Low-affinity anti-HER2-CAR T cells efficiently eradicate HER2+ and HER2low cancer cells with reduced toxicity on healthy tissue
11 affiliations
- 1Department of Internal Medicine III, Hematology & Internal Oncology, University Hospital Regensburg, Regensburg, Germany
- 2Division of Plastic and Reconstructive Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, United States
- 3Department of Oral and Maxillofacial Surgery, Charité–Universitätsmedizin Berlin, Berlin, Germany
- 4Leibniz Institute for Immunotherapy (LIT), Regensburg, Germany
- 5Division of Hematology and Oncology, Department of Medicine, Freiburg University Medical Center, Albert-Ludwigs-University, Freiburg, Germany
- 6Institute of Pathology, University Hospital Regensburg, Regensburg, Germany
- 7Institute of Pathology, Phillips University Marburg, Marburg, Germany
- 8School of Medicine, Center for Translational Cancer Research (TranslaTUM), Technical University of Munich, Munich, Germany
- 9German Cancer Consortium (DKTK), Partner-site Munich and German Cancer Research Center (DKFZ), Heidelberg, Germany
- 10Chair of Translational Cancer Research and Institute of Experimental Cancer Therapy, Klinikum Rechts der Isar, TUM School of Medicine and Health, Technical University of Munich, Munich, Germany
- 11Bavarian Cancer Research Center (BZKF), Regensburg, Germany
Abstract
Chimeric antigen receptor (CAR) T cell therapy is considered a therapeutic breakthrough in hematological malignancies. However, its translation to metastasized solid tumors remains limited by the paucity of “druggable” targets and the limited therapeutic potency of the cell therapeutics in solid cancers. Human epidermal growth factor receptor 2 (HER2), a promising target for treatment of metastasized solid cancers, is amplified in around 3% (HER2+ cancer) and overexpressed without amplification in ∼40% (HER2low cancer) of all carcinomas, yet the physiological expression of HER2 on healthy tissues poses the risk of on-target off-tumor effects. To address this, we utilized low-affinity (LA) Anti-HER2-CAR T cells. These CAR T cells exhibited efficient lysis of HER2+ SKOV3 ovarian cancer cells even at low effector-to-target ratios. Following stimulation through cancer cells, LA Anti-HER2-CAR T cells showed rapid proliferation and elevation of pro-inflammatory cytokines markers. Low numbers of CAR T cells were sufficient to induce durable complete remissions of systemically seeded ovarian cancer in NOD-Prkdc
scid
-IL2rg
Tm1 /Rj mice. LA Anti-HER2 CAR T cells also exhibited tumor regression and lasting tumor control in a subcutaneous in vivo model of HER2low LS174T cells. Additionally, the LA and high-affinity (HA) CAR T cells could effectively combat HER2low human colorectal cancer (CRC) cell lines and primary CRC organoids, while LA Anti-HER2-CAR T cells showed a trend-wise reduced lysis of healthy colon organoids. Our results suggest that LA Anti-HER2-CAR T cells provide a novel treatment option for HER2-overexpressing advanced systemic tumors. Importantly, they effectively distinguished between healthy colon tissue and HER2low cancer, broadening the scope of HER2-directed CAR T cells to this frequent cancer subset.
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BibTeX
@article{knoedler2026lowaffinity,
title = {{Low-affinity anti-HER2-CAR T cells efficiently eradicate HER2+ and HER2low cancer cells with reduced toxicity on healthy tissue}},
author = {Leonard Knoedler and Konstantin Herfeld and Julian N. Scherer and Kaiji Fan and Dhyani Shah and Sascha Goettert and Luisa Becker and Iria Lloshi and Suqi Li and Dennis C. Harrer and Matthias A. Fante and Tobias Wertheimer and Roland Schelker and Severin Guetter and Misbah Tariq and Omer Khalid and Alexander Scheiter and Wolfgang Herr and Christian Schmidl and Moritz Jesinghaus and Markus Tschurtschenthaler and Hendrik Poeck and Markus Perl},
journal = {Frontiers in Bioengineering and Biotechnology},
year = {2026},
month = oct,
doi = {10.3389/fbioe.2026.1895507},
url = {https://doi.org/10.3389/fbioe.2026.1895507},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Low-affinity anti-HER2-CAR T cells efficiently eradicate HER2+ and HER2low cancer cells with reduced toxicity on healthy tissue
AU - Leonard Knoedler
AU - Konstantin Herfeld
AU - Julian N. Scherer
AU - Kaiji Fan
AU - Dhyani Shah
AU - Sascha Goettert
AU - Luisa Becker
AU - Iria Lloshi
AU - Suqi Li
AU - Dennis C. Harrer
AU - Matthias A. Fante
AU - Tobias Wertheimer
AU - Roland Schelker
AU - Severin Guetter
AU - Misbah Tariq
AU - Omer Khalid
AU - Alexander Scheiter
AU - Wolfgang Herr
AU - Christian Schmidl
AU - Moritz Jesinghaus
AU - Markus Tschurtschenthaler
AU - Hendrik Poeck
AU - Markus Perl
PY - 2026
DA - 2026/10/12
JO - Frontiers in Bioengineering and Biotechnology
DO - 10.3389/fbioe.2026.1895507
UR - https://doi.org/10.3389/fbioe.2026.1895507
AB - Chimeric antigen receptor (CAR) T cell therapy is considered a therapeutic breakthrough in hematological malignancies. However, its translation to metastasized solid tumors remains limited by the paucity of “druggable” targets and the limited therapeutic potency of the cell therapeutics in solid cancers. Human epidermal growth factor receptor 2 (HER2), a promising target for treatment of metastasized solid cancers, is amplified in around 3% (HER2+ cancer) and overexpressed without amplification in ∼40% (HER2low cancer) of all carcinomas, yet the physiological expression of HER2 on healthy tissues poses the risk of on-target off-tumor effects. To address this, we utilized low-affinity (LA) Anti-HER2-CAR T cells. These CAR T cells exhibited efficient lysis of HER2+ SKOV3 ovarian cancer cells even at low effector-to-target ratios. Following stimulation through cancer cells, LA Anti-HER2-CAR T cells showed rapid proliferation and elevation of pro-inflammatory cytokines markers. Low numbers of CAR T cells were sufficient to induce durable complete remissions of systemically seeded ovarian cancer in NOD-Prkdc scid -IL2rg Tm1 /Rj mice. LA Anti-HER2 CAR T cells also exhibited tumor regression and lasting tumor control in a subcutaneous in vivo model of HER2low LS174T cells. Additionally, the LA and high-affinity (HA) CAR T cells could effectively combat HER2low human colorectal cancer (CRC) cell lines and primary CRC organoids, while LA Anti-HER2-CAR T cells showed a trend-wise reduced lysis of healthy colon organoids. Our results suggest that LA Anti-HER2-CAR T cells provide a novel treatment option for HER2-overexpressing advanced systemic tumors. Importantly, they effectively distinguished between healthy colon tissue and HER2low cancer, broadening the scope of HER2-directed CAR T cells to this frequent cancer subset.
SN - 2296-4185
ER -