PDCT-23. PROLIFERATION INDEX INFLUENCES INITIAL RESPONSE PATTERN OF PEDIATRIC HIGH-GRADE GLIOMAS TREATED WITH HSV-1 G207 ONCOLYTIC VIROTHERAPY

Abstract

Genetically engineered oncolytic HSV-1 G207, which lacks genes essential for replication in normal brain, is currently being studied in a first-in-human children clinical trial of intratumoral virus inoculation in recurrent or progressive supratentorial malignant tumors. We describe the initial pattern of response of patients treated at the first dose level (107 plaque-forming units). Patients underwent a biopsy to confirm viable tumor and then had up to four silastic catheters placed into enhancing areas of tumor. The following day, G207 was infused over 6 hours. Patients had an MRI prior to therapy, 3 days after therapy, and at day 28-36 post-G207. Immunohistochemistry was performed on biopsy specimens and MIB-1% was calculated. Four high-grade gliomas (3 glioblastoma and 1 anaplastic astrocytoma) in three subjects were treated; one subject had multifocal disease with two foci treated. Two tumors had a high proliferation index (up to 70%) and two had a low proliferation index (≤5%). Other than the changes related to catheter placement, no additional changes were noted on the day 3 MRI. The initial response at day 28-36 of the highly proliferative tumors included: 1) development of a necrotic center with enlargement of enhancing component; 2) worsening of peritumoral T2 abnormal areas; 3) new foci of intratumoral micro-hemorrhage; 4) increased mean apparent diffusion coefficient (mADC); 5) lowered mean relative cerebral blood volume (rCBV); and 6) increased T2 relaxation time with a clear gradient of these changes based on the distance from the catheter tip (maximum change closest to the catheter tip and no change farthest away). These MRI changes likely suggest pseudoprogression. Except for mild increase in the mADC, tumors with low proliferation index demonstrated no significant changes from the pretreatment MRI. This data suggests that the proliferation index may affect the pattern of response in pediatric high-grade gliomas treated with oncolytic HSV-1.