692. Bone Marrow Derived Neural Stem-Like Cells Expressing IL-27 Exhibit Antitumor Activity in Intracranial Gliomas

Abstract

Fetal brain derived neural stem cells are capable of tracking migratory and invasive brain tumor and delivering therapeutic molecules into the infiltrating tumor foci. In the present study we isolated neural stem-like cells from whole bone marrow of adult C57bl/6 mice. These bone marrow derived neural stem-like cells (BM-NSCs) grew as spheres morphologically indistinguishable from the neurospheres of fetal brain neural stem cells and expressed neural stem cell marker. Upon in vitro differentiation, the BM-NSCs were capable of producing progenies of three lineages, neurons, astrocytes, oligodendrocytes. After in vivo implantation, the cells were capable of tracking intracranial glioma cells by migrating into tumor mass and in immediate proximity to and intermixed with invading tumor |[ldquo]|island|[rdquo]|. We combined this tumor tracking property of BM-NSCs with gene immunotherapy by transducing the cells with a new discovered cytokine IL-27 that plays a role in the initiation of T help cell 1 responses. BM-NSCs transduced by an adenoviral vector carrying the single-chain IL-27 cDNA or by an empty vector as control were injected into the brain of C57bl/6 mice bearing intracranial GL-26 gliomas. About 50% mice survived intracranial gliomas after the implantation of IL-27 transduced BM-NSCs. In contrast, implanting empty vector transduced BM-NSCs did not rescue the intracranial glioma-bearing mice. Enhanced T cells infiltration within the tumors were observed in brain sections of the mice treated by IL-27 expressing BM-NSCs. Cytotoxic T lymphocyte (CTL) assay of the spleen cells from the survived mice shown that CTL activities against GL-26 glioma but not irrelevant tumor were augmented. In addition, the mice survived intracranial glioma after IL-27 expressing BM-NSCs treatment were resistant to intracranial rechallenge with the same GL-26 glioma cell line. Consistent with this observation, increased IFN-|[gamma]| expression was detected in the brain tissue after the rechallenge. Furthermore, depleting particular lymphocytes demonstrated that CD8+ T cells were crucial for the IL-27 expressing BM-NSCs antitumor activity. Taken together, these data suggest that BM-NSCs can be a tumor tracking vehicle for targeting refractory, migratory, invasive brain tumor to deliver therapeutic molecules into tumor foci. IL-27 as a new cytokine has potent ability to induce tumor-specific antitumor activity and protective immunity. By combining the tumor tracking property with the potent antitumor immunity, IL-27 expressing BM-NSCs may represent a promising gene therapy treatment for brain tumors.