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Front Immunol. 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.

Burger MC1,2,3,4, Zhang C3,4,5, Harter PN2,3,4,6, Romanski A7, Strassheimer F1,2, Senft C2,3,8, Tonn T4,9,10,11, Steinbach JP1,2,3,4, Wels WS2,3,4,5.

Author information

1
Institute for Neurooncology, Goethe University, Frankfurt am Main, Germany.
2
Frankfurt Cancer Institute, Goethe University, Frankfurt am Main, Germany.
3
German Cancer Consortium (DKTK), Partner Site Frankfurt/Mainz, Frankfurt am Main, Germany.
4
German Cancer Research Center (DKFZ), Heidelberg, Germany.
5
Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt am Main, Germany.
6
Neurological Institute (Edinger Institute), Goethe University, Frankfurt am Main, Germany.
7
German Red Cross Blood Donation Service Baden-Württemberg-Hessen, Frankfurt am Main, Germany.
8
Department of Neurosurgery, Goethe University, Frankfurt am Main, Germany.
9
German Red Cross Blood Donation Service North-East, Dresden, Germany.
10
Transfusion Medicine, Medical Faculty Carl Gustav Carus, Technical University Dresden, Dresden, Germany.
11
German Cancer Consortium (DKTK), Partner Site Dresden, Dresden, Germany.

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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