Transgenic expression of IL-2 in peripheral neuroectodermal tumor cells yields wild type tumor cell lysis

Systemic Interleukin-2 (IL-2) therapy in peripheral neuroectodermal tumor patients is often associated with severe side effects, in particular leukopenia and infection. Gene targeting experiments suggest that IL-2-induced immunodeficiency may be due to polyclonal T cell activation and induction of apoptosis. An alternative to systemic IL-2 therapy would be to achieve a local cytokine production in the proximity of the tumor, thereby expanding tumor restricted effector cells that can recirculate and reach distant sites of metastasis. In Cr cytotoxicity assays we were able to demonstrate Ewing Tumor cell lysis by allogenous as well as autologous mononuclear cells (MNCs) previously stimulated by exogenous addition of IL-2. We transfected Ewing tumor cells as well as fibroblasts with an IL-2 gene expression vector using a cationic liposome reagent. Upon using IL-2 secreting fibroblasts as source of IL-2 for priming MNCs we obtained tumor cell lysis in the Cr cytotoxicity assays . Stimulating MNCs in coculture with IL-2 secreting peripheral neuroectodermal tumor cells yielded wild type tumor cell lysis at a comparable level to that achieved by priming MNCs with exogenously adding 30 IU/ml IL-2. In patients receiving systemic IL-2 therapy, the average level of IL-2 measured in serum during application of the highest dose was 20 IU/ml. Our findings provide evidence that transgenic expression of IL-2 in peripheral neuroectodermal tumor cells yields wild type tumor cell lysis. Thus, transgenic expression of IL-2 within the tumors may expand tumor infiltrating effector cells without polyclonal T cell activation and apoptosis induction.