An Innovative Immune Activator
What It Is
How It Works
Vidutolimod works by two complementary mechanisms that together have a unique ability to drive a strong systemic anti-tumor T cell response. First, the VLP activates an immune response to the VLP, leading to the production of antibodies that deliver the VLP into plasmacytoid dendritic cells (pDC) and other immune cells via specialized receptors called FcR . This provides an initial stimulatory signal to pDC and brings the CpG-A to TLR9 (the receptor for CpG DNA) inside the (pDC). Second, CpG-A stimulates TLR9 in a manner that induces significantly higher levels of type I interferons (IFN-α and others) in pDC resulting in a stronger anti-tumor T cell response, as compared to other innate immune activators.
When activated by vidutolimod by this combination of signals, pDC recruit and coordinate a variety of other immune cells, culminating in the generation of a strong anti-tumor T cell response. Vidutolimod is given in combination therapy with a PD-1 checkpoint inhibitor, which blocks the PD-1 checkpoint on the anti-tumor T cells, so that these can attack the tumor unsuppressed.
How It’s Different
Many different approaches are being developed to activate the immune system against cancer, including for example activators of TLR7, TLR8, and/or TLR9, activators of the STING pathway, and oncolytic viruses. The immune effects of vidutolimod are unique for two reasons: first, the biologic VLP, in which the CpG-A is delivered, enhances the immune response by stimulating the production of antibodies that promote uptake of the VLP itself and provide extra activation of the pDC, leading to a more effective systemic anti-tumor T cell response. Second, the CpG-A self-assembles into structures called G-quadruplexes that mimic the replicative forms of viruses and retroviruses, and it has a native DNA backbone that can be cleaved during TLR9 activation, resulting in much greater induction of type I IFN production compared to other TLR activators that use nuclease-resistant phosphorothioate backbones. In contrast to oncolytic viruses, vidutolimod does not infect human cells, and so is not blocked by anti-viral antibodies, but instead is enhanced by these. Oncolytic viruses are suppressed by a strong type I IFN response, but vidutolimod is designed to induce this. Type I IFN are essential for the generation of a strong-antitumor immune response.
The Potential Benefits
PD-1 checkpoint inhibitors alone can help patients where anti-tumor T cells already are present and trying to fight the tumor, but in most patients with advanced cancer the treatment fails to stop the tumor. Vidutolimod alone is believed to induce and expand anti-tumor T cells, including in patients who do not have them and where checkpoint inhibitors would be inactive. However, these T cells express the PD-1 checkpoint, and may be inhibited by many tumors. The unique combination of vidutolimod with PD-1 checkpoint inhibitor therapy may result in increased clinical benefit and provide new treatment options for patients with cancer.
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