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Sci Transl Med. 2015 Nov 25;7(315):315ra188. doi: 10.1126/scitranslmed.aac4925.

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

Author information

1
Department of Biomedicine, University Hospital and University of Basel, CH-4031 Basel, Switzerland. ph.mueller@unibas.ch alfred.zippelius@usb.ch.
2
Department of Biomedicine, University Hospital and University of Basel, CH-4031 Basel, Switzerland.
3
Department of Biosystems Science and Engineering, ETH Zürich, CH-4058 Basel, Switzerland.
4
Department of Biomedicine, University Hospital and University of Basel, CH-4031 Basel, Switzerland. Department of Medical Oncology, University Hospital Basel, CH-4031 Basel, Switzerland.
5
Institute of Pathology, University Hospital Basel, CH-4031 Basel, Switzerland.
6
Breast Center, Department of Obstetrics and Gynecology, University of Munich, D-81377 Munich, Germany. West German Study Group, D-41061 Mönchengladbach, Germany.
7
West German Study Group, D-41061 Mönchengladbach, Germany. Women's Clinic, Heinrich Heine University Düsseldorf, D-40225 Düsseldorf, Germany. Breast Center Niederrhein, Ev. Bethesda Hospital, D-41061 Mönchengladbach, Germany.
8
West German Study Group, D-41061 Mönchengladbach, Germany. Breast Center Niederrhein, Ev. Bethesda Hospital, D-41061 Mönchengladbach, Germany.
9
First Department of Internal Medicine, University of Cologne, D-50937 Cologne, Germany.
10
West German Study Group, D-41061 Mönchengladbach, Germany. Institute of Pathology, Hannover Medical School, D-30625 Hannover, Germany.
11
Department of Biomedicine, University Hospital and University of Basel, CH-4031 Basel, Switzerland. Department of Medical Oncology, University Hospital Basel, CH-4031 Basel, Switzerland. ph.mueller@unibas.ch alfred.zippelius@usb.ch.

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.

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PMID:
26606967
DOI:
10.1126/scitranslmed.aac4925
[Indexed for MEDLINE]

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