CAR-NK cell therapy combined with checkpoint inhibition induces an NKT cell response in glioblastoma
Menée à l'aide de modèles murins de glioblastome, de la cytométrie spectrale en flux et d'une analyse par immunofluorescence multiplex d'échantillons tumoraux d'origine murine, cette étude démontre qu'une injection locale de lymphocytes CAR-NK en combinaison avec un traitement systémique par inhibiteur de contrôle immunitaire ciblant PD-1 augmente l'infiltration intratumorale des lymphocytes T et des cellules NK
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.
British Journal of Cancer , article en libre accès, 2025