Obstacles to effective Toll-like receptor agonist therapy for hematologic malignancies.

It has long been noted that products of microorganisms have clinical activity against hematologic malignancies. Recent advances suggest that Toll-like receptors (TLRs) activated by ligands in the microbial preparations might account for some of this activity, and that defined TLR agonists might improve the clinical efficacy of this approach. A potentially important mechanism of action of TLR agonists is their ability to cause tumor cells to differentiate into a 'tolerized' state in which they become highly sensitive to cytotoxic effector cells and chemotherapeutic drugs. TLR agonists as single agents have strong activity against cutaneous leukemias and lymphomas but are not as effective against systemic disease. A possible reason for this discrepancy is the hypoxic internal tumor microenvironment, which promotes glycolytic metabolism, and the presence of suppressive cytokines, prostaglandins and nucleosides that prevent strong TLR signaling in cancer cells. Accordingly, concomitant use of agents to counter this intrinsic microenvironmental inhibition, together with TLR agonists, may prove to be an effective treatment strategy for the hematologic malignancies.