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Updated: Jun 28, 2026
Advances in Human Induced Pluripotent Stem Cell-Derived Chimeric Antigen Receptor-Expressing Natural Killer Cells
Published on: February 14, 2025
Engineering antigen-specific primary human NK cells against HER-2 positive carcinomas
Anna Kruschinski1, Andreas Moosmann, Isabel Poschke
1Max-Delbrück Center for Molecular Medicine, D-13092 Berlin, Germany.
Abstract:
NK cells are promising effectors for tumor adoptive immunotherapy, particularly when considering the targeting of MHC class I low or negative tumors. Yet, NK cells cannot respond to many tumors, which is particularly the case for nonhematopoietic tumors such as carcinomas or melanoma even when these cells lose MHC class I surface expression. Therefore, we targeted primary human NK cells by gene transfer of an activating chimeric receptor specific for HER-2, which is frequently overexpressed on carcinomas. We found that these targeted NK cells were specifically activated upon recognition of all evaluated HER-2 positive tumor cells, including autologous targets, as indicated by high levels of cytokine secretion as well as degranulation. The magnitude of this specific response correlated with the level of HER-2 expression on the tumor cells. Finally, these receptor transduced NK cells, but not their mock transduced counterpart, efficiently eradicated tumor cells in RAG2 knockout mice as visualized by in vivo imaging. Taken together, these results indicate that the expression of this activating receptor overrides inhibitory signals in primary human NK cells and directs them specifically toward HER-2 expressing tumor cells both in vitro and in vivo.
Insights
Genetically engineered Natural Killer (NK) cells targeting HER-2 effectively combat carcinomas. These modified NK cells overcome tumor defenses, showing potent anti-cancer activity in preclinical models.
Area of Science:
- Immunology
- Cancer Therapy
- Genetic Engineering
Background:
- Natural Killer (NK) cells are crucial for adoptive immunotherapy, especially against tumors with low or absent MHC class I expression.
- However, NK cell efficacy is limited against many solid tumors, including carcinomas and melanoma, even when MHC class I is downregulated.
- Targeting specific tumor antigens is necessary to broaden NK cell applicability.
Purpose of the Study:
- To engineer primary human NK cells to target HER-2, a common antigen on carcinomas.
- To evaluate the in vitro and in vivo efficacy of these modified NK cells against HER-2-expressing tumors.
- To determine if the engineered receptor can overcome inhibitory signals in NK cells.
Main Methods:
- Gene transfer of a chimeric activating receptor specific for HER-2 into primary human NK cells.
- In vitro assessment of NK cell activation (cytokine secretion, degranulation) upon recognition of HER-2 positive tumor cells.
- In vivo efficacy studies using RAG2 knockout mice and HER-2 positive tumors, with tumor eradication visualized by imaging.
Main Results:
- Engineered NK cells showed specific activation against HER-2 positive tumor cells, including autologous targets.
- Activation levels correlated with HER-2 expression on tumor cells.
- Receptor-transduced NK cells demonstrated efficient tumor eradication in vivo, unlike control NK cells.
Conclusions:
- Expression of the HER-2 specific activating receptor overrides inhibitory signals in primary human NK cells.
- Engineered NK cells provide a targeted approach for combating HER-2 expressing carcinomas.
- This strategy holds promise for enhancing NK cell-based cancer immunotherapy.
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