Actual results may differ materially from those set forth in this press release due to the risks and uncertainties inherent in our business, including whether we can timely provide adequate clinical supplies; initiation, enrollment and completion of clinical trials of SD-101; whether data from mouse studies and interim and final results of current and future clinical trials will support the initiation or continuation of clinical trials; issues arising in the regulatory process; the ability to successfully develop and commercialize SD-101; and whether or not
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Source: Dynavax Technologies Corporation