ACTIVATION OF HUMAN EFFECTOR-CELLS BY A TUMOR REACTIVE RECOMBINANT ANTIGANGLIOSIDE GD(2) INTERLEUKIN-2 FUSION PROTEIN (CH14.18-IL2)

Cytotoxic effector cells interact with target cells through various me chanisms, CTLs use the antigen-specific T cell receptor, whereas Fc re ceptor-positive natural killer cells use this receptor to interact wit h antibody-coated target cells, We evaluated the tumor-binding and lym phocyte-activating capability of a recombinant fusion protein consisti ng of a tumor-selective human/mouse chimeric anti-ganglioside GD2 anti body (ch14,18) and recombinant human interleukin-2 (IL2) (ch14.18-IL2) , This fusion protein bound specifically to GD2-positive melanoma and neuroblastoma tumor cell lines, and its IL2 component stimulated in vi tro proliferation of an IL2-dependent cell line, as well as peripheral blood mononuclear cells, in healthy control individuals and in cancer patients receiving continuous infusion of IL2, The IL2 presented by t he fusion protein, when bound to tumor cells, induced proliferation of IL2-responsive cells as well as a comparable amount of soluble IL2 di d, This suggests that localization of IL2 at the site of contact betwe en tumor and effector cells is an effective way of presenting this cyt okine to IL2-responsive cells, The ch14,18-IL2 fusion protein also med iated antibody-dependent cellular cytotoxicity with Fc receptor-positi ve effector cells to an extent similar to ch14,18, These results, toge ther with those of previous studies documenting antitumor efficacy aga inst human tumor xenografts in SCID mice and GD2-positive murine tumor s in immunocompetent syngeneic mice, suggest that the ch14.18-IL2 fusi on protein should be tested in Phase I and II trials in patients with GD2-positive tumors.