Dynavax Technologies Corporation and 4SC AG announced the combination of 4SC’s orally available class I selective HDAC inhibitor domatinostat 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. 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 demonstrated even higher efficacy. SD-101 is a TLR9 agonist, which was specifically developed for cancer based upon its ability to stimulate both IFN-alpha 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 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.
Monday, April 1, 2019
Aptose Biosciences presents preclinical data on CG-806, APTO-253 at AACR
Aptose announced that new preclinical data for CG-806, its highly potent oral small molecule pan-FLT3/pan-BTK inhibitor, and APTO-253, its MYC inhibitor, are being presented in two separate posters at the 2019 AACR Annual Meeting in Atlanta, GA. The poster, CG-806, a pan-FLT3 / pan-BTK inhibitor, demonstrates superior potency against cells from IDH-1 mutant and other non-favorable risk groups of AML patients, explores the activity of CG-806 on primary patient samples with acute myeloid leukemia, in studies that were conducted in collaboration with the Beat AML Initiative. CG-806 demonstrated significant potency across sub-groups of AML cells, including relapsed/refractory AML and those with genetic abnormalities related to poor prognoses in AML patients. CG-806 demonstrated superior potency when compared to other FLT3 inhibitors, including midostaurin, sorafenib, sunitinib, dovitinib, quizartinib, crenolanib and gilteritinib. While patient samples with FLT3-ITD mutations were expected to have greater sensitivity to CG-806, the sensitivity of patient cells with IDH1 R132 mutations was an unexpected finding. In 28-day GLP toxicity and toxicokinetic studies, CG-806 continued to demonstrate a favorable safety profile. The poster, Resistance to APTO-253 caused by internal deletion and alternate promoter usage of the MYC gene in Raji B cells, presents in vitro studies that further define the mechanism of action of APTO-253. A novel small molecule, APTO-253 inhibits expression of the MYC oncogene, leading to apoptosis in human-derived solid tumor and hematologic cancer cells without the myelosuppression seen with other chemotherapies. Researchers found that APTO-253 targets a G-quadruplex motif in the P1/P2 promoter region of the MYC gene and inhibits MYC gene expression to induce apoptosis, resulting in its ability to potently kill hematologic malignant cell lines and primary samples from AML and chronic lymphocytic leukemia patients.
Trovagene jumps after reporting results from Acute Myeloid Leukemia trial
Shares of TrovaGene are up 86c, or 23%, to $4.61 following the company’s report of new data from its ongoing Phase 1b/2 study evaluating onvansertib in combination with standard-of-care chemotherapy in Acute Myeloid Leukemia, or AML. Objective response rate has been observed at last 3 highest dose levels of onvansertib with 5 of 19 evaluable patients achieving a complete response, the company reported.
NewLink higher after results posted for Phase II study of NLG207
Shares of NewLink Genetics are higher ahead of the tomorrow’s presentation at the American Association for Cancer Research’s annua; meeting. Results of a Phase II study of NLG207 combination with weekly paclitaxel in patients with recurrent or persistent epithelial ovarian, fallopian tube or primary peritoneal cancer has been posted online. The conclusion reads, “NLG207 is a potentially best-in-class topoisomerase 1 inhibitor with demonstrated antitumor activity in recurrent ovarian cancer including those who have become resistant to platinum therapy. AE profile of this combination is consistent with that seen for paclitaxel as a single agent except for cystitis, hematuria and UTI. It was well-tolerated in combination with weekly paclitaxel in heavily pre-treated patients. NLG207 warrants further investigation in combination therapy regimens for recurrent ovarian, fallopian tube or primary peritoneal cancer, particularly in platinum resistant patients.” Shares of NewLink Genetics are up 9%, or 18c, to $2.11 in afternoon trading.
CareDx CEO says company preparing for more competition
CareDx (CDNA), a molecular diagnostics company focused on the discovery, development and commercialization of diagnostic solutions for transplant recipients, joined The Fly for an exclusive interview. In the interview, CareDx CEO Peter Maag discussed competition and the company’s lawsuit against Natera (NTRA): “Natera is trying to cut corners in bringing their solution to the market. We have worked for 7/8 years to build and make this technology available to transplant patients. And now, I think they’re trying to adopt a fast follower strategy. I think it’s very important to realize that CareDx has relevant IP in the state and that we have established relationships with transplant centers. We’re making sure that we are linking ourselves with these 250 transplant centers in the country, being part of their workflow and caring for patients versus being a company that says, ‘oh I have one more test and I can do that as well.’ This is very critical as we are preparing for more competition in a market, in heart transplant, where we used to be the only company and now there might be other companies coming in the future. So, we are embracing competition.” “Meet the Company” is The Fly’s recurring series of exclusive short interviews with Executive Officers to offer a deeper look inside the company. https://thefly.com/landingPageNews.php?id=2886949
Turning Point Kinase Inhibitors Potent v. Targeted Oncogene Drivers, Mutations
Turning Point Therapeutics, Inc., a clinical-stage precision oncology company designing and developing novel drugs to address treatment resistance, presented data from four studies at AACR 2019, highlighting potent activity of its kinase inhibitors, including repotrectinib against targeted oncogene drivers and many of their resistance mutations, and TPX-0022, a novel MET/CSF1R/SRC inhibitor.
Two studies highlighted the higher potency of repotrectinib as compared to other proxy investigational and the currently approved ROS1 and TRK tyrosine kinase inhibitors (TKIs), Xalkori and Vitrakvi, against fusion ROS1s, wildtype TRK, and many resistance mutations, including solvent front, gatekeeper, and compound mutations.
Alexander Drilon, M.D., Clinical Director of the Early Drug Development Service at Memorial Sloan Kettering Cancer Center and an investigator in the Phase 1 portion of the ongoing TRIDENT-1 study of repotrectinib, said, “As physicians adopt next-generation sequencing to identify genomic alterations in different cancers, there is an increased need for precision therapies that target specific oncogenes, such as TRK and ROS1. Repotrectinib was found to have 10-fold or higher increased potency when compared to proxy investigational and the currently approved TRK inhibitors against wildtype (WT) TRK fusions and solvent-front mutations. The findings — while early — are significant and warrant continued clinical study.”
Data for TPX-0022, a novel, internally developed MET/CSF1R/SRC inhibitor approaching IND submission in 1H 2019, were presented for the first time at the conference. TPX-0022 was designed to target MET-driven tumor cells, but also modulate the tumor microenvironment by inhibition of CSF1R. This dual modulation has demonstrated significant tumor growth inhibition in preclinical models.
The data shown in two posters highlighted the ability of TPX-0022 to potently inhibit MET-driven cancer cells and the associated signaling of known cancer pathways, inhibiting tumor growth and reducing tumor associated macrophages. This dual mechanism of action showed tumor regression and growth inhibition in multiple xenograft tumor models harboring METamplification or MET exon 14 skipping mutations.
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