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BACKGROUND: Interleukin-2 (IL-2) is a cytokine indicated for treatment of melanoma and renal cell cancer. Unfortunately, it has also been shown to create serious side effects, including death, when systemically administered. We proposed that regional targeting of IL-2 directly to the lymphatic system using microneedle based intradermal (ID) delivery could increase the therapeutic efficacy and reduce the associated toxicity.

MATERIALS AND METHODS: C57BL/6 mice (n=10/condition) were implanted subcutaneously (SC) with B16F10 melanoma cells (ATCC, Inc.). IL-2 treatment (aldesleukin, Chiron)was initiated at d10 post implantation by either an intraperitoneal (IP) or ID route. Animal received one of three doses (50K, 100K or 200K IU) every eight hours for five days. Route-based differences in therapeutic efficacy were monitored via tumor volume and average mortality.

RESULTS: All treatment groups regardless of route and dose showed a reduction in tumor volume compared to negative controls. Likewise tumor volumes were inversely proportional to total dose for both routes. Intriguingly, at each dose level, ID therapy resulted in a longer term reduction in tumor volume compared to IP systemic dosing, and at day 32, average tumor size in the 50K ID dosed group (3,208mm3) was significantly smaller (p<0.04) compared with the IP dosed animals (6,151mm3). Substantial dose- related toxicity was observed at the 100K and 200K IU dosing levels for both routes, making statistical comparison difficult. Mortality rates at higher doses were similar to negative controls despite significantly smaller tumors. However, the average life span of low dose animals (50K IU) in ID and IP routes were significantly (p<0.003) longer than controls (33.5 and 33.2 days respectively vs. 23.6), although no significant differences were seen between routes.

CONCLUSIONS: Microneedle based ID therapy has been previously shown to administer drugs and vaccines rapidly to the lymphatic tissues. This region-specific targeting has a significant advantage for cytokine and other immunotherapies by maximizing dose to the effector organs and tissues. In this study of ID delivered IL-2, although no route-based survival benefits were observed, significant advantages in tumor responsiveness were conferred, especially at low dose. Overall tumor control vs. negative control improved as the IL-2 dose increased, unfortunately, mortality rates were also positively correlated to increased dose. We attribute the observed decrease in life span to the previously reported toxicity seen with IL-2 therapy.

Although a significant decrease in mortality was not seen between the two dosing routes, the tumor control benefit from low-dose ID delivery was encouraging. These data when combined with the dose-linked toxicity findings suggest that an optimized ID dosing regimen could confer a therapeutic benefit over systemic therapy.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA