Stimulation of natural killer cells with a CD137-specific antibody enhances trastuzumab efficacy in xenotransplant models of breast cancer
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
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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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 6

Increased expression of CD137 on circulating NK cells in patients receiving trastuzumab therapy.

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Increased expression of CD137 on circulating NK cells in patients receiv...
PBMCs were isolated from 11 patients with HER2-expressing breast cancer prior to and following trastuzumab treatment. (A) CD56 and CD3 expression on circulating lymphocytes and CD16 and CD137 expression on NK cell subsets CD3–CD56bight and CD3–CD56dim from a single representative patient at 3 time points, including prior to trastuzumab, and 24 hours and 7 days following trastuzumab. (B) Percentage of CD137+ cells among circulating CD3–CD56+ NK cells from 11 patients prior to and following trastuzumab, including 2 patients receiving their first dose of trastuzumab (patients 18345.BR.001 [white circles] and 18345.BR.006 [white squares]). Data are shown as mean ± SEM.