Oncolytic HSV-1 Encoding IL-12 and Anti-PD-1 Reprograms CNS Immunity: Open-Label Study of MVR-C5252 for Safety, Tolerability, and Efficacy (PuMP) 2259418

Abstract Introduction To overcome immunosuppression in glioblastoma (GBM), we evaluated MVR-C5252, an HSV-1 expressing interleukin-12 (IL-12) and an anti—PD-1 antibody fragment, coupling oncolysis with Th1 polarization and checkpoint blockade. Methods Stage 1 of PuMP (NCT06126744) established safety of a single convection-enhanced intratumoral infusion of MVR-C5252 in adults with recurrent IDH-wildtype GBM (5 × 106 or 1 × 108 PFU; n = 6). A reservoir in the contralateral ventricle collected CSF at baseline, 1 h, and 28 d post-infusion. Pre- and post-treatment tumors were analyzed by Xenium spatial transcriptomics and CODEX proteomics, whole-genome sequencing (WGS) of tumor and CSF quantified ctDNA and viral genome. LC—MS metabolomics targeted IFN-γ—linked tryptophan/kynurenine and arginine/NO pathways. Stage 2, now ongoing, uses an implanted SynchroMed pump for immune priming and boosting via repeat dosing. Results Adverse events were grade 1—2 only with no viral shedding in urine or saliva by PCR. At 28 d, CSF immune cells exhibited sustained IFN-γ—driven transcriptional programs. Dendritic cells upregulated cross-presentation genes (TAP1, TAPBP, CD83). CD8+ T cells expressed increased IFNG, GZMB, and PRF1 with minimal PDCD1 or LAG3 reinduction. NK cells showed transient suppression at 1 h followed by recovery of cytotoxic and IFN-γ—responsive programs (GZMB, PRF1, STAT1), indicating reactivation of antigen-presenting and effector circuits. Conclusion Analyses will relate immune and metabolic remodeling to viral kinetics and ctDNA dynamics. Single-cell and spatial profiling (CODEX, Xenium), LC—MS/MS metabolomics, and CSF—tumor—blood analyses to define immune—metabolic interactions. These findings establish a mechanistic model of localized IL-12/anti—PD-1 virotherapy converting an immunologically quiescent GBM microenvironment into a Th1-polarized, cytotoxic state. Stage 3 will refine dosing and schedule, and Stage 4 will expand at the Phase 2 dose to evaluate efficacy. Funding Source Immvira pharmaceutical grant Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)