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Updated: Aug 24, 2025
Non-Viral Engineering of Primary Human T Cells via Homology-Mediated End-Joining Targeted Integration of Large DNA Templates
Published on: May 9, 2025
The target antigen determines the mechanism of acquired resistance to T cell-based therapies
Alex Martínez-Sabadell1, Beatriz Morancho2, Irene Rius Ruiz3
1Preclinical Research Program, Vall d'Hebron Institute of Oncology (VHIO), 08035 Barcelona, Spain; Centro de Investigación Biomédica en Red de Cáncer, Monforte de Lemos, 08029 Madrid, Spain; Cancer Research Program, Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), 08003 Barcelona, Spain; Department of Biochemistry and Molecular Biology, Universitat Autónoma de Barcelona, 08193 Bellaterra, Spain.
Abstract:
Despite the revolution of immunotherapy in cancer treatment, patients eventually progress due to the emergence of resistance. In this scenario, the selection of the tumor antigen can be decisive in the success of the clinical response. T cell bispecific antibodies (TCBs) are engineered molecules that include binding sites to the T cell receptor and to a tumor antigen. Using gastric CEA+/HER2+ MKN45 cells and TCBs directed against CEA or HER2, we show that the mechanism of resistance to a TCB is dependent on the tumor antigen. Acquired resistant models to a high-affinity-CEA-targeted TCB exhibit a reduction of CEA levels due to transcriptional silencing, which is reversible upon 5-AZA treatment. In contrast, a HER2-TCB resistant model maintains HER2 levels and exhibit a disruption of the interferon-gamma signaling. These results will help in the design of combinatorial strategies to increase the efficacy of cancer immunotherapies and to anticipate and overcome resistances.
Insights
Mechanisms of resistance to T cell bispecific antibodies (TCBs) vary by tumor antigen. CEA-TCB resistance involves reduced CEA levels, while HER2-TCB resistance disrupts interferon-gamma signaling, guiding future cancer immunotherapy strategies.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Cancer immunotherapy, particularly with T cell bispecific antibodies (TCBs), has revolutionized treatment.
- Patient response to immunotherapy can be limited by the development of resistance.
- Tumor antigen selection is critical for the efficacy of TCBs.
Purpose of the Study:
- To investigate the distinct mechanisms of resistance to T cell bispecific antibodies (TCBs) targeting different tumor antigens.
- To elucidate how resistance to CEA-targeted TCBs differs from resistance to HER2-targeted TCBs.
Main Methods:
- Utilized gastric cancer MKN45 cells expressing CEA and HER2.
- Developed acquired resistant models using high-affinity CEA-targeted and HER2-targeted TCBs.
- Analyzed changes in tumor antigen expression and interferon-gamma signaling pathways.
Main Results:
- Resistance to CEA-targeted TCBs was associated with reduced CEA expression via transcriptional silencing, reversible with 5-AZA treatment.
- Resistance to HER2-targeted TCBs involved maintained HER2 levels but disrupted interferon-gamma signaling.
- Demonstrated antigen-dependent mechanisms of resistance to TCBs.
Conclusions:
- The specific tumor antigen targeted by TCBs dictates the mechanism of acquired resistance.
- Understanding these distinct resistance pathways is crucial for designing effective combination therapies.
- Findings provide insights for overcoming resistance and improving cancer immunotherapy efficacy.
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