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J Immunother Cancer. 2013 Dec 16;1:21. doi: 10.1186/2051-1426-1-21. eCollection 2013.

Expression of miR-17-92 enhances anti-tumor activity of T-cells transduced with the anti-EGFRvIII chimeric antigen receptor in mice bearing human GBM xenografts.

Author information

1
Brain Tumor Program, University of Pittsburgh Cancer Institute, 1.19E Research Pavilion at the Hillman Cancer Center, 5117 Centre Ave, Pittsburgh, PA 15213, USA ; Department of Neurosurgery, Nagoya University School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan ; Department of Neurological Surgery, University of Pittsburgh School of Medicine, 200 Lothrop Street, Pittsburgh, PA 15213, USA.
2
Brain Tumor Program, University of Pittsburgh Cancer Institute, 1.19E Research Pavilion at the Hillman Cancer Center, 5117 Centre Ave, Pittsburgh, PA 15213, USA ; Department of Neurological Surgery, University of Pittsburgh School of Medicine, 200 Lothrop Street, Pittsburgh, PA 15213, USA.
3
Department of Neurosurgery, Nagoya University School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
4
Department of Pathology and Laboratory Medicine, Abramson Family Cancer Research Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
5
Brain Tumor Program, University of Pittsburgh Cancer Institute, 1.19E Research Pavilion at the Hillman Cancer Center, 5117 Centre Ave, Pittsburgh, PA 15213, USA ; Department of Neurological Surgery, University of Pittsburgh School of Medicine, 200 Lothrop Street, Pittsburgh, PA 15213, USA ; Department of Surgery, University of Pittsburgh School of Medicine, 200 Lothrop Street, Pittsburgh, PA 15213, USA ; Department of Immunology, University of Pittsburgh School of Medicine, 200 Lothrop Street, Pittsburgh, PA 15213, USA.

Abstract

BACKGROUND:

Expression of miR-17-92 enhances T-cell survival and interferon (IFN)-γ production. We previously reported that miR-17-92 is down-regulated in T-cells derived from glioblastoma (GBM) patients. We hypothesized that transgene-derived co-expression of miR17-92 and chimeric antigen receptor (CAR) in T-cells would improve the efficacy of adoptive transfer therapy against GBM.

METHODS:

We constructed novel lentiviral vectors for miR-17-92 (FG12-EF1a-miR-17/92) and a CAR consisting of an epidermal growth factor receptor variant III (EGFRvIII)-specific, single-chain variable fragment (scFv) coupled to the T-cell receptor CD3ζ chain signaling module and co-stimulatory motifs of CD137 (4-1BB) and CD28 in tandem (pELNS-3C10-CAR). Human T-cells were transduced with these lentiviral vectors, and their anti-tumor effects were evaluated both in vitro and in vivo.

RESULTS:

CAR-transduced T-cells (CAR-T-cells) exhibited potent, antigen-specific, cytotoxic activity against U87 GBM cells that stably express EGFRvIII (U87-EGFRvIII) and, when co-transduced with miR-17-92, exhibited improved survival in the presence of temozolomide (TMZ) compared with CAR-T-cells without miR-17-92 co-transduction. In mice bearing intracranial U87-EGFRvIII xenografts, CAR-T-cells with or without transgene-derived miR-17-92 expression demonstrated similar levels of therapeutic effect without demonstrating any uncontrolled growth of CAR-T-cells. However, when these mice were re-challenged with U87-EGFRvIII cells in their brains, mice receiving co-transduced CAR-T-cells exhibited improved protection compared with mice treated with CAR-T-cells without miR-17-92 co-transduction.

CONCLUSION:

These results warrant the development of novel CAR-T-cell strategies that incorporate miR-17-92 to improve therapeutic potency, especially in patients with GBM.

KEYWORDS:

Adoptive immunotherapy; Chimeric antigen receptor; Glioblastoma; miR-17-92; microRNA

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