Abstract 6653: Oncolytic virotherapy induces a long-term immune antitumoral response leading to glioma eradication
Authors: Piaggio Francesca , Alessandrini Francesco , Riviera Chiara , Appolloni Irene , Ceresa Davide , Marubbi Daniela , Gianni Tatiana , Campadelli-Fiume Gabriella , Malatesta Paolo 
Published: March 2024

Abstract
Oncolytic herpes simplex viruses (oHSVs) have shown promise as effective treatments against various cancers. Our study evaluated the efficacy of R-115, an oHSV retargeted to human Her2 (hHer2), fully virulent in its target cells and expressing murine interleukin 12 (mIL12), in a high-grade, immunocompetent murine glioma model. This model is based on orthotopically transplant of cells derived from PDGFB-induced primary gliomas in syngeneic mice, engineered to express hHer2. Our experimental design compared the impact of R-115 on gliomas where all cells expressed hHer2 against a setup where only about 50% of cells expressed hHer2. The latter aimed to replicate the heterogeneity of patient’s high-grade gliomas, where not all cells express the target molecule. Strikingly, results in terms of overall survival and tumor eradication were similar in both setups, with about a quarter of animals showing complete glioma eradication. This suggests that mIL12-armed oHSV's impact is less about direct viral-induced cell death and more about the immune response elicited by the mIL12-expressing virus. This response effectively targets cells lacking the viral-targeted protein but likely sharing other neoantigens with hHer2-positive cells. Mice cured in both experimental setups were rechallenged with purely hHer2-negative cells. Almost all did not develop gliomas, indicating a strong immune response capable of rejecting the tumor. Plasma analysis revealed that R-115-treated mice from both setups were more immunoreactive against both hHer2-positive and negative cells compared to untreated mice. Further, co-culturing long-surviving mice's splenocytes with glioma cells showed increased cell division in CD8, CD4 and CD19 populations, and elevated IFN-γ, granzyme B, and TNF-α production. These findings underscore R-115's profound anti-cancer potential, especially its capacity to elicit an immune response effective against glioma cells, irrespective of their expression of the target molecule. This outcome, coupled with the results of the rechallenge experiments, is pivotal. It suggests that in a clinical context, an interleukin-12-expressing oHSV could effectively target not only residual cells post-surgical resection but also infiltrating cells that are distant from the site of virus administration. Encouraged by these promising findings, we are currently advancing our research with a novel oHSV that expresses mIL12 and targets EGFRvIII, a mutation found exclusively in tumor cells. This is aimed at enhancing the safety and translatability of this therapeutic approach.
Citation Format: Francesca Piaggio, Francesco Alessandrini, Chiara Riviera, Irene Appolloni, Davide Ceresa, Daniela Marubbi, Tatiana Gianni, Gabriella Campadelli-Fiume, Paolo Malatesta. Oncolytic virotherapy induces a long-term immune antitumoral response leading to glioma eradication [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6653.