In Vivo Effects of Interleukin 2 - Activated Lymphocytes

In several murine tumor models the adoptive transfer of sensitized lymphoid cells is capable of mediating the regression of established tumor (1-3). Identification of the most appropriate cells for use in adoptive transfer is a major problem. While cells specifically sensitized in vivo or in vitro to unique cancer antigens can be highly effective, it is often difficult to obtain these cells because of the poor immunogenicity of many murine tumors. This problem is especially cogent in considering human tumors in which poor immunogenicity and problems with availability of suitable preparations of human tumor cells for in vitro sensitization also exist. In both mice and humans we have extensively studied, in vitro, the activity and specificity of activated killer cells. These cells can be generated in vitro by exposure of normal lymphocytes to interleukin 2 (IL-2) 1 (4, 5), lectins (6, 7), or pooled alloantigens (8). These activated cells recognize and lyse fresh autologous (in the human) or syngeneic (in the mouse) natural killer (NK)-resistant cancer cells, but do not lyse normal cells. The serologic phenotype of the precursor and effector cells of these activated killer cells has been extensively studied in mouse and man (4, 7, 8). The biologic role of activated killer cells is unknown, though it is known they can lyse tumor cells in Winn assays (9-1 1). However, because of the ease of generation of these cells and their potential applicability to the treatment of human tumors we have explored the possible use of these cells, adoptively transferred, in the treatment of a highly metastatic and virulent murine tumor. This report is the first demonstration that lymphokine-activated killer cells (LAK cells), activated in vitro by IL-2, can inhibit the growth of established melanoma pulmonary metastases. The kinetics of this phenomenon, the nature of the cells involved, and the in vitro activation stimulus required have been studied. * Reprint requests should be addressed to Dr. S. A. Rosenberg, Chief of Surgery, National Cancer Institute, Bethesda, MD 20205. i Abbreviations used in this paper: C', complement; CM, complete medium; E, erythrocyte; HBSS, Hanks' Balanced Salt Solution; IL-2, interleukin 2; LAK, lymphokine-activated killer cells; NK, natural killer cells; PMA, phorbol 12-myristate-13-acetate; SDS-PAGE, sodium dodecyl sulfate polyacrylamide gel electrophoresis.