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Immunostimulatory Vaccine Cures Metastatic Cancer in Model

By BiotechDaily International staff writers
Posted on 12 Feb 2018
A novel method for treating various types of metastatic cancer based on injection of a pair of immune-stimulating agents directly into solid tumors was demonstrated in a mouse model.

This "in situ vaccination" approach depends on the injection of immunoenhancing agents locally into one tumor site, thereby triggering a T-cell immune response locally that then attacks cancer throughout the body. To develop this method, investigators at Stanford University (Stanford, CA, USA) used a screening strategy in which the same syngeneic tumor was implanted at two separate sites in the mouse. One tumor was then injected with the test agents, and the resulting immune response was detected by the regression of the distant, untreated tumor.

Image: The structure of the OX40 protein (Photo courtesy of Wikimedia Commons).
Image: The structure of the OX40 protein (Photo courtesy of Wikimedia Commons).

The investigators reported in the January 31, 2018, online edition of the journal Science Translational Medicine that the assay revealed that the combination of an unmethylated CG–enriched oligodeoxynucleotide (CpG) and an anti-OX40 antibody provided the most impressive results.

CpG oligodeoxynucleotides (or CpG ODN) are short single-stranded synthetic DNA molecules that contain a cytosine triphosphate deoxynucleotide ("C") followed by a guanine triphosphate deoxynucleotide ("G"). The "p" refers to the phosphodiester link between consecutive nucleotides. When these CpG motifs are unmethylated, they act as immunostimulants. TLR9 (Toll-like receptor 9) is usually activated by unmethylated CpG sequences in DNA molecules. Once activated, TLR9 moves from the endoplasmic reticulum to the Golgi apparatus and lysosomes, where it interacts with MyD88, the primary protein in its signaling pathway. TLR9 is cleaved at this stage to avoid whole protein expression on cell surface, which could lead to autoimmunity.

The current study showed that the combination of an agonistic OX40 antibody (clone OX86) injected directly into a tumor in combination with an unmethylated CpG oligonucleotide, which as a TLR9 ligand activated the expression of OX40, triggered a T-cell immune response, which was specific to the antigens of the injected tumor.

"When we use these two agents together, we see the elimination of tumors all over the body," said senior author Dr. Ronald Levy, professor of oncology at Stanford University. "This approach bypasses the need to identify tumor-specific immune targets and does not require wholesale activation of the immune system or customization of a patient's immune cells. Our approach uses a one-time application of very small amounts of two agents to stimulate the immune cells only within the tumor itself. In the mice, we saw amazing, body-wide effects, including the elimination of tumors all over the animal. This is a very targeted approach. Only the tumor that shares the protein targets displayed by the treated site is affected. We are attacking specific targets without having to identify exactly what proteins the T-cells are recognizing."

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