Related Experiment Video
Updated: Nov 1, 2025
Advances in Human Induced Pluripotent Stem Cell-Derived Chimeric Antigen Receptor-Expressing Natural Killer Cells
Published on: February 14, 2025
Expanded human NK cells armed with CAR uncouple potent anti-tumor activity from off-tumor toxicity against solid
Ana L Portillo1,2, Richard Hogg2, Sophie M Poznanski1,2
1Department of Medicine, McMaster University, Hamilton, ON L8N 3Z5, Canada.
Abstract:
Despite the remarkable success of chimeric antigen receptor (CAR)-T cells against hematologic malignancies, severe off-tumor effects have constrained their use against solid tumors. Recently, CAR-engineered natural killer (NK) cells have emerged as an effective and safe alternative. Here, we demonstrate that HER2 CAR-expression in NK cells from healthy donors and patients with breast cancer potently enhances their anti-tumor functions against various HER2-expressing cancer cells, regardless of MHC class I expression. Moreover, HER2 CAR-NK cells exert higher cytotoxicity than donor-matched HER2 CAR-T cells against tumor targets. Importantly, unlike CAR-T cells, HER2 CAR-NK cells do not elicit enhanced cytotoxicity or inflammatory cytokine production against non-malignant human lung epithelial cells with basal HER2 expression. Further, HER2 CAR-NK cells maintain high cytotoxic function in the presence of immunosuppressive factors enriched in solid tumors. These results show that CAR-NK cells may be a highly potent and safe source of immunotherapy in the context of solid tumors.
Insights
Chimeric antigen receptor (CAR)-engineered natural killer (NK) cells show potent anti-tumor activity against HER2-expressing cancers. These CAR-NK cells offer a safer alternative to CAR-T cells for solid tumor immunotherapy.
Area of Science:
- Immunology
- Oncology
- Biotechnology
Background:
- Chimeric antigen receptor (CAR)-T cell therapy has shown success in hematologic cancers but faces limitations in solid tumors due to off-tumor effects.
- CAR-engineered natural killer (NK) cells are emerging as a promising alternative for cancer immunotherapy.
- HER2 is a validated target in several solid tumors, including breast cancer.
Purpose of the Study:
- To evaluate the efficacy and safety of HER2-targeted CAR-NK cells against HER2-expressing solid tumors.
- To compare the anti-tumor functions of HER2 CAR-NK cells with HER2 CAR-T cells.
- To assess the performance of HER2 CAR-NK cells in the immunosuppressive tumor microenvironment.
Main Methods:
- Generation of HER2 CAR-NK cells from healthy donors and breast cancer patients.
- Assessment of NK cell cytotoxicity against various HER2-expressing cancer cell lines.
- Comparison of HER2 CAR-NK cell and HER2 CAR-T cell cytotoxicity against tumor targets.
- Evaluation of CAR-NK cell activity in the presence of immunosuppressive factors.
- Testing for off-tumor effects on non-malignant lung epithelial cells.
Main Results:
- HER2 CAR-NK cells demonstrated potent anti-tumor activity against HER2-expressing cancer cells, irrespective of MHC class I expression.
- HER2 CAR-NK cells exhibited superior cytotoxicity compared to HER2 CAR-T cells against tumor targets.
- Unlike CAR-T cells, HER2 CAR-NK cells did not induce enhanced cytotoxicity or inflammatory cytokine release against non-malignant lung cells with low HER2 expression.
- HER2 CAR-NK cells maintained high cytotoxic function within an immunosuppressive tumor microenvironment.
Conclusions:
- CAR-NK cells expressing HER2 CAR are a potent and safe immunotherapy candidate for solid tumors.
- HER2 CAR-NK cells overcome key limitations associated with CAR-T cell therapy in solid tumors.
- This approach holds significant promise for improving cancer treatment outcomes.
Related Concept Videos
01:27Cytotoxic T Cells-mediated Immune Response
Immunological surveillance is the ability of immune cells to monitor and eliminate infected cells with intracellular pathogens, neoplastically transformed cells, and cells with non-self antigens. Cytotoxic T cells and NK...
01:27Tumor Immunotherapy
01:28Cells of the Innate Immune Response
Phagocytes
Phagocytes police the peripheral tissues by removing cellular debris and responding to the invasion of foreign substances or pathogens. Many phagocytes attack and remove microorganisms even before lymphocytes detect them. The human body has two general...