Abstract
Abstract Background: Oncolytic viruses (OV) have been a topic of great interest as therapeutic agents for indications such as glioblastoma multiforme (GBM), where current treatment options are poor and limited. Alongside engineering these viruses, finding useful pre-clinical models to elucidate the efficacy of the OV has been challenging. In particular, these viruses have been developed to overcome immune resistance, allowing for the reinvigoration of the immune contexture in the tumor microenvironment (TME). Current pre-clinical models, such as mouse models, are limited in their ability to recapitulate the TME fully. Thus, there is a need for more relevant pre-clinical models to study the efficacy of OV and downstream effects in the TME. Methods: rQNestin34.5v.1 herpes simplex virus (rQNestin) has previously been investigated in both in vitro and in vivo studies of GBM. To assimilate the effects of rQNestin on the TME, a more humanized system was employed; CANscriptTM. CANscript is an ex vivo human tumor model, that recapitulates the native, patient-autologous TME, incorporating autologous patient-derived peripheral blood mononucleated cells. We treated GBM tissue (n=10) with rQNestin, capable of expressing GFP, and profiled GFP expression as a proxy for replication efficiency. We coupled this analysis with gene expression of immune-related pathways to gauge the modulation of the immune contexture by rQNestin. In addition, we performed multiplex cytokine analysis and multiplex immunohistochemistry to investigate the impact of rQNestin on the spatial context and activity of the immune compartment in the TME, ex vivo. Results: Immunohistochemistry established that viral replication and tissue penetration was observed, ex vivo. Furthermore, RNA transcriptional profiling and cytokine analysis revealed that the oHSV-1 was capable of dynamically altering the tumor microenvironment, and dysregulating immune subsets within the tumor. Further stratification of tumor samples based on the pharmacodynamic profile identified subsets of patient tumors that induce adaptive immunity. Concluding remarks: Here, we report that CANscript, an ex vivo human tumor model, can be used to evaluate the effects of OV in the TME - not only viral replication but also the direct effect on the immune compartment. CANscript will be an invaluable tool to investigate the response and resistance to OV. This platform has the potential to enable better pre-clinical modeling of OV development. Citation Format: Munisha Smalley, Vidushi Kapoor, Douglas Best, Carmela Passaro, Michal O. Nowicki, Suniti K. Saha, Komal Prasad, E. Antonio Chiocca, Sean E. Lawler, Aaron Goldman. Translational efficacy of oncolytic HSV-1 in glioblastoma using a human autologous ex vivo platform, CANscript™ [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5009.
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