CAR-Engineered NK Cells for the Treatment of Glioblastoma: Turning Innate Effectors Into Precision Tools for Cancer Immunotherapy

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.

Anti-PSMA CAR-Engineered NK-92 Cells: An Off-the-Shelf Cell Therapy for Prostate Cancer

“…Although information about the clinical application of irradiated NK-92/CAR cells is still scarce [38], such a concept seems supported by data from a recent clinical trial in relapsed and refractory acute myeloid leukemia [39] and in several other early phase clinical trials with CAR-engineered NK-92 cells that are presently ongoing in Europe, China, and the US. Regarding glioblastoma (GB), where patients' median survival remains less than 1 year, despite multimodal regimes, a phase I clinical trial "Intracranial Injection of NK-92/5.28.z Cells in Patients With Recurrent HER2-positive Glioblastoma" (i.e., CAR2BRAIN, NCT03383978, clinicaltriaols.gov) was started in 2017, in order to evaluate the feasibility, safety and tolerability of the direct injection of irradiated NK-92 CAR-recognizing ErbB2 antigen into the wall of the resection cavity [40]. In this case the local therapy approach was chosen to increase the accumulation of the engineered cells at the site of the lesion overcoming the problems associated with the blood-brain barrier passage.…”

Highly Efficient Generation of Transgenically Augmented CAR NK Cells Overexpressing CXCR4

“…Although, for basic research, several NK cell lines exist, the only clinically applicable cell line is NK-92. CAR-expressing NK-92 cells are currently under clinical evaluation, but clinical efficacy has to be awaited ( 30 , 31 ). One major disadvantage of CAR NK-92 cells is their lymphoma origin, requiring irradiation before infusion, limiting their persistence, proliferation, and cytotoxic potential ( 7 ).…”

Glioblastoma Immune Landscape and the Potential of New Immunotherapies

“…A CAR-engineered NK cell targeting both WT EGFR and EGFRvIII mutant, NK-92-EGFR-CAR, was similarly efficient in targeting and killing GBM cells in mice engrafted with patients' mesenchymal GBM stem cells ( 85 ). Additional CAR target antigens in GBM include B7-H3 ( 86 , 87 ), HER2 ( 88 – 90 ) and EphA2 ( 91 ), as demonstrated in preclinical studies, and in a phase I dose escalation clinical trial using a HER2-CAR ( 92 ). Interestingly, generation of a tri-cistronic transgene encoding three CAR molecules against HER2, EphA2 and IL13Rα2, dubbed universal CAR-T (UCAR), was shown to overcome interpatient heterogeneity and target 100% of tumor cells ( 93 ).…”