THE USE OF INTERLEUKIN-6 TO GENERATE TUMOR-INFILTRATING LYMPHOCYTES WITH ENHANCED IN-VIVO ANTITUMOR-ACTIVITY

Tumor-infiltrating lymphocytes (TIL) are cytotoxic T cells isolated fr om solid tumors and expanded in vitro in recombinant interleukin-2 (rI L-2). TIL have antitumor effects in murine models and in some patients with melanoma. In an effort to generate murine TIL with enhanced in v ivo therapeutic efficacy, viable tumor cells were coinjected with a co llagen matrix plus recombinant human IL-6 (rIL-6) subcutaneously into syngeneic mice to achieve sustained local concentrations of rIL-6 at t he tumor site from which TIL were derived. In five separate experiment s, single cell suspensions of tumors were admired with either (a) Hank s' balanced salt solution (HBSS), (b) 2% (20 mg/ml) collagen matrix on ly, (c) 250 mu g rIL-6 only, or (d) 250 mu g rIL-6 in a 2% collagen ma trix (prolonged release) before subcutaneous inoculation. These tumors were subsequently resected and TIL were isolated and expanded in vitr o. TIL generated from tumors admired with matrix plus rIL-6 were signi ficantly more effective than TIL expanded from tumors admired with HBS S (four of five experiments), TIL from tumors admired with matrix only (five of five experiments), and TIL from tumors admired with rIL-6 on ly (three of four experiments) in an established tumor treatment model . In no experiment was any other TIL culture superior to TIL grown fro m tumors augmented with collagen matrix plus rIL-6. These results sugg est that strategies designed to increase the local concentrations of c ytokines at tumor sites may lead to the generation of more potent TIL for clinical administration.