Cancer Drug Improves Immune Picture in Visceral Leishmaniasis

A drug already approved for treatment of some types of cancer has been shown to be an effective adjunct therapy for visceral leishmaniasis by helping to restore immunocompetence by stimulating the remodeling of the microarchitecture of the infected spleen.

Visceral leishmaniasis (VL), caused by the protozoan parasites Leishmania donovani and L. infantum, is one of the most important of the neglected tropical diseases, with approximately 500,000 new cases and 70,000 deaths reported per annum. Pentavalent antimonial drugs remain the first-line therapy for VL in most parts of the world, although increasing drug resistance now limits their use in India. Drug toxicity, increasing drug resistance, and a paucity of new drugs on the horizon have focused attention on the need to develop new combined approaches to therapy, including therapeutic vaccination, and on the development of dose-sparing regimens.

Investigators at York University (United Kingdom) evaluated the drug sunitinib maleate (SM) for its potential to reduce the dosages of antimonial agents used to treat VL. SM is a small-molecule inhibitor of multiple receptor tyrosine kinases involved in cancer, including vascular endothelial growth factor receptors, platelet-derived growth factor receptors and the KIT receptor. It was approved by the U.S. FDA for the treatment of gastrointestinal stromal tumors and advanced renal-cell carcinoma in January 2006.

The investigators reported in the April 1, 2010, issue of the Journal of Clinical Investigation that SM both blocked the vascular remodeling and progressive splenomegaly associated with experimental visceral leishmaniasis and restored the integrity of the splenic microarchitecture. Similar alterations to splenic architecture are also observed in other infectious causes of splenomegaly, including experimental malaria, trypanosomiasis, and following infection with lymphocytic choriomeningitis virus (LCMV).

Although restoration of splenic architecture was accompanied by an increase in the frequency of interferon producing cells, SM treatment alone did not cause a reduction in tissue parasite burden. However, preconditioning with SM was shown to be successful as a dose-sparing strategy for use with conventional antimonial drugs that are known to be immune dependent for their efficacy in vivo.

Senior author Dr. Paul Kaye, professor of immunology at York University, said, "It is particularly exciting that this potential has been discovered in a class of drugs that are already well-established in clinical practice. While our research has focused on leishmaniasis, the findings could have implications for a range of globally important diseases.”

Related Links:
York University