Science Translational Medicine 2015-11-25

Trastuzumab emtansine (T-DM1) renders HER2+ breast cancer highly susceptible to CTLA-4/PD-1 blockade.

Philipp Müller, Matthias Kreuzaler, Tarik Khan, Daniela S Thommen, Kea Martin, Katharina Glatz, Spasenija Savic, Nadia Harbeck, Ulrike Nitz, Oleg Gluz, Michael von Bergwelt-Baildon, Hans Kreipe, Sai Reddy, Matthias Christgen, Alfred Zippelius

Index: Sci. Transl. Med. 7 , 315ra188, (2015)

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Abstract

Targeted drug delivery with antibody-drug conjugates such as the HER2-directed ado-trastuzumab emtansine (T-DM1) has emerged as a powerful strategy for cancer therapy. We show that T-DM1 is particularly effective in eliciting antitumor immunity in patients with early breast cancer (WSG-ADAPT trial) and in a HER2-expressing orthotopic tumor model. In the latter, despite primary resistance to immunotherapy, combined treatment with T-DM1 and anti-CTLA-4/PD-1 (cytotoxic T lymphocyte-associated protein-4/programmed cell death protein-1) was curative because it triggered innate and adaptive immunity. Tumor rejection was accompanied by massive T cell infiltration, TH1 (T helper 1) cell polarization, and, notably, a substantial increase in regulatory T cells. Depletion of regulatory T cells resulted in inflammation and tissue damage, implying their essential role in protecting the host during therapy. This study provides insights into the mechanisms of T-DM1's therapeutic activity and a rationale for potential therapeutic combination strategies with immunotherapy. Copyright © 2015, American Association for the Advancement of Science.