Cancer researchers have been looking for ways to harness the immune system and to reinstate immune surveillance, to kill
cancer cells without collateral damage. Here we scan current approaches to targeting the immune system against
cancer, and emphasize our own approach. We are using chemical vectors attached to a specific
ligand, to introduce synthetic dsRNA, polyinosine/
cytosine (polyIC), into
tumors. The
ligand binds to a receptor
protein that is overexpressed on the surface of the
tumor cells. Upon
ligand binding, the receptor complex is internalized, introducing the polyIC into the cell. In this fashion a large amount of synthetic dsRNA can be internalized, leading to the activation of dsRNA-
binding proteins, such as dsRNA dependent
protein kinase (PKR),
Toll-like receptor 3 (TLR3),
retinoic acid-inducible gene I (RIG-1), and
melanoma differentiation-associated gene 5 (MDA5). The simultaneous activation of these signaling
proteins leads to the rapid demise of the targeted cell and to
cytokine secretion. The
cytokines lead to a strong bystander effect and to the recruitment of immune cells that converge upon the targeted cells. The bystander effects lead to the destruction of neighboring
tumor cells not targeted themselves by the vector. Normal cells, being more robust than
tumor cells, survive. This strategy has several advantages: (1) recruitment of the immune system is localized to the
tumor. (2) The response is rapid, leading to fast
tumor eradication. (3) The bystander effects lead to the eradication of
tumor cells not harboring the target. (4) The multiplicity of pro-death signaling pathways elicited by PolyIC minimizes the likelihood of the emergence of resistance. In this chapter we focus on EGFR as the targeted receptor, which is overexpressed in many
tumors. In principle, the strategy can be extended to other
tumors that overexpress a
protein that can be internalized by a
ligand, which can be a small molecule, a single chain antibody, or an affibody.