Blockade of hyaluronan, a CD44 ligand, inhibits IL-2–induced vascular leak syndrome while maintaining effective treatment of melanoma (48.30)

Abstract

Abstract High-dose IL-2 therapy is an effective mode of treatment against melanomas; however, its use is limited by accompaniment of vascular leak syndrome (VLS), a life-threatening toxicity. The precise mechanism/s of VLS is unclear and there is no specific therapy to block VLS and enhance IL-2 based immunotherapy. Previous studies from our laboratory demonstrated that CD44 plays a critical role in VLS; administration of hyaluronan (HA), a primary ligand for CD44, caused a marked increase in IL-2 induced VLS. In this study, we report a novel means to prevent VLS by blocking endogenous HA with HA-specific binding peptide, Pep-1. Our results demonstrated that administration of Pep-1 into IL-2 treated mice dramatically inhibited IL-2-induced VLS in the lungs and liver. Interestingly, Pep-1 treatment did not affect the effectiveness of IL-2 in treatment of melanoma. Pep-1 treatment did not affect the emigration of lymphocytes across the endothelium and the activation of CTL seen during IL-2 treatment. Also, blocking HA with Pep-1 maintained endothelial integrity and prevented their apoptosis. Our results demonstrate that HA plays a role in regulating endothelial damage and blockade of HA could be a novel means for prevention and treatment of VLS thereby facilitating IL-2-induced immunotherapy of melanomas. (Supported by NIH grants RO1 AI 053703, RO1 DA 016545, RO1 AI 058300, RO1 HL 058641 and RO1 ES 09098)