Bystander Killing of Malignant Glioma by Bone Marrow–derived Tumor-Infiltrating Progenitor Cells Expressing a Suicide Gene

Abstract

Adult stem cells are promising cellular vehicles for therapy of malignant gliomas as they have the ability to migrate into these tumors and even track infiltrating tumor cells. However, their clinical use is limited by a low passaging capacity that impedes large-scale production. In the present study, a bone marrow-derived, highly proliferative subpopulation of mesenchymal stem cells (MSCs)-here termed bone marrow-derived tumor-infiltrating cells (BM-TICs)-was genetically modified for the treatment of malignant glioma. Upon injection into the tumor or the vicinity of the tumor, BM-TICs infiltrated solid parts as well as the border of rat 9L glioma. After intra-tumoral injection, BM-TICs expressing the thymidine kinase of herpes simplex virus (HSV-tk) and enhanced green fluorescent protein (BM-TIC-tk-GFP) were detected by non-invasive positron emission tomography (PET) using the tracer 9-[4-[(18)F]fluoro-3-hydroxymethyl)butyl]guanine ([(18)F]FHBG). A therapeutic effect was demonstrated in vitro and in vivo by BM-TICs expressing HSV-tk through bystander-mediated glioma cell killing. Therapeutic efficacy was monitored by PET as well as by magnetic resonance imaging (MRI) and strongly correlated with histological analysis. In conclusion, BM-TICs expressing a suicide gene were highly effective in the treatment of malignant glioma in a rat model and therefore hold great potential for the therapy of malignant brain tumors in humans.

Fiber-modified adenovirus-mediated suicide gene therapy can efficiently eliminate bladder cancer cells in vitro and in vivo

“…Because the bladder is an anatomically accessible organ, the therapeutic adenovirus can come in direct contact with the bladder cancer through intravesicular administration. Furthermore, approximately 80% of newly diagnosed bladder cancer patients have non-muscle-invasive bladder cancer (NMIBC) or carcinoma in situ (CIS) [26], so bladder instillation may be clinically effective for RGDAd-UPII-TK and GCV delivery, and the bystander killing effect of phosphorylated GCV can expand the apoptosis of the remaining uninfected bladder cancer cells [18]. Another problem is that the efficacy was poor when the therapeutic adenoviruses were used as standalone therapies, but suitable efficacy was obtained when used in combination with conventional therapies such as chemotherapy and radiotherapy [27].…”

“…HSV-TK can convert ganciclovir (GCV) into GCV-monophosphate (GCV-MP), which will be recognized by cellular kinases and then converted into GCV-triphosphate (GCV-TP), which is a guanine nucleoside analogue that may cause DNA chain termination and subsequent apoptosis cell death. Additionally, GCV-MP can passively diffuse into neighboring cells to exert a “bystander effect”, which can expand the elimination of tumor cells [18–21]. …”

Integrated Transcriptomic and Glycomic Profiling of Glioma Stem Cell Xenografts

“…BM-hMSCs demonstrate significant promise as cell-based delivery vehicles for anti-glioma therapeutics 13, 15-17, 19, 43, 44 . However, evidence suggests that in GSCXs, the ‘gold standard’ of glioma models, these cells do not home or extravasate equally 14 .…”

Stem Cell-Based Therapies for Cancer

“…Miletic and colleagues found that MSCs engineered to express herpes simplex virus thymidine kinase (HSV-TK) and injected into the tumor or the vicinity of the tumor, infiltrated solid parts as well as the border of glioma models in rats, and ultimately showed high therapeutic efficacy by significant reduction of tumor volumes through bystander-mediated glioma cell killing (Miletic et al, 2007). In 2012, Choi et al studied human adipose tissue (hAT)-derived MSCs and prodrug gene therapy against brainstem gliomas in rat models.…”