1. Preclinical efficacy of a HER2 synNotch/CEA-CAR combinatorial immunotherapy against colorectal cancer with HER2 amplification.
- Author
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Cortese M, Torchiaro E, D'Andrea A, Petti C, Invrea F, Franco L, Donini C, Leuci V, Leto SM, Vurchio V, Cottino F, Isella C, Arena S, Vigna E, Bertotti A, Trusolino L, Sangiolo D, and Medico E
- Subjects
- Humans, Animals, Mice, Cell Line, Tumor, Carcinoembryonic Antigen immunology, Carcinoembryonic Antigen genetics, Gene Amplification, Killer Cells, Natural immunology, Killer Cells, Natural metabolism, Immunotherapy methods, Immunotherapy, Adoptive methods, Disease Models, Animal, Female, Colorectal Neoplasms therapy, Colorectal Neoplasms genetics, Colorectal Neoplasms immunology, Receptor, ErbB-2 metabolism, Receptor, ErbB-2 genetics, Receptors, Chimeric Antigen immunology, Receptors, Chimeric Antigen genetics, Receptors, Chimeric Antigen metabolism, Xenograft Model Antitumor Assays
- Abstract
HER2 amplification occurs in approximately 5% of colorectal cancer (CRC) cases and is associated only partially with clinical response to combined human epidermal growth factor receptor 2 (HER2)/epidermal growth factor receptor (EGFR)-targeted treatment. An alternative approach based on adoptive cell therapy using T cells engineered with anti-HER2 chimeric antigen receptor (CAR) proved to be toxic due to on-target/off-tumor activity. Here we describe a combinatorial strategy to safely target HER2 amplification and carcinoembryonic antigen (CEA) expression in CRC using a synNotch-CAR-based artificial regulatory network. The natural killer (NK) cell line NK-92 was engineered with an anti-HER2 synNotch receptor driving the expression of a CAR against CEA only when engaged. After being transduced and sorted for HER2-driven CAR expression, cells were cloned. The clone with optimal performances in terms of specificity and amplitude of CAR induction demonstrated significant activity in vitro and in vivo specifically against HER2-amplified (HER2amp)/CEA
+ CRC models, with no effects on cells with physiological HER2 levels. The HER2-synNotch/CEA-CAR-NK system provides an innovative, scalable, and safe off-the-shelf cell therapy approach with potential against HER2amp CRC resistant or partially responsive to HER2/EGFR blockade., Competing Interests: Declaration of interests The authors declare no potential conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2024
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