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 5

Anti-CD137 agonistic mAb enhances anti–breast cancer activity of trastuzumab in vivo while retaining HER2 specificity against HER2-overexpressing breast cancer cell lines and a primary breast tumor.

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Anti-CD137 agonistic mAb enhances anti–breast cancer activity of trastuz...
nu/nu mice were inoculated with 5 × 106 MCF7 breast tumor cells s.c. on the left flank and 5 × 106 HER18 breast tumor cells s.c. on the right flank (A). (A–C) After tumor inoculation, mice received either trastuzumab on day 3 or trastuzumab on day 3 and anti-CD137 antibody on day 4, with each treatment repeated weekly for a total of 3 weeks. (B) Mice (10 per group) were monitored for tumor growth of MCF7 on the left flank (white circles) and HER18 on the right flank (white squares) when treated with trastuzumab, and MCF7 on the left flank (black circles) and HER18 on the right flank (black squares) when treated with trastuzumab and anti-CD137 mAbs (*P < 0.001). (C) Representative mice (3 of 10 per group) at 25 and 50 days after tumor inoculation. SCID mice were inoculated with 1 × 106 HER2+ primary breast tumor cells (SU-258) by intramammary injection 24 hours after 200 cGy total body irradiation (TBI). (D and E). On day 40, mice were randomized to 1 of 4 groups (5 mice per group) including IgG control with treatment on day 40 (circles), trastuzumab on day 40 (squares), anti-CD137 mAbs on day 41 (diamonds), or trastuzumab on day 40 and anti-CD137 mAbs on day 41 (triangles). Treatment was repeated weekly in each group for a total of 3 treatments. Mice were monitored for tumor growth (D, *P = 0.016) and overall survival (E, *P = 0.002). Data are shown as mean ± SEM.