Gene Therapy of Intracranial Glioma Using Interleukin 12–Secreting Human Umbilical Cord Blood–Derived Mesenchymal Stem Cells

Abstract

Clinical trials of gene therapy using a viral delivery system for glioma have been limited. Recently, gene therapy using stem cells as the vehicles for delivery of therapeutic agents has emerged as a new treatment strategy for malignant brain tumors. In this study, we used human umbilical cord blood-derived mesenchymal stem cells (UCB-MSCs) as delivery vehicles with glioma-targeting capabilities, and modified interleukin-12 (IL-12p40N220Q; IL-12M) as a novel therapeutic gene. We also engineered UCB-MSCs to secret IL-12M (UCB-MSC-IL12M) via tetrameric cell-permeable peptide (4HP4)-mediated adenoviral transduction. We confirmed the migratory capacity of UCB-MSC-IL12M toward GL26 mouse glioma cells by an in vitro migration assay and in vivo injection of UCB-MSC-IL12M into the ipsilateral hemisphere of implanted gliomas in C57BL/6 mice. In vivo efficacy experiments showed that intratumoral injection of UCB-MSC-IL12M significantly inhibited tumor growth and prolonged the survival of glioma-bearing mice compared with control mice. Antitumor effects were associated with increased local IL-12M levels, followed by interferon-γ secretion and T-cell infiltration in intracranial gliomas, as well as antiangiogenesis. Interestingly, tumor-free mice after UCB-MSC-IL12M treatment were resistant to ipsilateral and contralateral tumor rechallenge, which was closely associated with tumor-specific long-term T-cell immunity. Thus, our results provide the rationale for designing novel experimental protocols to induce long-term antitumor immunity against intracranial gliomas using UCB-MSCs as an effective delivery vehicle for therapeutic cytokines including IL-12M.

Current Status of Gene Therapy for Brain Tumors∗

“…MSCs expressing IL-12 (UCB-MSC-IL12M; Table III) inhibited GL26 intracranial tumor growth and prolonged survival when administered in the contralateral brain hemisphere. 161 The surviving mice were protected from re-challenge with GL26 cells in both contralateral and ipsilateral sides of the brain, indicating a memory response against tumor antigens. 161…”

The homing of human cord blood stem cells to sites of inflammation

“…Kim et al 41 conducted in vivo efficacy experiments and showed that intratumoral injection of engineered hUCBSC significantly inhibited tumor growth and prolonged the survival of glioma-bearing mice as compared with controls. Ryu et al (2011), 42 recently studied the migratory capacity of hUCBSC mediated by IL-12 toward GL26 mouse glioma cells in vitro and in vivo in gliomas implanted in C57BL/6 mice. Similarly, Park, et al 43 found that overexpression of the SDF-1α receptor CXCR4 in hUCBSC enhanced the migratory capacity toward gliomas.…”

Development of Anti-Cancer Stem Cells as Theranostic Agents in the Treatment of Different Cancer Types: An Update

“…The underlying principle is that the immunosuppressive cancer location can be changed into one that makes the immune action, not in favour of cancer [167]. Some of the human MSCs have made for the release of IL-12 or IL-18 and they have been experienced in mice having carcinoma of renal cell, cervical tumor and glioblastoma [168][169][170][171][172]. All of these researches to cancer and stem cells inter-related continued company of ILs released by SC along with transfers in immune profile, involving high concentrations of IFNγ, establishment of natural, healthy killer cells and employment of tumor-specific T cells, thus leads to prolonged existence and the estimation of proceeds.…”