Targeting the immune system to cancer

Human cancers represent heterogeneous populations of cells whose genomes constantly change, so targeted therapies must be aimed at continuously changing networks. To overcome this difficulty a most promising strategy has been developed, which involves using a ligand-guided vector carrying a double-stranded RNA (dsRNA) such as poly-inosine/cytosine, or polyIC. Upon ligand-induced receptor internalization, polyIC triggers the production of cytokines as well as chemokines, which in turn attract immune cells to the tumor. In mice, an EGFR targeted vector carrying polyIC, eradicates tumors that over express the EGF-receptor using either local or systemic application. The treatment also eliminates mixed tumors, in which about half of the cells over express EGFR and the other half carry a truncated version of the receptor. This "bystander effect" is mediated by polyIC-induced cytokines generated by the tumor. Immune cells that accumulate in the tumor also produce pro-apoptotic cytokines. Reconstituting the immune system of SCID mice with human peripheral blood mononuclear cells immediately after treatment keeps the mice alive and cancer-free for more than a year. This strategy could be utilized to treat any cancer with a significant population of cells that overexpress a protein that can be induced to internalize by a ligand.