Title |
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
|
---|---|
Published in |
Journal for Immunotherapy of Cancer, December 2013
|
DOI | 10.1186/2051-1426-1-21 |
Pubmed ID | |
Authors |
Masasuke Ohno, Takayuki Ohkuri, Akemi Kosaka, Kuniaki Tanahashi, Carl H June, Atsushi Natsume, Hideho Okada |
Abstract |
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. 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. 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. 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. |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
Japan | 1 | 1% |
United States | 1 | 1% |
Germany | 1 | 1% |
Switzerland | 1 | 1% |
Unknown | 84 | 95% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Student > Ph. D. Student | 19 | 22% |
Researcher | 19 | 22% |
Student > Master | 11 | 13% |
Student > Bachelor | 8 | 9% |
Student > Doctoral Student | 6 | 7% |
Other | 10 | 11% |
Unknown | 15 | 17% |
Readers by discipline | Count | As % |
---|---|---|
Agricultural and Biological Sciences | 21 | 24% |
Biochemistry, Genetics and Molecular Biology | 20 | 23% |
Medicine and Dentistry | 14 | 16% |
Immunology and Microbiology | 6 | 7% |
Pharmacology, Toxicology and Pharmaceutical Science | 3 | 3% |
Other | 8 | 9% |
Unknown | 16 | 18% |