Mueller, 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 ORCID: 0000-0002-9177-0857, Christgen, Matthias and Zippelius, Alfred (2015). Trastuzumab emtansine (T-DM1) renders HER2(+) breast cancer highly susceptible to CTLA-4/PD-1 blockade. Sci. Transl. Med., 7 (315). WASHINGTON: AMER ASSOC ADVANCEMENT SCIENCE. ISSN 1946-6242

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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 tumormodel. 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 bymassive T cell infiltration, T(H)1 (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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Mueller, PhilippUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kreuzaler, MatthiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Khan, TarikUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thommen, Daniela S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Martin, KeaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Glatz, KatharinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Savic, SpasenijaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Harbeck, NadiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nitz, UlrikeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gluz, OlegUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
von Bergwelt-Baildon, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kreipe, HansUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reddy, SaiUNSPECIFIEDorcid.org/0000-0002-9177-0857UNSPECIFIED
Christgen, MatthiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zippelius, AlfredUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-386778
DOI: 10.1126/scitranslmed.aac4925
Journal or Publication Title: Sci. Transl. Med.
Volume: 7
Number: 315
Date: 2015
Publisher: AMER ASSOC ADVANCEMENT SCIENCE
Place of Publication: WASHINGTON
ISSN: 1946-6242
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
REGULATORY T-CELLS; TUMOR-INFILTRATING LYMPHOCYTES; ANTIBODY-DRUG; ADJUVANT TRASTUZUMAB; BRENTUXIMAB VEDOTIN; ANTITUMOR IMMUNITY; CHEMOTHERAPY; THERAPY; PLUS; IPILIMUMABMultiple languages
Cell Biology; Medicine, Research & ExperimentalMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/38677

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