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Link to original content: https://pubmed.ncbi.nlm.nih.gov/31798595/
CAR-Engineered NK Cells for the Treatment of Glioblastoma: Turning Innate Effectors Into Precision Tools for Cancer Immunotherapy - PubMed Skip to main page content
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Review
. 2019 Nov 14:10:2683.
doi: 10.3389/fimmu.2019.02683. eCollection 2019.

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

Michael C Burger  1   2   3   4 , Congcong Zhang  3   4   5 , Patrick N Harter  2   3   4   6 , Annette Romanski  7 , Florian Strassheimer  1   2 , Christian Senft  2   3   8 , Torsten Tonn  4   9   10   11 , Joachim P Steinbach  1   2   3   4 , Winfried S Wels  2   3   4   5
Affiliations
Review

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

Michael C Burger et al. Front Immunol. .

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.

Keywords: NK-92; adoptive cancer immunotherapy; chimeric antigen receptor; glioblastoma; natural killer cells.

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Figures

Figure 1
Figure 1
Killing of tumor cells by CAR-NK cells. Specific binding of the chimeric antigen receptor to its target antigen on the tumor-cell surface triggers CAR activation. This results in re-orientation of cytotoxic granules toward the immunological synapse formed between NK and target cell, followed by release of perforin and granzymes from cytotoxic granules into the synaptic cleft. Perforin and granzymes taken up by the target cell then trigger apoptotic cell death indicated by membrane blebbing and disintegration of the nucleus. The confocal microscopy image to the right shows conjugate formation between human GB cells co-expressing EGFR and EGFRvIII with NK-92/225.28.z CAR-NK cells that recognize both target antigens (71). Tumor (T) and EGFP-positive CAR-NK cells (N, green) were co-incubated for 1 h, fixed, permeabilized and stained for perforin (red) to identify cytotoxic granules. Cell nuclei were labeled with DAPI (blue).
Figure 2
Figure 2
Phase I clinical trial with ErbB2-specific CAR NK-92 cells in glioblastoma patients. Patients with recurrent ErbB2-positive glioblastoma in the dose escalation cohort of the CAR2BRAIN phase I clinical trial (NCT03383978, clinicaltrials.gov) receive a single treatment with irradiated ErbB2-specific NK-92/5.28.z cells injected into the resection margin during relapse surgery. In the subsequent expansion cohort, patients are scheduled to receive in addition up to 12 weekly treatments applied into the resection cavity through an implanted catheter and reservoir. MRI images are for illustration only and do not show an actual patient treated in the study.
See this image and copyright information in PMC

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