Gene Transfer to Glial Tumors Using Herpes Simplex Virus

Glial tumors occur as intraaxial masses in the brain and are uniformly fatal due to lack of effective therapy. Resection combined with radiation and chemotherapy fails to eradicate malignant cells infiltrating into normal brain, and recurrence at the original site is ultimately fatal. Gene transfer offers the potential to enhance tumor cell killing while sparing surrounding normal brain. Several approaches have been developed to deliver genes to tumor cells in order to kill these cells. The first strategy involves the use of viral vectors that are replication-competent, but depend on attributes unique to the tumor cell to support viral growth. Both replication-competent adenovirus and herpes simplex virus (HSV) vectors have been employed in pre-clinical studies and most recently in human clinical trials (1 –3 ). For this purpose, HSV vectors have been engineered that replicate in dividing cells, such as tumor cells, but not in normal neurons. The use of conditional replication competent viruses could allow for their spread in tumor tissue while minimizing damage to normal brain, thus increasing the specificity and effectiveness. Such mutants include those lacking the viral thymidine kinase (tk) gene (4 –7 ), ribonucleotide reductase gene (8 ,9 ), a protein kinase gene (10 ), or a gene (γ34.5) required for growth specifically in neurons (11 –13 ). Deleting these genes in combination creates viruses that are highly compromised for their ability to replicate in and kill neuronal cells, yet retain the ability to replicate in and kill dividing tumor cells. Although these vectors are compromised for replication in nondividing cells, they have been shown to replicate and kill ependymal cells lining the ventricles following inoculation of vector into rodent brain. These vectors have shown no gross signs of toxicity to date in two Phase I/II human clinical trials (14 ,15 ) and have shown some preliminary indication of efficacy. Although these recombinant viruses are replication competent, they remain difficult to grow and purify.