Scientists use PBMC from HemaCare for experiments that show the potential of a new cancer vaccine adjuvant. T cells answer the alarm!
Science continues to unravel how the immune system works, as well as how tumors thwart detection. One mechanism that cancer cells use is expression of “tolerance” molecules that put surveillance T cells at ease in their midst. Can science counter this in a tactical gambit by using “alarm” molecules to outmaneuver cancer cells?
Signature particles from pathogens that trigger an immune response could be considered as "alarm" molecules. Bacteria are a source of cyclic dinucleotide (CDN) molecules, which our immune system categorizes as pathogen-associated molecular pattern molecules (PAMPs). When PAMPs are encountered by T cells, they trigger production of the STING protein.
The STING protein in T cells is a “stimulator of interferon genes” that up-regulates type 1 interferon (IFN) molecules, which warn nearby cells and trigger the protective defenses of the immune system . Moreover, type 1 IFNs have been demonstrated to have anti-tumor effects and are used therapeutically in cancer.
A group of scientists from Aduro Biotech, Johns Hopkins University, University of California-Berkeley, and University of Washington-Seattle came together to ask whether CDNs could be incorporated in cancer vaccines as an adjuvant with the potential to enhance immune response to the vaccine antigen.
This group previously formulated GVAX, a therapeutic vaccine made with irradiated tumor cells that have the granulocyte-macrophage colony-stimulating factor (GM-CSF) gene transfected in. GM-CSF is a cytokine that stimulates immune cells. In the current study they formulated STINGVAX using irradiated tumor cells transfected with GM-CSF that were further incubated with CDN molecules.
Using mouse models, this group showed that STINGVAX was superior to GVAX in the activation of dendritic cells in lymph nodes. This finding was important, for dendritic cells announce the presence of tumor vaccine antigens to T cells. Furthermore, in mouse models for liver metastasis of pancreatic cancer, the median survival was >90 days for Cy/STINGVAX in comparison to 49 days for Cy/GVAX. (Cy was discussed previously). Indeed, the addition of CDN alarm molecules was demonstrated to augment cancer vaccines, shrinking tumors in several aggressive models.
Using peripheral blood mononuclear cells (PBMC), this group demonstrated that their synthetic CDN molecules could stimulate human monocytes, dendritic cell precursors. Additionally, dendritic cells stimulated in this manner successfully activated T cells, implying that CDN molecules used in the clinical setting could have adjuvant properties when combined with cancer vaccines.
- Fu J, Kanne DB, Leong M, Glickman LH, McWhirter SM, Lemmens E, Mechette K, et al. STING agonist formulated cancer vaccines can cure established tumors resistant to PD-1 blockade. Sci Transl Med. 2015. 7(283):283ra52.