Human Lymphokine-Activated Killer Cells Augment Immunotherapy of Human Colon Carcinoma Xenografts with Monoclonal Antibody D612

Abstract

The tumoricidal properties of an anti-human colon carcinoma monoclonal antibody (MAb), designated D612 (IgG2a), alone and in combination with IL-2-activated human lymphocytes were investigated in athymic mice bearing LS-174T colon tumor xenografts. Treatment of mice bearing LS-174T tumors (1 day, s.c.) with a single i.v. dose of 400 micrograms of D612 alone resulted in a significant inhibition of tumor growth. Lower doses of D612 had an intermediate effect on tumor growth. Similar inhibition of tumor growth was obtained when D612 was administered in three doses of 400 or 800 micrograms each during the first week after tumor implantation. Mouse macrophages but not splenocytes mediated antibody-dependent cellular cytotoxicity with D612, suggesting that tumor inhibition was due to the participation of host macrophages with D612. Human lymphokine-activated killer (LAK) cells were generated by incubating human peripheral blood mononuclear cells (PBLs) from normal donors with 100 U/ml of IL-2 for 24 h. An administration of human LAK cells did not significantly inhibit the growth of the human xenograft tumor. Adoptive transfer of a single dose of human LAK cells (2 x 10(7), i.v.) into mice treated with a suboptimal dose of D612 (200 micrograms) significantly inhibited tumor growth compared to that obtained with either D612 or LAK cells alone. Similar results were obtained with three doses of D612 plus human LAK cells although there was a tendency for multiple doses of LAK cells alone to show some antitumor effects. LAK cells or PBLs had similar antitumor activities when used in conjunction with D612. When larger established tumors were treated, single or multiple doses of D612 or LAK cells alone were without effect; however, LAK cells plus D612 elicited significant growth inhibition. These results demonstrate that the tumoricidal properties of LAK cells and the D612 MAb can be augmented when used together in the immunotherapy of human colon cancer xenografts.