Abstract
Glioblastoma (GB) is the most common and aggressive primary brain tumor in adults and currently incurable. Despite multimodal treatment regimens, median survival in unselected patient cohorts is <1 year, and recurrence remains almost inevitable. Escape from immune surveillance is thought to contribute to the development and progression of GB. While GB tumors are frequently infiltrated by natural killer (NK) cells, these are actively suppressed by the GB cells and the GB tumor microenvironment. Nevertheless, ex vivo activation with cytokines can restore cytolytic activity of NK cells against GB, indicating that NK cells have potential for adoptive immunotherapy of GB if potent cytotoxicity can be maintained in vivo. NK cells contribute to cancer immune surveillance not only by their direct natural cytotoxicity which is triggered rapidly upon stimulation through germline-encoded cell surface receptors, but also by modulating T-cell mediated antitumor immune responses through maintaining the quality of dendritic cells and enhancing the presentation of tumor antigens. Furthermore, similar to T cells, specific recognition and elimination of cancer cells by NK cells can be markedly enhanced through expression of chimeric antigen receptors (CARs), which provides an opportunity to generate NK-cell therapeutics of defined specificity for cancer immunotherapy. Here, we discuss effects of the GB tumor microenvironment on NK-cell functionality, summarize early treatment attempts with ex vivo activated NK cells, and describe relevant CAR target antigens validated with CAR-T cells. We then outline preclinical approaches that employ CAR-NK cells for GB immunotherapy, and give an overview on the ongoing clinical development of ErbB2 (HER2)-specific CAR-NK cells currently applied in a phase I clinical trial in glioblastoma patients.
Highlights
Glioblastoma (GB) is the most frequent malignant primary brain tumor in adults, without any curative treatment options available at present
In addition to ongoing work with chimeric antigen receptors (CARs)-engineered natural killer (NK)-92 cells, other allogeneic off-the-shelf therapeutics based on donor-derived peripheral blood or cord blood NK cells, or NK cells differentiated from induced pluripotent stem cells (iPSCs) may be tested for their effectiveness against brain tumors in the near future
NK cells naturally exhibit broad cytotoxicity triggered by interaction of their activating receptors with stress ligands expressed by tumor cells, which is retained by CAR-NK cells and may help to eliminate glioblastoma cells with low or absent expression of the CAR target antigen
Summary
Glioblastoma (GB) is the most frequent malignant primary brain tumor in adults, without any curative treatment options available at present. Recent clinical trials with chimeric antigen receptor (CAR)engineered T cells demonstrated the feasibility and safety of this approach for the treatment of recurrent glioblastoma, with signs of clinical activity and transient responses observed in some of the patients [10,11,12].
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