Too much of a good thing
The innate immune system is capable of recognizing foreign substances and invading cells, and mobilizes various immune defense mechanisms to disable and destroy invasive pathogens. In addition, it can recognize and eliminate abnormal or otherwise damaged “self” cells, and thus provides a means of defense against tumors. These natural defense mechanisms can be exploited in a directed fashion by using small synthetic molecules of appropriate design to stimulate the receptors that form the frontline of the innate immune system.
One of these receptors is the so-called Toll-like receptor 7 (TLR7). Synthetic ligands are available that stimulate the receptor, allowing tumor tissue to be effectively recognized as foreign, and be attacked by the immune system. One particular synthetic TLR7 ligand called imiquimod is already in use for topical therapy of skin tumors. However, attempts to use the agent for the systemic therapy of other types of tumor have met with less success. “In these cases the TLR7 ligands are injected into the bloodstream several times a week. We therefore asked whether this regime of repeated stimulation might not lead to systemic immune tolerance, which would account for the limited efficacy of the treatment,” explains Bourquin.
And indeed, the researchers found that repeated administration of the synthetic ligand over a relatively short period led to the induction of receptor tolerance. The response of TLR7 was blunted, and the receptor remained refractory to restimulation for up to five days. “Frequent immune stimulation could therefore be responsible for the weak impact of the therapy,” says Bourquin. Not content with a simple error analysis, the team developed an alternative treatment schedule based on their findings. This regimen did not provoke receptor tolerance and resulted in a marked reduction in the size of tumors in mice, in spite of the fact that the total dose used was lower than that employed in the more conventional approach.
“Our study shows that the timing of systemic therapy with TLR7 ligands plays a decisive role in determining clinical efficacy,” says Bourquin, “and our results are of immediate relevance for similar studies in humans and for immune therapy in general.” Indeed, given that receptor tolerance is a widespread phenomenon, the new insights are very probably applicable to the design of other immune-based therapies also. (göd/PH)
Systemic cancer therapy with a small molecule agonist of Toll-like receptor 7 can be improved by circumventing TLR tolerance.
C. Bourquin, C. Hotz, D. Noerenberg, A. Voelkl, S. Heidegger, L.C.M. Roetzer, B. Storch, N. Sandholzer, C. Wurzenberger, D. Anz, S. Endres.
Cancer Research. Published online, June 22, 2011.
Prof. Dr. Carole Bourquin
Division of Clinical Pharmacology, Medical Center of the University of Munich
Phone: +49 89 / 5160 - 7331
Fax: +49 89 / 5160 - 7330