On April 1, 2019 Dynavax Technologies Corporation (NASDAQ: DVAX) and 4SC AG (FSE Prime Standard: VSC) reported the combination of 4SC’s orally available class I selective HDAC inhibitor domatinostat (4SC-202) with Dynavax’s intratumoral TLR9 agonist SD-101 induced a systemic anti-tumoral immune response in tumor mouse models, resulting in the significant decrease in tumor size of both target tumors and distant site metastases (Press release, Dynavax Technologies, APR 1, 2019, View Source [SID1234534838]).
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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 Dynavax will present the data in a poster presentation at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) meeting, which takes place from 29 March to 3 April 2019 in Atlanta, USA.
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 Eddie Gray, CEO of Dynavax. "SD-101 has demonstrated significant antitumor effects by direct enhancement of innate immunity and adds meaningful clinical benefit to anti-PD-1 therapy. The addition of domatinostat to this combination shows encouraging results and we look forward to continuing to assess the potential of this combination."
Jason Loveridge, Ph.D., CEO of 4SC, added: "We thank Eddie Gray and his team at Dynavax for performing these highly promising experiments. We are very impressed by the data on the triple-combination of SD-101, domatinostat and PD-1 blockade and believe there is significant potential for novel combinations based on immunotherapeutics such as these to fight cancer, especially in patients who are resistant to or progressing on treatment with prior immunotherapies. Of particular importance to us was the clear demonstration of domatinostat’s superiority as compared to competing HDAC inhibitors."
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
Further information
About SD-101
SD-101, the Company’s lead clinical candidate, is a proprietary, second-generation, Toll-like receptor 9 (TLR9) agonist CpG-C class oligodeoxynucleotide. Dynavax is evaluating this intratumoral TLR9 agonist in several clinical studies to assess its safety and activity, including a Phase 2 study in combination with KEYTRUDA (pembrolizumab), an anti-PD-1 therapy, in patients with advanced melanoma and in patients with head and neck squamous cell cancer, in a clinical collaboration with Merck. Dynavax maintains all commercial rights to SD-101.
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. David Cunningham of The Royal Marsden NHS Foundation Trust (London, UK).
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).