NATURAL-KILLER CELL-MEDIATED ERADICATION OF NEUROBLASTOMA METASTASES TO BONE-MARROW BY TARGETED INTERLEUKIN-2 THERAPY

Targeted interleukin-2 (IL-2) therapy with a genetically engineered an tidisialoganglioside GD(2) antibody-IL-2 fusion protein induced a cell -mediated antitumor response that effectively eradicated established b one marrow and liver metastases in a syngeneic model of neuroblastoma. The mechanism involved is exclusively natural killer (NK) cell-depend ent, because NK-cell deficiency abrogated the antitumor effect, In con trast, the fusion protein remained completely effective in the T-cell- deficient mice or immuno-competent mice depleted of CD8(+) T cells in vivo. A strong stimulation of NK-cell activity was also shown in vitro . Immunohistology of the leukocytic infiltrate of livers from treated mice revealed a strong staining for NK cells but not for CD8(+) T cell s. The therapeutic effect of the fusion protein was increased when com bined with NK-cell-stimulating agents, such as poly I:C or recombinant mouse interferon-gamma. In conclusion, these data show that targeted delivery of cytokines to the tumor microenvironment offers a new strat egy to elicit an effective cellular immune response mediated by NK cel ls against metastatic neuroblastoma. This therapeutic effect may have general clinical implications for the treatment of patients with minim al residual disease who suffer from T-cell suppression after high-dose chemotherapy but are not deficient in NK cells. (C) 1998 by The Ameri can Society of Hematology.