Limited efficacy of gene transfer in herpes simplex virus-thymidine kinase/ganciclovir gene therapy for brain tumors

Abstract

Rapid elimination of TK expression from dividing tumor cells and focal transduction of the brain tumor were most likely responsible for the limited bystander effect in this approach. Immediate administration of GCV is crucial to assure maximal efficacy in the elimination of cancer cells. In addition, the complete or diffused transduction of a brain tumor with TK may be required for its total eradication.

Stereological Analysis on Migration of Human Neural Stem Cells in the Brain of Rats Bearing Glioma

“…4,8 NSCs encoded with the herpes simplex virus thymidine kinase gene (HSV-tk) also resulted in decreases in tumor volume, 23,24 indicating that NSCs can be used as highly effective therapeutic tools for brain tumors. 25,26 Migration of NSCs and tumor regression in response to gene targeting have been studied by real-time imaging with dual luciferase/substrate imaging. 22 However, little is known about the number of NSCs that migrate to the tumor site over time, the rate of migration from the injection site to the tumor region, where NSCs migrate within the brain parenchyma, and how long NSCs remain in these regions.…”

Adeno-associated virus (AAV) vectors in cancer gene therapy

“…Due to their inability to replicate or efficiently integrate in transduced tumor cells, AAV vectors may have a limited potential for sustained oncolytic or pro-apoptotic effects, as evidenced by some in vitro and in vivo studies [184]. Instead, AAV vectors may be an excellent platform for eliciting protective anti-tumor effects via tumor suppression and immunostimulation – a strategy that ongoing AAV cancer clinical trials are currently employing.…”

“…Additionally, residues that have been removed to insert protein-binding peptides [58] are depicted in green. Images were produced with Pymol [184]. …”

Delivery of Local Therapeutics to the brain: Working Toward Advancing Treatment for Malignant Gliomas

“…In 2003, Prados et al evaluated the efficacy of direct injection of herpes simplex virus thymidine kinase gene vector-producer cells followed by intravenous ganciclovir administration on 30 patients and found adverse effects in 16 patients [62]. Moreover, these studies using biological agents found that gene expression in the injected tissue was only present at distances of only a few millimeters from the resection cavity [69,79]. While local delivery initially seemed to have promising results, its use in clinical trials has dramatically decreased.…”