Local conditions in the host influence immunotherapy with interleukin-2 and LAK cells

Production of biological response modifiers through recombinant techniques has stimulated interest in immunotherapy of cancer. One of these, interleukin-2 (IL-2), will induce in vivo as well as in vitro proliferation of noncommitted T lymphocytes into lymphokine-activated killer (LAK) cells: cells cytolytic for a broad range of tumor cells. We have demonstrated earlier that immunotherapy with IL-2 and LAK cells will reduce tumor load and prolong survival in a significant way in an intraperitoneal (ip) tumor model as well as in other models. Nevertheless, mice die of one or two metastases escaping immunotherapy. Activation of the host immune system might boost endogenous IL-2 production. Activation might also enhance immunotherapy by increasing the necessary cofactors. Loco-regional allogeneic pretreatment ip 14 days prior to syngeneic tumor challenge did not enhance, but completely abrogated, ip IL-2 and LAK cell therapy (peritoneal cancer index, 0.6 +/- 0.3 vs 2.6 +/- 0.2, P2 = 0.003). Tumor bulk is not the reason for escape of immunotherapy either. One week after intracutaneous (ic) tumor inoculation a noncurative or sham tumor resection was performed, followed by IL-2 and LAK cell therapy either ip or in and around the tumor nodule. No significant difference in tumor diameter or survival of mice was seen. Allogenic tumor cells admixed with syngeneic tumor cells will induce an inflammatory reaction locally and regionally. This inflammatory reaction in the syngeneic host will enhance the treatment with IL-2. The allogeneic (P815) and syngeneic (MCA-105) tumor cell mixture was injected ic. Growth rate was retarded and survival prolonged in a significant way when the cell mixture was treated with ip IL-2 injections; no difference was seen when the admixture was not treated or the syngeneic ic tumor alone was treated with IL-2. We conclude that host immune status and recruitment of immunocompetent cells locally to the tumor site determine the outcome of immunotherapy with IL-2 and LAK cells.