Currently IL-2 cancer therapy has limited applicability due to significant treatment associated toxicity. ReGel is a proprietary triblock copolymer based on poly (lactide-co-glycolide) and polyethylene glycol, is entirely aqueous based, and functions as a thermoreversible injectable depot delivery system. ReGel has been successfuly formulated for local and systemic delivery of a number of sensitive molecules such as proteins and peptides. Preliminary results of peritumoral ReGel/IL-2 demonstrated improved immunorecognition of cancer cells, as evidenced by tumor growth inhibition and improved survival, while minimizing toxicity over conventional IL-2 therapy. Further optimization of this formulation is warranted prior to proceeding into formal GLP safety/toxicity studies in support of a phase I clinical trial application. The following studies will identify the best candidates in preparation for clinical studies. The release profile of IL-2 from four novel ReGel/IL-2 formulations will be determined in vitro. The bioactivity of the released IL-2 will then be evaluated and compared for these formulations using two cell based assays, which monitor T-cell proliferation and activation of cytotoxic NK-cells. The in vivo antitumor activity, and survival, will be compared for these four formulations to identify an optimal pharmacokinetic release profile in terms of initial burst level and duration of IL-2 release. In addition, the effect of the initial burst and sustained release on IL-2 induced toxicity (hypotension) will be established. Preliminary studies using peritumoral injections of ReGel/-IL-2 demonstrated an enhancement in efficacy over conventional IL-2. The outlined studies are designed to optimize the release profile to provide the best balance between an effective dose and minimum toxicity. The Phase II application of this SBIR will continue with the best candidate(s) selected from these studies in GLP preclinical studies that will facilitate protocol design for a phase I clinical study. High-dose i.v. IL-2 immunotherapy is a promising treatment option for a small subset of cancer patients, resulting in a small percentage of long-term cures. The primary limitation to the current therapy is toxicity associated with IL-2 treatment. ReGel/IL-2 therapy offers a unique opportunity to increase the concentration of IL-2 at the site of action while simultaneously reducing the side effects, in an attempt to increase therapeutic utility of this cytokine.
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