A Phase 1 Trial of Oncolytic HSV-1, G207, Given in Combination With Radiation for Recurrent GBM Demonstrates Safety and Radiographic Responses

Abstract

G207, a mutant herpes simplex virus (HSV) type 1, is safe when inoculated into recurrent malignant glioma. We conducted a phase 1 trial of G207 to demonstrate the safety of stereotactic intratumoral administration when given 24 hours prior to a single 5 Gy radiation dose in patients with recurrent malignant glioma. Nine patients with progressive, recurrent malignant glioma despite standard therapy were included. Patients received one dose of G207 stereotactically inoculated into the multiple sites of the enhancing tumor margin and were then treated focally with 5 Gy radiation. Treatment was well tolerated, and no patient developed HSV encephalitis. The median interval between initial diagnosis and G207 inoculation was 18 months (mean: 23 months; range: 11-51 months). Six of the nine patients had stable disease or partial response for at least one time point. Three instances of marked radiographic response to treatment occurred. The median survival time from G207 inoculation until death was 7.5 months (95% confidence interval: 3.0-12.7). In conclusion, this study showed the safety and the potential for clinical response of single-dose oncolytic HSV therapy augmented with radiation in the treatment of malignant glioma patients. Additional studies with oncolytic HSV such as G207 in the treatment of human glioma are recommended.

Design of a Phase I Clinical Trial to Evaluate M032, a Genetically Engineered HSV-1 Expressing IL-12, in Patients with Recurrent/Progressive Glioblastoma Multiforme, Anaplastic Astrocytoma, or Gliosarcoma

“…Other adverse events that might be expected based on the viral origin of M032 and on the inherent risks of malignant glioma include hematoma, encephalitis, hepatitis, disseminated HSV infection, allergic response to M032, nuchal rigidity, photophobia, and autoimmune response to CNS tissues. 10,27,28 As a gene vector, M032 has the potential to produce IL-12-related toxicity. In the unlikely event that a cytokine storm is encountered, it will be treated with antiviral therapy (i.e., acyclovir), antiinflammatory medications (i.e., corticosteroids), and close observation.…”

Rationale and Design of a Phase 1 Clinical Trial to Evaluate HSV G207 Alone or with a Single Radiation Dose in Children with Progressive or Recurrent Malignant Supratentorial Brain Tumors

“…[22][23][24] Twenty-one adult patients were treated in seven cohorts of three each by stereotactic intratumoral injection of HSV G207 in a standard dose escalation fashion from 1 · 10 6 pfu as a single injection in 0.1-0.3 mL up to 3 · 10 9 pfu given at 0.2 mL each in five sites. 22 While some patients developed complications frequently seen with malignant glioma, no serious adverse events were ascribed to G207, and therefore a maximum tolerated dose was not reached.…”

“…24 Preclinical studies demonstrated in vivo synergism of engineered HSV-1 and radiation through several potential mechanisms. [26][27][28][29][30] Ionizing radiation increases transcription of cellular genes that complement viral gene deletions such as ribonucleotide reductase and potentially activates late HSV-1 promoters through activation of the p38 mitogen-activated protein kinase pathway thereby enhancing virus replication.…”

Trial Watch—Oncolytic viruses and cancer therapy

“…in combination with cisplatin-based chemoradiation 188,189 (NCT01584284). 190 Moreover, (1) G207 (a conditionally replicating HSV-1 strain) 191 has been tested in combination with radiation therapy in nine patients with progressive, recurrent glioblastoma (NCT00157703); 192 (2) the therapeutic profile of NTX-010 (a native, replication-competent variant of the Seneca Valley picornavirus, also known as SVV-001) 193 in combination with metronomic cyclophosphamide has been assessed in 22 children with neuroendocrine tumors (NCT01048892); 194 (3) Ad5-yCD/mutTKSR39rep-ADP (a replication competent adenoviral strain endowed with superior oncolytic potential) 195 has been tested in combination with intensity modulated radiation therapy 196,197 in 44 prostate carcinoma patients; 198 (4) the clinical activity of HF10 (a replicative HSV-1 strain) 199 has been investigated in 17 subjects with advanced malignancies, who received HF10 intratumorally as standalone immunotherapeutic intervention; 200 (5) MV-NIS (a strain of oncolytic measles virus encoding the human thyroidal sodium iodide symporter), 201,202 has been tested as standalone immunotherapeutic intervention in two myeloma patients; 203 (6) the safety and efficacy of OBP-301 (an oncolytic adenovirus engineered to selectively target telomerase reverse transcriptase (TERT)-overexpressing cells, also known as telomelysin) 204 has been assessed in six elderly subjects with esophageal carcinoma, who received OBP-301 i.t. in combination with radiation therapy (UMIN000010158); 205 and (7) the clinical profile of an oncolytic variant Western Reserve vaccinia virus artificially endowed with improved specificity 206 has been evaluated in 16 individuals with advanced solid malignancies, who were treated with oncolytic virothapy i.t.…”