Background Expression of miR-17-92 confers type-1 phenotype and enhanced survival of T-cells. We have 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 improves 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 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 In addition to antigen-specific and potent cytotoxic activities against U87 GBM cells stably expressing EGFRvIII (U87-EGFRvIII), CAR-transduced T-cells (CAR-T-cells) 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 potent therapeutic effects without demonstrating any uncontrolled growth of CAR-T-cells. However, when these mice were re-challenged with U87-EGFRvIII cells in the 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 development of novel CAR-T-cell strategies by incorporation of miR-17-92 to improve the therapeutic potency, especially in patients with GBM. Citation Format: Masasuke Ohno, Takayuki Ohkuri, Akemi Kosaka, Carl H. June, Atsushi Natsume, Hideho Okada. Expression of miR-17-92 enhances antitumor activity of T cells transduced with the anti-EGFRvIII chimeric antigen receptor in mice bearing human GBM xenografts. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2804. doi:10.1158/1538-7445.AM2014-2804
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Ohno et al. (2014) studied this question.