Abstract A031: Early Immune Activation and Repair Cytokine Signatures Associate with Survival in Herpes-Based Oncolytic Virotherapy in Recurrent Glioma

Abstract Introduction: Glioblastoma multiforme (GBM) is a primary brain malignancy that has a poor prognosis and normally recurs. Previous trials investigating effects of herpes simplex virus (HSV) oncolytic virotherapy M032 and C134 have shown promise in preclinical models. Recent phase I clinical trials evaluating treatment of GBM with both oHSVs was conducted. This study evaluates serum cytokine analysis in patients infused with oHSVs with recurrent GBM. Methods: We enrolled 30 patients with recurrent GBM in phase I, dose-escalating trials and administered intratumoral injections of M032 virus at 105 pfu and C134 virus at 105 –107.5 pfu. Serum samples were collected at days 0-30, and quantified cytokines levels were determined by Human Cytokine/Chemokine 71-Plex Discovery Assay (Eve Technologies, Calgary, AB Canada). We log-transformed and z-scored values. We separated cytokine levels by median and compared survival based on log-rank test and Kaplan-Meier. Next, long-term survivors (LTS) and short-term survivors (STS) were separated based on median overall survival, and cytokine levels were compared between both groups using a Wilcoxon rank-sum test. Finally, we investigated whether temporal changes in cytokines were associated with survival; a landmark cox proportional hazards model implemented early induction (days 1-3 vs baseline) and late cytokine level persistence (days 7-10 vs days 1-3) as covariates. Results: Subjects experienced improved survival associated with baseline immune responses with higher IL-12, IFN-γ, IL-15, IL-9, and MIP-1α (CCL3), cytokines associated with T-cell /NK-mediated activation and adaptive immunity (all p<0.05). LTS exhibited significantly higher IL-12 levels compares to STS (p = 0.015). Early increases from baseline to days 1-3 of PDGF-AA and PDGF-AB/BB were independently protective (HR=0.36, p=0.0078; HR=0.40, p=0.0017, respectively), suggesting activation of neural repair programs and glial activation following oncolysis could improve survival. Patients experienced worse survival with higher levels of CCL2 (MCP-1) (p = 0.044) involved in monocyte migration and innate immunity, and early and late increases of IL-8 were worse for survival (HR=4.48, p=0.0050; HR=5.75 , p=0.0057, respectively), promoting neutrophil migration and glial angiogenesis. Late persistence of EGF was also worse for survival (HR=1.98, p=0.0321), a cytokine involved in angiogenesis and tumorigenesis. Conclusion: Survival following OV in glioma could be improved with activation of adaptive immunity and CNS repair responses, while innate immune activation and tumorigenic cytokines could predict poorer outcomes. These findings suggest baseline and temporal cytokine changes could predict outcomes in OV for gliomas. Following this response to OV could lead to helpful markers in early treatment monitoring. Citation Format: Mohammad Hamo, Dagoberto Estevez-Ordonez, Kevin A. Cassady, James M. Markert. Early Immune Activation and Repair Cytokine Signatures Associate with Survival in Herpes-Based Oncolytic Virotherapy in Recurrent Glioma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Brain Cancer; 2026 Mar 23-25; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(6_Suppl):Abstract nr A031.