Comparison of herpes simplex virus- and conditionally replicative adenovirus-based vectors for glioblastoma treatment

Abstract

In this study we compared side-by-side the anti-neoplastic activity of the oncolytic herpes simplex virus-1 (HSV-1) vector G47D with that of a conditionally replicative adenoviral vector for the treatment of glioblastoma. We analyzed the transduction efficiency of permanent glioblastoma cell lines and short-term cultures of glioblastoma cells with HSV.Luc and four adenovirus type 5 (Ad5)-based vectors that differed only in their fiber gene (Ad5.Luc, AdlucRGD, and the fiber chimeric vectors Ad5/3.Luc and Ad5/35.Luc). In the tested short-term cultures of glioblastoma cells the vectors Ad5/35.Luc and HSV.Luc had an equal transduction efficiency which was B70% higher than that of Ad5.Luc. In a subcutaneous xenograft glioblastoma model in nude mice we observed a significantly higher local tumor control with the G47D vector compared to the conditionally replicative Ad5/35 adenovirus. We confirmed in glioblastoma that the intratumoral expression of measles virus fusogenic membrane glycoproteins (FMG) encoded by replication-defective Ad5/35 or HSV-1 amplicon vectors synergistically enhances chemotherapy with temozolomide. The antineoplastic effect was superior when the replication-defective FMG encoding vectors were trans-complemented for replication with the respective oncolytic vector. This approach was necessary due to packaging constraints of adenovirus. At day 100, of 6 treated animals 1 was alive that received the Ad5/35-and 3 that received the HSV-1-based triple therapy. In an intracranial glioblastoma xenograft model we demonstrated the applicability of this strategy. Due to the higher oncolytic efficacy and packaging capacity of the HSV-1 vectors compared to adenovirus, these vectors are promising for the treatment of glioblastoma.

Oncolytic Vesicular Stomatitis Virus Induces Apoptosis in U87 Glioblastoma Cells by a Type II Death Receptor Mechanism and Induces Cell Death and Tumor Clearance In Vivo

“…1 was to determine if the death receptor pathway is also important for the induction of apoptosis by M51R VSV in human GBM cells. The U87 cell line was chosen for these experiments since it has been widely used in studies of susceptibility of GBM cells to oncolysis by VSV and other viruses (19,29,30,34,40,52,53). U87 GBM cells were stably transfected with either an empty vector (EV) or a vector expressing a dominant negative form of the Fas death receptor (dnFas).…”

Stem cell-based therapies for cancer treatment: separating hope from hype

“…Oncolytic HSV (oHSV) has been modified for tumour-selective replication and is inherently neurotropic, which makes it a promising candidate for brain tumour therapy 68,79 . Although Phase I and Ib clinical trials using oHSV for treating malignant glioblastoma post-tumour resection have shown antitumour activity, clinical response rates have been sub-optimal 80–82 .…”

Epigenetic mechanisms of irinotecan sensitivity in colorectal cancer cell lines

“…The dose reduction index (DRI) was also calculated. DRI determines the magnitude of dose reduction allowed for each drug when given in synergistic combination, as compared with the concentration of a single agent that is needed to achieve the same effect level (28). In this case, DRI >1 indicates synergism.…”