Taking the STING out of tumors

Aduro's CDN molecules target the STING pathway, show preclinical anti-tumor activity

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BERKELEY, Calif.—Aduro Biotech Inc. has announced the publication of results of investigating the anti-tumor activity of its synthetic cyclic dinucleotide (CDN) molecules against aggressive metastatic cancers in preclinical models.
In preclinical cancer models, the researchers showed that intratumoral injections of ADU-S100 caused profound regression of established melanoma, colon cancer and breast cancer tumors in mouse models; this was seen both in the injected tumors as well as distal, untreated lesions. Additionally, treating a single tumor led to a systemically effective T cell response that prevented metastases. This response was durable and provided long-lived immunologic memory and lasting anti-tumor protection.
The results appeared in the paper “Direct activation of STING in the tumor microenvironment leads to potent and systemic tumor regression and immunity,” which was published in Cell Reports.
The second article, titled “STING agonist formulated cancer vaccines can cure established tumors resistant to PD-1 blockade,” described how the increased anti-tumor activity of GVAX cancer vaccines developed with CDN molecules was STING-dependent and correlated with increased activation of dendritic cells and antigen-specific CD8+ T cells. Additionally, tumors in treated mice also displayed notable up-regulation of PD-L1. The combination therapy of CDN molecules formulated with GVAX cancer vaccines and antibodies blocking the PD-1 immune checkpoint engendered significant regression or elimination of tumors that had resisted treatment with anti-PD-1 inhibitors alone. The paper appeared in Science and Translational Medicine.

"Having our data peer-reviewed and featured in these major journals is a tremendous validation of our CDN technology and approach to activating the novel STING receptor," Dr. Thomas W. Dubensky, Jr., chief scientific officer for Aduro, said in a press release. "In preclinical animal models, our synthetic CDN molecules potently activate immune stimulating cells including dendritic cells through this central pathway, altering the tumor microenvironment which leads to induction of tumor-specific T cells, durable immune-mediated tumor shrinkage and immune protection when re-challenged with the same tumor cells. In addition, we have shown that our synthetic CDN molecules activate all known variants of human STING receptors. Our ultimate goal with ADU-S100 and other novel CDN candidates is to design compounds that offer an off-the-shelf therapeutic approach to stimulate personalized responses to fight each patient's specific cancer."
Aduro's CDNs are synthetic small-molecule immune modulators designed to target and activate a receptor known as the Stimulator of Interferon Genes, or STING. This receptor is generally expressed at high levels in immune cells, and once activated, it initiates a significant innate immune response via multiple pathways, generating the expression of a range of cytokines, including interferons and chemokines. This in turn leads to an effective tumor antigen-specific T cell adaptive immune response. Aduro acquired the GVAX assets from BioSante Pharmaceuticals Inc. in 2013. These cancer vaccines use human cancer cell lines that are genetically modified to secrete the immunostimulant granulocyte-macrophage colony-stimulating factor. The cell lines are then irradiated to prevent cell division, though they remain metabolically active.
A little over a month ago, in late March, Aduro signed a major collaboration with Novartis to develop its CDN platform to target the STING pathway in oncology. Novartis paid Aduro $200 million up front, with a commitment to pay up to an additional $500 million in development milestones. Novartis has also invested $50 million in equity in Aduro. Aduro will lead commercialization and book sales in the United States for any products that result from the deal, while Novartis will lead commercialization is all other regions. Both companies will share profits in the United States, Japan and major European countries, and Aduro will receive a double-digit royalty on sales in the rest of the world.

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