Stimulation of natural killer cells with a CD137-specific antibody enhances trastuzumab efficacy in xenotransplant models of breast cancer
Holbrook E. Kohrt, … , Lieping Chen, Ronald Levy
Holbrook E. Kohrt, … , Lieping Chen, Ronald Levy
Published February 13, 2012
Citation Information: J Clin Invest. 2012;122(3):1066-1075. https://doi.org/10.1172/JCI61226.
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Research Article Oncology

Stimulation of natural killer cells with a CD137-specific antibody enhances trastuzumab efficacy in xenotransplant models of breast cancer

Abstract

Trastuzumab, a monoclonal antibody targeting human epidermal growth factor receptor 2 (HER2; also known as HER-2/neu), is indicated for the treatment of women with either early stage or metastatic HER2+ breast cancer. It kills tumor cells by several mechanisms, including antibody-dependent cellular cytotoxicity (ADCC). Strategies that enhance the activity of ADCC effectors, including NK cells, may improve the efficacy of trastuzumab. Here, we have shown that upon encountering trastuzumab-coated, HER2-overexpressing breast cancer cells, human NK cells become activated and express the costimulatory receptor CD137. CD137 activation, which was dependent on NK cell expression of the FcγRIII receptor, occurred both in vitro and in the peripheral blood of women with HER2-expressing breast cancer after trastuzumab treatment. Stimulation of trastuzumab-activated human NK cells with an agonistic mAb specific for CD137 killed breast cancer cells (including an intrinsically trastuzumab-resistant cell line) more efficiently both in vitro and in vivo in xenotransplant models of human breast cancer, including one using a human primary breast tumor. The enhanced cytotoxicity was restricted to antibody-coated tumor cells. This sequential antibody strategy, combining a tumor-targeting antibody with a second antibody that activates the host innate immune system, may improve the therapeutic effects of antibodies against breast cancer and other HER2-expressing tumors.

Authors

Holbrook E. Kohrt, Roch Houot, Kipp Weiskopf, Matthew J. Goldstein, Ferenc Scheeren, Debra Czerwinski, A. Dimitrios Colevas, Wen-Kai Weng, Michael F. Clarke, Robert W. Carlson, Frank E. Stockdale, Joseph A. Mollick, Lieping Chen, Ronald Levy

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Figure 1

Trastuzumab induces CD137 upregulation on human NK cells following exposure to HER2-overexpressing tumor cells.

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Trastuzumab induces CD137 upregulation on human NK cells following expos...
Purified NK cells from the peripheral blood of 3 healthy donors were analyzed for CD137 expression after 24-hour culture with breast cancer cell lines or no tumor and IgG control, rituximab, or trastuzumab. (A) Percentage of CD137+ cells among CD3–CD56+ NK cells from 3 healthy donors cultured with MCF7, BT474M1, HER18, and SKBR3 breast cancer cell lines. *P = 0.046; **P < 0.001. Data are shown as mean ± SEM. (B) HER2 surface expression on breast cancer cell lines, with histograms colored according to the log10-fold increase in MFI of breast cancer cell line relative to isotype. (C) CD137 and CD16 expression on NK cell subsets CD3–CD56bight and CD3–CD56dim from a representative healthy donor after 24-hour culture with IgG control alone, HER18 and IgG control, HER18 and rituximab, or HER18 and trastuzumab. Percentages of total NK cells per quadrant are indicated.