CD137 and PD-L1 targeting with immunovirotherapy induces a potent and durable antitumor immune response in glioblastoma models

Abstract

BackgroundGlioblastoma (GBM) is a devastating primary brain tumor with a highly immunosuppressive tumor microenvironment, and treatment with oncolytic viruses (OVs) has emerged as a promising strategy for these tumors. Our group constructed a new OV named Delta-24-ACT, which was based on the Delta-24-RGD platform armed with 4-1BB ligand (4-1BBL). In this study, we evaluated the antitumor effect of Delta-24-ACT alone or in combination with an immune checkpoint inhibitor (ICI) in preclinical models of glioma.MethodsThe in vitro effect of Delta-24-ACT was characterized through analyses of its infectivity, replication and cytotoxicity by flow cytometry, immunofluorescence (IF) and MTS assays, respectively. The antitumor effect and therapeutic mechanism were evaluated in vivo using several immunocompetent murine glioma models. The tumor microenvironment was studied by flow cytometry, immunohistochemistry and IF.ResultsDelta-24-ACT was able to infect and exert a cytotoxic effect on murine and human glioma cell lines. Moreover, Delta-24-ACT expressed functional 4-1BBL that was able to costimulate T lymphocytes in vitro and in vivo. Delta-24-ACT elicited a more potent antitumor effect in GBM murine models than Delta-24-RGD, as demonstrated by significant increases in median survival and the percentage of long-term survivors. Furthermore, Delta-24-ACT modulated the tumor microenvironment, which led to lymphocyte infiltration and alteration of their immune phenotype, as characterized by increases in the expression of Programmed Death 1 (PD-1) on T cells and Programmed Death-ligand 1 (PD-L1) on different myeloid cell populations. Because Delta-24-ACT did not induce an immune memory response in long-term survivors, as indicated by rechallenge experiments, we combined Delta-24-ACT with an anti-PD-L1 antibody. In GL261 tumor-bearing mice, this combination showed superior efficacy compared with either monotherapy. Specifically, this combination not only increased the median survival but also generated immune memory, which allowed long-term survival and thus tumor rejection on rechallenge.ConclusionsIn summary, our data demonstrated the efficacy of Delta-24-ACT combined with a PD-L1 inhibitor in murine glioma models. Moreover, the data underscore the potential to combine local immunovirotherapy with ICIs as an effective therapy for poorly infiltrated tumors.

The Oncolytic Adenovirus XVir-N-31, in Combination with the Blockade of the PD-1/PD-L1 Axis, Conveys Abscopal Effects in a Humanized Glioblastoma Mouse Model

“…It has been shown for OVs that oncolysis often induces lymphocyte infiltration into the tumor [ 21 , 22 ]. As OV mediated therapeutic effects can be fostered by the treatment with ICIs [ 21 , 23 , 24 , 25 ], we were interested in whether an additional blockade of the PD-1/PD-L1 interaction further enhanced the number of TILs. For this, in one group of mice, we intratumorally injected XVir-N-31 and systemically applied nivolumab, whilst another group received a single intratumoral injection of XVir-N-31-anti-PD-L1.…”

Transcriptome Analysis and Single-Cell Sequencing Analysis Constructed the Ubiquitination-Related Signature in Glioma and Identified USP4 as a Novel Biomarker

“…The presence of the blood-brain barrier(BBB) is thought to be a barrier to drug action in intracranial tumors, attenuating their efficacy ( 39 ). It should also be mentioned that gliomas have long been considered “cold” tumors with a high degree of immunosuppression ( 40 ). As a result, more research into the immune microenvironment of glioblastoma is required to offer a foundation for immunotherapy.…”

Immunology Meets Bioengineering: Improving the Effectiveness of Glioblastoma Immunotherapy

“…Results showed that Delta-24-ACT exerted a cytotoxic effect on human glioma cell lines and tumors in the murine models, implying that the expressed 4-1BBL was able to stimulate T cells in vitro and in vivo. The combination of Delta-24-ACT with an anti-PD-L1 antibody extended the median survival and generated immune memory, which indicated the potential of combining immune-virotherapy with immune checkpoint inhibitors as a promising and effective strategy for the treatment of poorly infiltrated tumors such as glioma [ 119 ].…”