Research Project
7491940
DESCRIPTION (provided by applicant): High-dose IL-2 produces complete remissions in a small percentage (5-10%) of patients with metastatic renal carcinoma or melanoma. It is intriguing that many of the IL-2 induced complete remissions have proven durable, with up to 18-year follow-up. The clinical use of IL-2 is limited by severe side effects, particularly hypotension and "vascular leak syndrome"(VLS). Patients treated with high-dose IL-2 require hospitalization for close monitoring and administration of fluids, colloids and pressor medications to treat low blood pressure that occurs in a dose dependent manner. A substantial fraction (1/3 to 1/2) of planned IL-2 doses is usually omitted due to cardiovascular toxicity, which may compromise effectiveness. Our laboratory and clinical studies have shown that synthesis of nitric oxide (NO) is strongly induced following IL-2 treatment. NO is an important mediator of hypotension and vascular leak. We have recently identified a promising new agent, PHP, a pyridoxalated hemoglobin polyoxyethylene conjugate, that appears to be safe in humans and has the potential to prevent both IL-2 induced hypotension and VLS due to its ability to catabolize NO, as well as other potentially injurious oxidative radicals. This grant application is designed to support a Phase I clinical investigation of PHP in conjunction with high-dose IL-2 treatment to evaluate safety of this compound and to establish an effective dose. In Specific Aim 1 we will assess the safety of PHP in patients with metastatic renal carcinoma or malignant melanoma. This study will establish dose-limiting toxicity (if any) of this agent in combination with high dose IL-2, and define a biologically effective dose for reversal of IL-2 induced hypotension. In Specific Aim 2 we will determine the effect of PHP on hemodynamic function in IL-2 treated patients, including assessment of blood pressure, systemic vascular resistance, cardiac index, pulmonary artery pressure and capillary wedge pressure and the total dose of pressors required during each course of high-dose IL-2. In Specific Aim 3, we will assess the potential usefulness of intermediate biomarkers for activation of the nitric oxide synthesis pathway in patients treated with IL-2 with or without PHP, to develop assays for phase II testing. It should be stressed that knowledge gained from evaluation of mechanisms of IL-2 toxicity is likely to be broadly relevant to understanding the pathophysiology of hypotension and vascular leak induced by other cytokines, such as IL-1, TNF, VEGF and IL-12.
