Curing glioblastoma: Oncolytic HSV-IL12 and checkpoint blockade

Cancer immunotherapy has recently revolutionized how we approach the treatment of cancers, including fatal glioblastoma (GBM), but still fails to effectively treat the majority of cancer patients [1]. There are several key factors that may contribute to therapy failure, including, but not limited to: (i) low mutational loads and poor tumor immunogenicity; (ii) immune suppressive tumor microenvironment (regulatory T cells, pro-tumoral M2-like macrophages); and (iii) tumor heterogeneity, including therapy-resistant GBM stem cells (GSCs). GSCs contribute to tumor initiation, progression, maintenance, and recurrence, and are thus critical targets for therapy. Recently, we described a new stringent difficult-to-treat stem cell-based immune competent GBM model (005 GSC) that addresses aforementioned features of therapeutic hindrance: low mutational load with only two known somatic mutations; relatively non-immunogenic, lacking MHCI and II expression, with PD-L1 only expressed on a minority of 005 GSCs; highly tumorigenic and invasive; and an immune suppressive tumor microenvironment [2, 3]. This model has been used to test immunotherapeutic strategies for GBM.