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Updated: May 21, 2025
Advances in Human Induced Pluripotent Stem Cell-Derived Chimeric Antigen Receptor-Expressing Natural Killer Cells
Published on: February 14, 2025
CAR-NK cell therapy combined with checkpoint inhibition induces an NKT cell response in glioblastoma
F Strassheimer1,2,3, P Elleringmann1,2,3, G Ludmirski1,2
1Goethe University, Dr. Senckenberg Institute of Neurooncology, Goethe University Hospital, Frankfurt, Germany.
Background:
Glioblastoma is the most aggressive primary brain tumor with limited efficacy of established therapies, and a pronounced immunosuppressive tumor microenvironment. Targeting HER2 with local immunotherapy allows for high tumor specificity in the brain with physiologically very low expression. Monotherapy with CAR-NK cells targeted against HER2 has previously shown efficacy in medium-sized GL261/HER2 tumors.
Methods:
Advanced GL261/HER2 tumors were treated by local CAR-NK cell injection combined with systemic anti-PD-1 checkpoint blockade. Tumor growth and survival were monitored. In-depth characterization of the microenvironment was performed by multiplex immune fluorescence, spectral flow cytometry and RNAseq.
Results:
Untreated GL261/HER2 tumors were characterized by local immunosuppression and high PD-L1 expression. Combined treatment with NK-92/5.28.z and systemic anti-PD-1 induced robust anti-tumor response and long-term survival. Multiplex immunofluorescence and spectral flow cytometry showed increased CD4+ T cell infiltration in mice treated with CAR-NK cell and anti-PD-1 combination therapy. A cluster of T cells specifically emerging in the combination therapy group expressed markers of NKT cells, which was further verified by immunofluorescence staining.
Conclusion:
The combination therapy reverted the immunosuppressive tumor microenvironment with increased T and NKT cell infiltration. This resulted in successful treatment of advanced orthotopic tumors refractory to CAR-NK cell monotherapy.
Insights
Combining HER2-targeted CAR-NK cells with anti-PD-1 therapy effectively treats advanced glioblastoma by overcoming tumor immunosuppression and increasing T and NKT cell infiltration for long-term survival.
Area of Science:
- Immunology
- Oncology
- Neuroscience
Background:
- Glioblastoma is an aggressive brain tumor with a highly immunosuppressive microenvironment.
- Current therapies have limited efficacy.
- HER2 is a potential target for brain tumor immunotherapy due to low physiological expression.
Purpose of the Study:
- To evaluate the efficacy of combining HER2-targeted CAR-NK cell therapy with anti-PD-1 checkpoint blockade in advanced glioblastoma models.
- To investigate the impact of this combination therapy on the tumor microenvironment.
Main Methods:
- Utilized GL261/HER2 glioblastoma model in mice.
- Administered local CAR-NK cell (NK-92/5.28.z) injection combined with systemic anti-PD-1 therapy.
- Assessed tumor growth, survival, and characterized the tumor microenvironment using multiplex immunofluorescence, spectral flow cytometry, and RNAseq.
Main Results:
- The combination therapy demonstrated a robust anti-tumor response and significantly improved long-term survival in mice with advanced tumors.
- Characterization revealed a reversion of the immunosuppressive tumor microenvironment, evidenced by increased CD4+ T cell and NKT cell infiltration.
- PD-L1 expression was high in untreated tumors, suggesting its role in immune suppression.
Conclusions:
- Combination therapy of HER2-targeted CAR-NK cells and anti-PD-1 is a promising strategy for treating advanced glioblastoma.
- This approach effectively overcomes tumor-induced immunosuppression and enhances anti-tumor immunity.
- The therapy successfully treated tumors that were refractory to CAR-NK cell monotherapy.
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