New Research Article Published in the December
Edition of the Journal for ImmunoTherapy of Cancer
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
Masasuke Ohno, Takayuki Ohkuri, Akemi Kosaka, Kuniaki Tanahashi, Carl H June, Atsushi Natsume and Hideho Okada
Journal for ImmunoTherapy of Cancer 2013, 1:21 (16 December 2013)
Background
Expression of miR-17-92 enhances T-cell survival and interferon (IFN)-y 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 CD3z 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 3 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.
“We have been dedicated to develop effective immunotherapy aimed at a daunting challenge in oncology – malignant brain tumors. While malignant gliomas, such as glioblastoma, are extremely aggressive even in rodent models, our “3rd generation” chimeric antigen receptor (CAR) targeting the glioblastoma-specific antigen EGFRvIII revealed extremely potent efficacy in vivo, and co-expression of miR-17-92 enhanced durability of the therapeutic response. These data provide us with a strong basis for developing CAR strategies for patients with glioblastoma.”
– Hideho Okada, MD, PhD
To view entire article in JITC, please click here.
SITC is pleased to announce that JITC has been accepted to PubMed Central. All previously published JITC articles will be retrospectively added before the end of 2013.
Submit Your Research to JITC!
Article processing charges are waived again for Society members who submit their manuscript to JITC through 2014! This $2,420 USD savings is provided as a way to say thank you for all the dedicated SITC members who work tirelessly in advancing the science and ultimately improving the lives of patients with cancer.
To take advantage of this member benefit or to become a SITC member, please contact the SITC Executive Office for more information (Ph: +414-271-2456, Email: info@sitcancer.org)
JITC Editor-in-Chief
Pedro J. Romero, MD, Ludwig Center for Cancer Research
Members and non-members, alike, are invited to submit their manuscript in the following categories:
- Basic Tumor Immunology
Section Editor: Cornelis J.M. Melief, MD, PhD, ISA Therapeutics BV - Clinical/Translational Cancer Immunotherapy
Section Editor: F. Stephen Hodi, Jr., MD, Dana-Farber Cancer Institute - Immunotherapy Biomarkers
Section Editor: Lisa H. Butterfield, PhD, University of Pittsburgh Cancer Institute - Reviews/Editorials
Section Editors: Bernard A. Fox, PhD, Earle A. Chiles Research Institute
Thomas F. Gajewski, MD, PhD, University of Chicago
SITC also thanks JITC’s new associate editors who will assist in furthering the mission of the journal through the peer review process and prompt publication.
