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

Abstract

Primary central nervous system tumors are the most common solid neoplasm of childhood and the leading cause of cancer-related death in pediatric patients. Survival rates for children with malignant supratentorial brain tumors are poor despite aggressive treatment with combinations of surgery, radiation, and chemotherapy, and survivors often suffer from damaging lifelong sequelae from current therapies. Novel innovative treatments are greatly needed. One promising new approach is the use of a genetically engineered, conditionally replicating herpes simplex virus (HSV) that has shown tumor-specific tropism and potential efficacy in the treatment of malignant brain tumors. G207 is a genetically engineered HSV-1 lacking genes essential for replication in normal brain cells. Safety has been established in preclinical investigations involving intracranial inoculation in the highly HSV-sensitive owl monkey (Aotus nancymai), and in three adult phase 1 trials in recurrent/progressive high-grade gliomas. No dose-limiting toxicities were seen in the adult studies and a maximum tolerated dose was not reached. Approximately half of the 35 treated adults had radiographic or neuropathologic evidence of response at a minimum of one time point. Preclinical studies in pediatric brain tumor models indicate that a variety of pediatric tumor types are highly sensitive to killing by G207. This clinical protocol outlines a first in human children study of intratumoral inoculation of an oncolytic virus via catheters placed directly into recurrent or progressive supratentorial malignant tumors.

Enhanced Sensitivity of Patient-Derived Pediatric High-Grade Brain Tumor Xenografts to Oncolytic HSV-1 Virotherapy Correlates with Nectin-1 Expression

“…Two γ 1 34.5-deleted viruses, G207, which also contains a lacZ insertion within the UL39 gene that encodes viral ribonucleotide reductase, and M032, which expresses human IL-12, are currently being studied in a phase I brain tumor clinical trial in children (clinicaltrials.gov NCT02457845) and adults (NCT02062827) respectively 10 , 11 . G207 was proven safe with evidence of efficacy in some patients in three completed phase I studies in adults with recurrent high-grade glioma 12 – 14 .…”

The rapidly evolving state of gene therapy

“…In the course of developing replication‐defective rAd and HSV recombinant vectors, certain tumor cells showed a permissiveness for viral replication. That is, these tumor cells showed a predilection for supporting viral replication of adenoviruses, herpesviruses, measles viruses, and others (18, 19, 24‐26, 50, 52, 53, 56‐71). Although these oncolytic viruses are not exclusively selective for tumor cells, they show the properties of a “silver bullet,” replicating in and damaging tumor cells selectively over normal cells.…”

“…HSV vectors have been developed for human gene therapy of brain tumors, such as glioblastoma multiforme, and for conditions such as chronic pain (37)(38)(39)(40)(41)(42)(43)(44). The greatest number of trials have been done for malignant brain tumors, where HSV vectors have been used to deliver prodrug-activating enzymes, resulting in so-called "suicide gene" therapy and in some cases resulting in the release of tumor-specific antigens at a locus at which inflammation was triggered by the viral components of the vector (45)(46)(47)(48)(49)(50)(51)(52)(53)(54)(55).…”

Immunotherapy for pediatric brain tumors

“…To date, at least five oncolytic viruses have been evaluated clinically in children with brain tumors: recombinant poliovirus [27,28] , adenovirus [29] , reovirus [30] , herpesvirus [31,32] , and new castle disease virus [33,34] .…”