Abstract CT056: A phase 1 study of intratumoral HSV1 co-expressing IL-12 and PD1 blocking antibody (MVR-C5252) in recurrent high-grade glioma

Abstract Background: Recurrent glioblastomas (GBM) and other high-grade gliomas (HGG) have poor outcomes. Oncolytic viruses (OVs) offer a novel treatment strategy by inducing selective tumor lysis and immune activation. MVR-C5252, a genetically engineered oncolytic HSV1, encodes IL-12 and an anti-PD1 antibody fragment to potentiate anti-tumor immune responses. This Phase 1 trial evaluates the safety, tolerability, and preliminary efficacy of MVR-C5252 delivered intratumorally via convection-enhanced delivery (CED), bypassing the blood-brain barrier. Methods: This multicenter open-label, multistage trial includes four stages: Stage 1 (Single Infusion): Cohorts 1A and 1B of 3 patients (pts) each will evaluate the safety and dissemination of a single MVR-C5252 infusion (externalized Ascenda catheter and externalized SynchroMed Pump) at two dose levels: 5x106 and 1x108 PFU. If 3 pts treated at the lower dose do not experience dose-limiting toxicity (DLT) during a 28-day DLT observation period, 3 additional pts will receive the higher dose. Stage 2 (One cycle with infusions on days 1 and 28). A cohort of 3 pts will be treated using the highest tolerable dose level established in stage 1; the DLT observation period will extend 28 days after the second infusion. Stage 3 (Dose Escalation). A Bayesian Optimal Interval design will determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D). Pts will receive the first infusion in a cycle on day 1 with the second infusion 7 days later. The initial 28-day cycle will be the DLT observation period. Three dose levels will be considered, and a maximum of 15 pts will be enrolled in stage 3.Stage 4 (Dose expansion) Fleming’s 2-stage design with 12 and 24 pts in the two stages will assess the efficacy of MVR-C5252 at the established MTD/RP2D, as measured by progression-free 6 months survival (PFS6). Results: Enrollment is ongoing; 5 patients have been enrolled: 3 in the 1A, and 2 in the 1B cohort. The 3 patients in Stage 1A who received 5×106 PFU of MVR-C5252 have completed the DLT period. No serious adverse events (SAEs), DLTs, or Grade 3-5 adverse events (AE) occurred. Grade 1-2 Treatment Related AEs included fatigue. Unrelated AEs included flu-like symptoms, and cognitive disturbance. Serial CSF cytokine analysis from the first cohort showed dynamic immune responses with post-infusion changes reflected by cytokine z-scores, despite some values below detection limits. Single-cell RNA sequencing of longitudinal CSF samples will be presented to detail treatment impacts. Conclusions: Preliminary findings indicate MVR-C5252 delivered via CED is safe and well-tolerated in recurrent HGG, with early immune activation suggesting intended biologic activity. Ongoing dose escalation and immune analyses aim to define the therapeutic potential of MVR-C5252. Clinical Trial Identifier: NCT06126744. Citation Format: Kelly Hotchkiss, Michael C. Brown, Stevie Threatt, Justin T. Low, Monika Anand, Melody Goldston, Claire Bradbury, Karen Dean, James E. Herndon, Anoop P. Patel, Gerald A. Grant, David M. Ashley, Annick Desjardins, Mustafa Khasraw. A phase 1 study of intratumoral HSV1 co-expressing IL-12 and PD1 blocking antibody (MVR-C5252) in recurrent high-grade glioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT056.