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BACKGROUND CAN-3110 (rQNestin34.5v2) is an HSV-1 oncolytic viral immunotherapy with one copy of the inflammatory ICP34.5 gene under transcriptional control of the Nestin glioma-specific promoter. We completed a phase 1 sequential dose-escalation trial of CAN-3110 in recurrent high-grade glioma (rHGG). METHODS CAN-3110 was injected intratumorally starting at 1x106 plaque forming units (pfu) and dose- escalated by half log up to 1x1010 pfu in biopsy confirmed rHGG. An expansion cohort of 12 patients was then accrued at 1x109 pfus. Blood and post-injection rHGG were collected. RESULTS 41 rHGG patients were treated (42 separate interventions): median age 56 years (range 27-74); 21 females, 20 males; median baseline KPS 90 (range 70-100). CAN-3110 administration was well-tolerated with no dose limiting toxicities. Median overall survival (mOS) was 11.9 months. Histologic and molecular analyses showed significantly increased T cell infiltration in post treatment samples with elevated T cell and/or B cell receptor (TCR/BCR) transcripts which correlated with patient survival (HR 0.26 for patients with elevated TCR/BCR rearrangements as compared to patients with low). Volumetric analyses of MRI suggest a trend between reduction in the relative change in tumor growth, TCR/BCRs enrichment and survival in CAN-3110 treated patients. CLINICAL IMPLICATIONS Administration of CAN-3110 into rHGG was well tolerated. OS of CAN-3110 treated subjects compare favorably to historical controls. The association of increased TCR/BCR transcripts with survival suggests that CAN-3110 induces T cell responses against rHGG, supporting further clinical development of CAN-3110 viral immunotherapy.

BackgroundRecurrent high-grade glioma (HGG) represents a significant clinical unmet need with expected survival between 6 to 9 months. Oncolytic viruses are a new therapeutic approach for solid tumors that deploy oncolytic activity combined with local and systemic immune activation. CAN-3110 (rQNestin34.5v2) is an oncolytic herpes simplex virus (HSV), modified to encode the HSV1 ICP34.5 protein under control of the nestin promoter. Selective expression of nestin in brain tumors confers tumor-restricted replication of CAN-3110. We conducted an open-label dose-escalation phase 1 clinical trial in patients with recurrent HGG to evaluate safety, tolerability, and immunological changes after CAN-3110 treatment.MethodsThirty patients with biopsy-confirmed recurrent HGG were enrolled from September 2017 to February 2020. CAN-3110 was injected intratumorally starting at 1x106 plaque forming units (pfu) and dose-escalated by half log to 1x1010 pfu. Patients also received standard of care. Peripheral blood mononuclear cells (PBMCs), plasma and tumor samples were collected for analysis at different time-points post treatment. We evaluated HSV antigen expression in tumor tissue. RNA sequencing and T cell receptor (TCR) rearrangement analysis was performed in matched tissue and PBMCs. Cytokine profiling was completed in 29 patients at baseline, day 2, and day 28 post treatment.ResultsEighteen patients were recruited at their first recurrence and 12 at the second recurrence. Three patients presented with multifocal disease. Tumor volume ranged from 357.4 to and 54,036.1mm3 (median 7,733.9mm3, SDV 15,610.2). CAN-3110 was well-tolerated with no dose-limiting toxicity. Median overall survival was 11.7 months. We demonstrated persistence of HSV antigen and CD8+ T cell infiltrates at the site of injected tumor. Preliminary analysis revealed expansion of shared TCR clonotypes and upregulation of pro-inflammatory genes in post-treatment tumors and peripheral blood samples. Longitudinal modeling of cytokine profiling demonstrated increased levels of IL-6, VEGF alpha, CCL2 and IL1-RA and a decrease in GCP-2 levels at day 2 post-treatment (p ConclusionsIntratumoral administration of CAN-3110 appears well-tolerated in recurrent HGG. Histologic, molecular, and cytokine analyses demonstrate persistence of viral antigen as well as local and systemic immune activation after treatment.Ethics ApprovalThe study was approved by the Office for Human Research Studies at Dana-Farber Cancer Institute, Protocol Number 16–557.