title: Targeting breast cancer stem cells with HER2-specific antibodies and natural killer cells.
abstract: Breast cancer is the most common cancer among women worldwide. Every year, nearly 1.4 million new cases of breast cancer are diagnosed, and about 450.000 women die of the disease. Approximately 15-25% of breast cancer cases exhibit increased quantities of the trans-membrane receptor tyrosine kinase human epidermal growth factor receptor 2 (HER2) on the tumor cell surface. Previous studies showed that blockade of this HER2 proto-oncogene with the antibody trastuzumab substantially improved the overall survival of patients with this aggressive type of breast cancer. Recruitment of natural killer (NK) cells and subsequent induction of antibody-dependent cell-mediated cytotoxicity (ADCC) contributed to this beneficial effect. We hypothesized that antibody binding to HER2-positive breast cancer cells and thus ADCC might be further improved by synergistically applying two different HER2-specific antibodies, trastuzumab and pertuzumab. We found that tumor cell killing via ADCC was increased when the combination of trastuzumab, pertuzumab, and NK cells was applied to HER2-positive breast cancer cells, as compared to the extent of ADCC induced by a single antibody. Furthermore, a subset of CD44(high)CD24(low)HER2(low) cells, which possessed characteristics of cancer stem cells, could be targeted more efficiently by the combination of two HER2-specific antibodies compared to the efficiency of one antibody. These in vitro results demonstrated the immunotherapeutic benefit achieved by the combined application of trastuzumab and pertuzumab. These findings are consistent with the positive results of the clinical studies, CLEOPATRA and NEOSPHERE, conducted with patients that had HER2-positive breast cancer. Compared to a single antibody treatment, the combined application of trastuzumab and pertuzumab showed a stronger ADCC effect and improved the targeting of breast cancer stem cells.
authors.affiliation: Junior research group "tumor progression and immune escape", Interdisciplinary Center for Clinical Research (IZKF), University of Würzburg Medical School Josef-Schneider-Str. 4, 97080 Würzburg, Germany ; Department for Obstetrics and Gynecology, University of Würzburg Medical School Josef-Schneider-Str. 4, 97080 Würzburg, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Diessner
authors.forename: Valentin
authors.initials: V
authors.lastname: Bruttel
authors.forename: Kathrin
authors.initials: K
authors.lastname: Becker
authors.forename: Miriam
authors.initials: M
authors.lastname: Pawlik
authors.forename: Roland
authors.initials: R
authors.lastname: Stein
authors.forename: Sebastian
authors.initials: S
authors.lastname: Häusler
authors.forename: Johannes
authors.initials: J
authors.lastname: Dietl
authors.forename: Jörg
authors.initials: J
authors.lastname: Wischhusen
authors.forename: Arnd
authors.initials: A
authors.lastname: Hönig
keywords: ADCC; Trastuzumab; breast cancer; pertuzumab; tumor stem cells