Malignant gliomas represent one of the most challenging tumors to treat. Gene-based therapeutics have been advocated as a novel treatment modality. Although initial results from clinical trials have revealed the safety of this approach, evidence for efficacy has been elusive. Analysis of tumor tissue has been shown that gene delivery mediated by replication-defective vectors occurred in the immediate vicinity of the needle infection delivery tract. A potential avenue that could increase the volumetric extension of gene delivery consists of using replication- conditional (tumor-selective, oncolytic viruses as gene delivery vehicles. Over the last four years, we have engineered herpes viruses (HSV) that are defective in the function of he viral ICP6 (encoding the viral ribonucleotide reductase function) and/or the ICP34.5 (encoding a virulence function) genes. Our studies have revealed that the viral oncolytic effect can produce tumor growth inhibition and regression and that and regression and that this effect can be augmented by delivery of pro-drug-activating genes. We thus propose to increase the oncolytic efficiency of these mutants by cloning into their genome the CYP2B1 and RED genes, responsible for the activation of pro-drugs of the oxazosphorine class, such as cyclophosphamide (CPA), and the CE gene, responsible for the activation of pro-drug, irinotecan (CPT11). This new viral mutant (MGH2) will be employed to test the following hypotheses: 1) Combined intratumoral transfect of two pro-drug-activating gene therapies enhances tumor cell oncolysis by MGH, 2) This strategy provides for effective treatment in animal models of herpes simplex encephalitis, and 3) Modifications in the function of viral genes responsible for host cell toxicity and production of viral progeny alter the extent of vector-mediated pro-drug activation. Taken in conjunction, these studies will provide not only justification for a treatment modality that we will be able to test in phase I clinical trials, but also a mechanistic insight into the variables affecting cytotoxicity by the viral and pro-drug activation.
Showing the most recent 10 out of 223 publications
