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

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Abstract
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 by a humanized anti‐Her2 / neu monoclonal antibody (mAb) (rhu4D5 or Herceptin). Natural killer (NK) cells are capable of mediating antibody‐dependent cell cytotoxicity (ADCC) against antibody‐coated targets via their expression of a low‐affinity receptor for IgG (FcγRIII 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‐7Her2 / neu) and Her2 / neu– (MDA‐468) breast cancer cell lines in a 4‐h 51Cr‐release cytotoxicity assay in the presence or absence of rhu4D5 mAb (effector : target ratio = 10 : 1). Specific lysis of rhu4D5‐coated MCF‐7Her2 / neu and MDA‐468 target cells by IL‐2‐activated NK cells was 35 % and 3 %, respectively (p < 0.05). Lysis was less than 5 % when targets were treated with either the non‐humanized mu4D5 mAb or control huIgG. Lysis of rhu4D5‐coated MCF‐7Her2 / 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. Enhanced ADCC of MCF‐7Her2 / neu target cells was seen when the effector cells consisted of mononuclear cells obtained from a patient demonstrating significant expansion of NK cells secondary to therapy with low‐dose IL‐2. Serum from patients receiving infusions of rhu4D5 mAb could substitute for exogenous antibody in the ADCC assay. NK cells activated by rhu4D5‐coated tumor cells in the presence of IL‐2 also produced large amounts of IFN‐γ with concomitant up‐regulation of cell‐surface activation markers CD25 and CD69. 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.

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