First-in-human CAN-3110 (ICP-34.5 expressing HSV-1 oncolytic virus) in patients with recurrent high-grade glioma.

Abstract

2009 Background: Recurrent glioma patients have few therapeutic options and an expected survival of only 7 to 10 months. New treatments to improve the prognosis of this patient population are a dire medical need. Oncolytic viruses (OVs) are emerging as important new agents for cancer treatment. The first FDA approved OV was talimogene laherparepvec (Imlygic, T-Vec) for treatment of melanoma. T-Vec, as most other clinical HSV-1 based OVs, is deleted in the ICP34.5 gene, which is responsible for HSV-1 neurovirulence. However, deletion of ICP34.5 also impedes efficient viral replication. CAN-3110 (rQNestin34.5v2) maintains a copy of the HSV1 ICP34.5 gene under transcriptional control of the tumor-specific promoter for nestin to drive robust tumor-selective replication. CAN-3110 replicates in malignant glioma cells far above levels seen with ICP34.5 deleted viruses. This potency also created the hypothetical risk for increased neurovirulence, thus the regulatory advice to conduct a cautious nine-dose-level Phase-1 dose escalation study in patients with recurrent high-grade glioma (HGG). Methods: From September 2017 to February 2020, thirty patients with biopsy-confirmed recurrent high-grade glioma were treated in an open label clinical trial. Patients with multifocal, multicentric, tumors larger than 5 cm, and tumors that had recurred multiple times were eligible. All patients received best standard of care treatments as indicated by their physician. CAN-3110 was injected intratumorally starting at 1x106 plaque forming units (pfu) and dose-escalating (3+3 design) by half log increments up to 1x1010 pfu. Tissue (when possible) and blood samples were obtained before and during treatment for experimental medicine analyses. Results: CAN-3110 was well tolerated with no dose limiting toxicity observed. The initial tissue diagnosis of the recurrent tumor for the 30 subjects was 26 glioblastoma, 3 anaplastic oligodendroglioma, and 1 anaplastic astrocytoma. The median overall survival (mOS) of the entire study group is 13.25 months. Post-treatment tissue is available for 18/30 subjects and revealed persistence of HSV antigen and CD8+ T cell infiltrates. Additional response, immunologic (including T cell receptor repertoire), transcriptomic and single cell RNA sequencing analyses are ongoing. Conclusions: Administration of CAN-3110 into recurrent glioma was well tolerated without evidence of ICP34.5-induced encephalitis/meningitis. Histological and molecular analyses showed evidence of biological activity and that CAN-3110 injection was associated with immune activation and viral antigen persistence. Although definitive clinical efficacy cannot be determined in this small phase 1 study, OS of CAN-3110 treated subjects compares favorably to historical reports and warrants further clinical studies. Clinical trial information: NCT03152318.