The incubation of murine or human lymphocytes in high concentrations of purified Interleukin 2 (IL 2) induces the generation of cytolytic effector cells, termed lymphokine activated killer (LAK) cells. LAK cells are markedly cytotoxic in vitro to a wide spectrum of tumor cell targets, including fresh autologous human tumor; and, the adoptive transfer of LAK cells has been shown to be effective therapy for a variety of murine tumors. Similarly, the administration of high-dose IL 2 in vivo can induce LAK activity from host precursor cells and mediate an anti-tumor effect. Phase I clinical trials for the use of IL 2 and/or LAK cells in humans for cancer therapy have been initiated by several research groups including our own. The purpose of the proposed studies is to further evaluate in murine models the immunobiology, therapeutic efficacy and toxicity of LAK cells and of high-dose IL 2 in order to elucidate the principles necessary for the effective use of such therapy in man.
The specific aims of the proposed research are: (1) To determine the phenotype of LAK effector cells potentially operative in tumor therapy; (2) To determine whether LAK effector cells can be expanded in number by long-term culture in vitro and thereby rendered more effective in therapy; (3) To determine the kinetics of survival and the distribution of donor LAK cells in vivo; (4) To determine the effect of exogenous IL 2 on the survival, distribution and function of donor LAK cells in vivo; (5) To determine whether host immunosuppression can increase the transferability and function of donor LAK cells; (6) To determine the kinetics of LAK cell generation in vivo induced by administration of high-dose IL 2; (7) To compare the efficacy and toxicity of high-dose IL 2 in vivo versus adoptively transferred LAK cells plus lower-dose IL 2; and, (8) To determine the effect of cytotoxic chemotherapy or radiation therapy on the subsequent ability to generate LAK cells in vitro or in vivo.
