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.

Figure 1

Sequential images of patient 107 after treatment. (a,b) Enhancement present 4 months after resection and G207 treatment. Enhancing infiltrative tumor was left at the time of resection because of positive stimulation with subcortical mapping done intraoperatively. (c,d) Residual enhancement 12 months post-G207 treatment is decreased in the area of inoculation (red arrow), but new enhancement has appeared in the contralateral hemisphere (blue arrow). This new enhancement in the left hemisphere progressed 14 months post-G207 treatment (e,f). On stereotactic biopsy, this left hemispheric lesion was found to represent glioblastoma multiforme. T2 images (data not shown) showed the development of marked T2 changes throughout the left hemisphere at this time.

Figure 2

Immunohistochemical staining of patient 101 tumor tissue pre- and post-G207 treatment. Sections from paraffin blocks of tumor tissue obtained from patient 101 pre- and post-G207 treatment were evaluated for presence of tumor-infiltrating lymphocytes and macrophages. Monoclonal antibodies used for detection were CD3 (for detection of infiltrating T cells), CD8 (for detection of cytotoxic/suppressor T cells), CD20 (B-cell infiltrates), and HAM56 (for detection of monocyte/macrophage populations). Samples were stained as described in Materials and Methods. Original magnification ×40.

Figure 3

Immunohistochemical staining for HSV-1 gC (late gene) expression, using a mouse monoclonal antibody specific for gC, was performed in tumors resected from patients 107 (top panels) and 108 (bottom panels) 5 days following G207 injection. Tumor sections are shown at low magnification (×40, a,c) and high magnification (×200, b,d) for each patient tissue. b and d are high magnification of regions indicated in a and c by the rectangular box.