Phase Ib Trial of Mutant Herpes Simplex Virus G207 Inoculated Pre-and Post-tumor Resection for Recurrent GBM

Abstract

We have previously demonstrated safety of G207, a doubly mutated (deletion of both gamma(1)34.5 loci, insertional inactivation of U(L)39) herpes simplex virus (HSV) for patients stereotactically inoculated in enhancing portions of recurrent malignant gliomas. We have now determined safety of two inoculations of G207, before and after tumor resection. Inclusion criteria were histologically proven recurrent malignant glioma, Karnofsky score >or=70, and ability to resect the tumor without ventricular system breach. Patients received two doses of G207 totaling 1.15 x 10(9) plaque-forming units with 13% of this total injected via a catheter placed stereotactically in the tumor. Two or five days later, tumor was resected en bloc with catheter in place. The balance of G207 dose was injected into brain surrounding the resection cavity. Six patients with recurrent glioblastoma multiforme were enrolled. Two days after the second G207 inoculation, one patient experienced transient fever, delirium, and hemiparesis, which entirely resolved on high-dose dexamethasone. No patient developed HSV encephalitis or required treatment with acyclovir. Radiographic and neuropathologic evidence suggestive of antitumor activity is reported. Evidence of viral replication was demonstrated. G207 appears safe for multiple dose delivery, including direct inoculation into the brain surrounding tumor resection cavity.

Increased oncolytic efficacy for high-grade gliomas by optimal integration of ionizing radiation into the replicative cycle of HSV-1

“…2 As most tumor recurrences are within the initial tumor bed, direct injection of attenuated oncolytic viruses such as herpes simplex virus-1 (HSV-1) has been proposed as an adjuvant treatment and utilized in Phase I clinical trials for high-grade gliomas. [3][4][5][6][7] HSV-1 is a double-stranded DNA virus expressing its genes in a sequential cascade of immediate-early (a), early (b), and late (g) genes. 8 Immediate-early genes encode for viral transcriptional regulators.…”

“…10 Phase I clinical trials in patients with glioma have been completed with neuro-attenuated HSV-1 deleted of g 1 34.5 that have demonstrated the safety and feasibility of this approach. [4][5][6] However in creating clinically safe, replication-competent viruses, the therapeutic trade-off is decreased viral replication to maintain safety that hampers anti-tumor efficacy.…”

Oncolytic viruses: From bench to bedside with a focus on safety

“…9,10 This was confirmed by early clinical trials in patients injected intratumorally (glioma) with oHSVs: sporadic shedding of HSV in saliva was noted, but this was shown to be wildtype virus as opposed to the injected oHSV. 11,12 Other studies have observed limited leakage of oHSV from injection sites up to 2 weeks post treatment, without other excreta containing viable oHSV. [13][14][15] Intra-arterial hepatic injection did not result in detectable environmental shedding either.…”

Gene therapy for pancreatitis pain

“…62 Attenuated HSVs have already been successfully used in Phase I/II trials for treatment of central nervous system (CNS) glioblastoma without apparent nonspecific toxic effects. 63,64 The efficacy and potency of peripheral opioid effects are generally enhanced when drugs are administered during active inflammatory conditions. [65][66][67][68][69] Development of opiate tolerance?…”

“…[79][80][81][82][83][84] Replication-deficient virus has been used safely without spread when injected directly into brain as treatment for glioblastoma. 63,64,84 Owing to the success of opioid gene therapy we have described in recent published studies for rats with pancreatitis, 20,21 continued efficacy and safety testing of HSV viral vector therapies for patient use is warranted.…”