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

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)...

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Bibliographic Details
Published in:Science translational medicine 2015-11, Vol.7 (315), p.315ra188-315ra188
Main Authors: Müller, Philipp, Kreuzaler, Matthias, Khan, Tarik, Thommen, Daniela S, Martin, Kea, Glatz, Katharina, Savic, Spasenija, Harbeck, Nadia, Nitz, Ulrike, Gluz, Oleg, von Bergwelt-Baildon, Michael, Kreipe, Hans, Reddy, Sai, Christgen, Matthias, Zippelius, Alfred
Format: Article
Language:English
Subjects:
Animals
Antibodies, Monoclonal, Humanized - pharmacology
Antineoplastic Agents - pharmacology
Breast Neoplasms - drug therapy
Breast Neoplasms - genetics
Breast Neoplasms - therapy
CTLA-4 Antigen - antagonists & inhibitors
Female
Genes, erbB-2
Humans
Maytansine - analogs & derivatives
Maytansine - pharmacology
Mice
Programmed Cell Death 1 Receptor - antagonists & inhibitors
Trastuzumab
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Summary: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.
ISSN:1946-6234
1946-6242
DOI:10.1126/scitranslmed.aac4925