Glioblastoma (GB), the most aggressive and common primary brain tumor in adults, remains incurable. Even with multi-modal treatment, median survival is less than a year, and recurrence is almost certain. Immune system evasion contributes significantly to GB’s development and progression. Natural killer (NK) cells, frequently found within GB tumors, are suppressed by the tumor cells and their microenvironment. However, activating these NK cells ex vivo with cytokines can restore their ability to destroy GB cells. This suggests NK cells hold potential for adoptive immunotherapy if their potent cytotoxicity can be maintained in vivo.
NK cells play a crucial role in cancer immune surveillance. They possess natural cytotoxicity, rapidly triggered by germline-encoded cell surface receptors. They also enhance T-cell mediated anti-tumor responses by maintaining dendritic cell quality and improving tumor antigen presentation. Like T cells, NK cells can be significantly enhanced by expressing chimeric antigen receptors (CARs), allowing for the development of targeted NK-cell therapies for cancer immunotherapy.
The GB tumor microenvironment actively hinders NK cell function. Early treatment attempts using ex vivo activated NK cells have shown promise. Similar to CAR-T cell therapies, CAR-NK cells offer a promising approach for GB immunotherapy. Relevant CAR target antigens already validated with CAR-T cells can be utilized in this context.
Preclinical studies are exploring the use of CAR-NK cells for GB immunotherapy, focusing on enhancing their ability to target and eliminate tumor cells while overcoming the suppressive tumor microenvironment. These approaches involve genetic modification of NK cells to express specific CARs that recognize antigens on GB cells. This targeted approach offers the potential for more effective and precise tumor cell destruction while minimizing damage to healthy tissue.
Currently, a phase I clinical trial is investigating the use of ErbB2 (HER2)-specific CAR-NK cells in glioblastoma patients. This trial represents a significant step towards translating preclinical findings into clinical practice. The outcome of this and future clinical trials will be crucial in determining the efficacy and safety of CAR-NK cell therapy for glioblastoma.
The development of CAR-NK cell therapy represents a new frontier in the fight against glioblastoma. This innovative approach leverages the inherent tumor-killing capabilities of NK cells, enhanced by the precision targeting of CAR technology. While still in early stages, the preclinical and clinical data suggest that CAR-NK cells hold significant potential as a novel immunotherapy for this devastating disease.
