Interleukin-2 enhances the natural killer cell response to Herceptin-coated Her2/neu-positive breast cancer cells

The Her2/neu (c-erbB-2) oncogene encodes a 185-kDa protein tyrosine kinase which is overexpressed in 20% of breast adenocarcinomas and is recognized b y a humanized anti-Her2/neu monoclonal antibody (mAb) (rhu4D5 or Herceptin) . Natural killer (NK) cells are capable of mediating antibody-dependent cel l cytotoxicity (ADCC) against antibody-coated targets via their expression of a low-affinity receptor for IgG (Fc gamma RIII or CD16). NK cells can be expanded in cancer patients via the administration of low-dose interleukin -2 (IL-2) and become potent cytotoxic effectors following exposure to high doses of IL-2. We tested IL-2-activated NK cells against Her2/neu(+) (MCF-7 (Her2/neu)) and Her2/neu(-) (MDA-468) breast cancer cell lines in a 4-h Cr- 51-release cytotoxicity assay in the presence or absence of rhu4D5 mAb (eff ector: target ratio = 10:1). Specific lysis of rhu4D5-coated MCF-7(Her2/neu ) and MDA-468 target cells by IL-2-activated NK cells was 35% and 3%, respe ctively (P < 0.05). Lysis was less than 5 % when targets were treated with either the non-humanized mu4D5 mAb or control hulgG. Lysis of rhu4D5-coated MCF-7(Her2/neu) cells was inhibited by 80% when NK cells were pre-treated with an anti-Fc receptor antibody prior to use in the cytotoxicity assay. E nhanced ADCC of MCF-7(Her2/neu) target cells was seen when the effector cel ls consisted of mononuclear cells obtained from a patient demonstrating sig nificant expansion of NK cells secondary to therapy with low-dose IL-2. Ser um from patients receiving infusions of rhu4D5 mAb could substitute for exo genous antibody in the ADCC assay. NK cells activated by rhu4D5-coated tumo r cells in the presence of IL-2 also produced large amounts of IFN-gamma wi th concomitant up-regulation of cell-surface activation markers CD25 and CD 69. These results lend support to the concurrent use of rhu4D5 mAb and IL-2 therapy in patients with cancers that express the Her2/neu oncogene.