Immu-12. the Histone Deacetylase Inhibitor Valproic Acid Augments the Susceptibility of Oncolytic Virus-infected Glioblastoma Cells to Pd-1 Blockade Therapy
Year: 2017
Type: conference-abstract
Abstract: Oncolytic Herpes Simplex Virus-1(oHSV1) is currently being tested in clinical trials for the treatment of recurrent glioblastoma. Our group has previously shown that valproic acid (VPA), a pan Histone Deacetylase inhibitor (panHDACi) increases the cytotoxic effect of oHSV within tumor cells. VPA has also been shown to significantly increase the survival of oHSV1-treated mice in orthotopic xenograft glioma model. With the increasing interest in combining oncolytic virotherapy with immune checkpoint blockade, the effect of VPA and oncolytic virotherapy on the expression of immune-stimulatory and immunoinhibitory molecules within the tumor micro-environment, and its impact on this combinatorial therapy is not known. Here, we show that VPA augments the expression of PD-L1 on oHSV1–infected mouse glioblastoma cell lines, rendering them particularly susceptible to PD-1 blockade therapy. We also found that VPA treatment prior to oncolytic virotherapy led to significant downregulation of MHC-I on infected tumour cells, therefore making the cells particularly more susceptible to NK cell killing. Indeed, our preliminary in-vivo studies show that VPA treatment augments the rescue of exhausted antigen-specific CD8 T cells in a model of chronic LCMV infection, further suggesting that VPA might enhance the response of tumor to oncolytic virotherapy and immune checkpoint blockade. Our data therefore provide a rationale for exploring the synergistic effect of HDACi on the efficacy of oncolytic HSV and immune checkpoint blockade in the treatment of glioblastoma.
Source: Neuro-Oncology
Institutions: Brigham and Women's Hospital, Harvard University
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2767520184