Design and application of oncolytic HSV vectors for glioblastoma therapy

Abstract

Glioblastoma multiforme is one of the most common human brain tumors. The tumor is generally highly infiltrative, making it extremely difficult to treat by surgical resection or radiotherapy. This feature contributes to recurrence and a very poor prognosis. Few anticancer drugs have been shown to alter rapid tumor growth and none are ultimately effective. Oncolytic vectors have been employed as a treatment alternative based on the ability to tailor virus replication to tumor cells. The human neurotropic herpes simplex virus (HSV) is especially attractive for development of oncolytic vectors (oHSV) because this virus is highly infectious, replicates rapidly and can be readily modified to achieve vector attenuation in normal brain tissue. Tumor specificity can be achieved by deleting viral genes that are only required for virus replication in normal cells and permit mutant virus replication selectively in tumor cells. The anti-tumor activity of oHSV can be enhanced by arming the vector with genes that either activate chemotherapeutic drugs within the tumor tissue or promote anti-tumor immunity. In this review, we describe current designs of oHSV and the experience thus far with their potential utility for glioblastoma therapy. In addition, we discuss the impediments to vector effectiveness and describe our view of future developments in vector improvement.

Cellular effects of oncolytic viral therapy on the glioblastoma microenvironment

“…7 Therefore, subsequent developments of HSV-1-based glioma therapy have focused on ways to enhance antitumor efficacy. 8 Two main strategies have been followed: modifying the vectors by deleting the immunoattenuating genes coded for by the virus, to allow enhanced immunorecognition of vector-infected cells, 9 or, by inserting immunostimulatory or therapeutic transgenes, [10][11][12][13] as well as by combining the vectors with other clinical treatment forms such as chemotherapy 14 or irradiation. 15 In neuro-oncology, the validity of experimental data obtained from preclinical evaluation of potential clinical therapies has been compromised by the widespread use of tumor-cell-line-based animal models.…”

In Vivo Evaluation of a Cancer Therapy Strategy Combining HSV1716-Mediated Oncolysis with Gene Transfer and Targeted Radiotherapy

“…Generation of safe, selectively replication-competent viruses has been predominantly accomplished by disruption of the HSV virulence factor ICP34.5 (1,2). Several such viruses have been used in clinical trials (3,4) and have demonstrated efficacy in preclinical studies (5).…”

“…Accordingly, secondgeneration viruses are being developed. These combine the oncolytic activity and safety of the first-generation HSV-1 mutants with the delivery of tumoricidal transgenes (2,4,5). Because of the difficulty in targeting every cell within a tumor, either for oncolysis or for transgene delivery, a successful cancer gene therapy strategy will mediate killing of infected and noninfected bystander tumor cells.…”

Gene therapy-mediated delivery of targeted cytotoxins for glioma therapeutics

“…This specificity is particularly required when designing therapies for brain tumors, such as glioblastoma multiforme (GBM), in which tumor cells infiltrate the normal brain. GBM is the most common primary brain cancer in adults, and carries a dismal prognosis (14-to 21-mo median survival), in spite of an advanced standard of care, namely surgery, radiotherapy, and chemotherapy with temozolomide (6)(7)(8).…”