title: Trastuzumab emtansine (T-DM1) renders HER2+ breast cancer highly susceptible to CTLA-4/PD-1 blockade.
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.
authors.affiliation: Department of Biomedicine, University Hospital and University of Basel, CH-4031 Basel, Switzerland. ph.mueller@unibas.ch alfred.zippelius@usb.ch.
authors.forename: Philipp
authors.initials: P
authors.lastname: Müller
authors.affiliation: Department of Biomedicine, University Hospital and University of Basel, CH-4031 Basel, Switzerland.
authors.forename: Matthias
authors.initials: M
authors.lastname: Kreuzaler
authors.affiliation: Department of Biosystems Science and Engineering, ETH Zürich, CH-4058 Basel, Switzerland.
authors.forename: Tarik
authors.initials: T
authors.lastname: Khan
authors.affiliation: Department of Biomedicine, University Hospital and University of Basel, CH-4031 Basel, Switzerland. Department of Medical Oncology, University Hospital Basel, CH-4031 Basel, Switzerland.
authors.forename: Daniela S
authors.initials: DS
authors.lastname: Thommen
authors.affiliation: Department of Biomedicine, University Hospital and University of Basel, CH-4031 Basel, Switzerland.
authors.forename: Kea
authors.initials: K
authors.lastname: Martin
authors.affiliation: Institute of Pathology, University Hospital Basel, CH-4031 Basel, Switzerland.
authors.forename: Katharina
authors.initials: K
authors.lastname: Glatz
authors.affiliation: Institute of Pathology, University Hospital Basel, CH-4031 Basel, Switzerland.
authors.forename: Spasenija
authors.initials: S
authors.lastname: Savic
authors.affiliation: Breast Center, Department of Obstetrics and Gynecology, University of Munich, D-81377 Munich, Germany. West German Study Group, D-41061 Mönchengladbach, Germany.
authors.forename: Nadia
authors.initials: N
authors.lastname: Harbeck
authors.affiliation: 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.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Nitz
authors.affiliation: West German Study Group, D-41061 Mönchengladbach, Germany. Breast Center Niederrhein, Ev. Bethesda Hospital, D-41061 Mönchengladbach, Germany.
authors.forename: Oleg
authors.initials: O
authors.lastname: Gluz
authors.affiliation: First Department of Internal Medicine, University of Cologne, D-50937 Cologne, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: von Bergwelt-Baildon
authors.affiliation: West German Study Group, D-41061 Mönchengladbach, Germany. Institute of Pathology, Hannover Medical School, D-30625 Hannover, Germany.
authors.forename: Hans
authors.initials: H
authors.lastname: Kreipe
authors.affiliation: Department of Biosystems Science and Engineering, ETH Zürich, CH-4058 Basel, Switzerland.
authors.forename: Sai
authors.initials: S
authors.lastname: Reddy
authors.affiliation: West German Study Group, D-41061 Mönchengladbach, Germany. Institute of Pathology, Hannover Medical School, D-30625 Hannover, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Christgen
authors.affiliation: 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.
authors.forename: Alfred
authors.initials: A
authors.lastname: Zippelius
mesh_terms: D000080044:Ado-Trastuzumab Emtansine; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000628:therapy; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors*; D005260:Female; D018734:Genes, erbB-2; D006801:Humans; D008453:Maytansine / Q000031:analogs & derivatives* / Q000494:pharmacology; D051379:Mice; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors*; D000068878:Trastuzumab
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D060908:CTLA-4 Antigen; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D008453:Maytansine; D000068878:Trastuzumab; D000080044:Ado-Trastuzumab Emtansine