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Natural Killer Cell-Mediated Eradication of Neuroblastoma Metastases
to Bone Marrow by Targeted Interleukin-2 Therapy
Holger N. Lode,
Rong Xiang,
Torsten Dreier,
Nissi M. Varki,
Stephen D. Gillies, and
Ralph A. Reisfeld
From The Scripps Research Institute, Department of Immunology; the
University of California, Cancer Center, La Jolla, CA; and Fuji
ImmunoPharmaceuticals Corp, Lexington, MA.
Targeted interleukin-2 (IL-2) therapy with a genetically engineered
antidisialoganglioside GD2 antibody-IL-2 fusion protein induced a cell-mediated antitumor response that effectively eradicated established bone marrow and liver metastases in a syngeneic model of
neuroblastoma. The mechanism involved is exclusively natural killer
(NK) cell-dependent, because NK-cell deficiency abrogated the
antitumor effect. In contrast, the fusion protein remained completely effective in the T-cell-deficient mice or
immunocompetent 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 cells. The therapeutic effect of the fusion
protein was increased when combined with NK-cell-stimulating agents,
such as poly I:C or recombinant mouse interferon- . In
conclusion, these data show that targeted delivery of cytokines to the
tumor microenvironment offers a new strategy to elicit an effective
cellular immune response mediated by NK cells against metastatic
neuroblastoma. This therapeutic effect may have general clinical
implications for the treatment of patients with minimal residual
disease who suffer from T-cell suppression after high-dose chemotherapy
but are not deficient in NK cells.
Blood, Vol. 91 No. 5 (March 1), 1998:
pp. 1706-1715
© 1998 by The American Society of Hematology.
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