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

P Müller, M Kreuzaler, T Khan, DS Thommen… - Science translational …, 2015 - science.org
P Müller, M Kreuzaler, T Khan, DS Thommen, K Martin, K Glatz, S Savic, N Harbeck, U Nitz…
Science translational medicine, 2015science.org
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 …
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.
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