Abstract
Glioblastoma, one of the most aggressive primary brain tumors, is characterized by highly immunosuppressive microenvironment. This contributes to glioblastoma resistance to standard treatment modalities and allows tumor growth and recurrence. Several immune-targeted approaches have been recently developed and are currently under preclinical and clinical investigation. Oncolytic viruses, including the autonomous protoparvovirus H-1 (H-1PV), show great promise as novel immunotherapeutic tools. In a first phase I/IIa clinical trial (ParvOryx01), H-1PV was safe and well tolerated when locally or systemically administered to recurrent glioblastoma patients. The virus was able to cross the blood–brain (tumor) barrier after intravenous infusion. Importantly, H-1PV treatment of glioblastoma patients was associated with immunogenic changes in the tumor microenvironment. Tumor infiltration with activated cytotoxic T cells, induction of cathepsin B and inducible nitric oxide (NO) synthase (iNOS) expression in tumor-associated microglia/macrophages (TAM), and accumulation of activated TAM in cluster of differentiation (CD) 40 ligand (CD40L)-positive glioblastoma regions was detected. These are the first-in-human observations of H-1PV capacity to switch the immunosuppressed tumor microenvironment towards immunogenicity. Based on this pilot study, we present a tentative model of H-1PV-mediated modulation of glioblastoma microenvironment and propose a combinatorial therapeutic approach taking advantage of H-1PV-induced microglia/macrophage activation for further (pre)clinical testing.
Highlights
GlioblastomaGlioblastoma is the most common and aggressive primary brain tumor
The ability of H-1 protoparvovirus (H-1PV)-infected tumor cells to activate antitumor immune responses has been demonstrated in several preclinical cancer models, in particular hepatoma [34], melanoma [35], pancreatic [36], colorectal [37,38] and nasopharyngeal [39] carcinomas
In line with the above, CD 40 ligand (CD40L) expression was detected in non-macrophage, EGFR-positive, i.e., most likely glioblastoma cells
Summary
Glioblastoma is the most common and aggressive primary brain tumor It has a dismal prognosis and is typically characterized by largely inevitable recurrence within six months to one year after initial treatment [1,2]. Standard cytotoxic agents, corticosteroids, TMZ rechallenge, carboplatin and irinotecan are applied, among other agents, to palliate symptoms and improve quality of life, but fail to prolong the time to progression [6]. In 2009, the humanized monoclonal antibody bevacizumab targeting tumor angiogenesis (through the vascular endothelial growth factor (VEGF)), was approved for the treatment of recurrent glioblastoma patients on the basis of its ability to achieve superior progression-free survival (PFS), yet in the lamentable absence of meaningful overall survival (OS) improvement [7]
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