Efficacy of a novel double-controlled oncolytic adenovirus driven by the Ki67 core promoter and armed with IL-15 against glioblastoma cells

Abstract

Background Glioblastoma (GBM) is an immunosuppressive, highly vascular and devastating malignant brain tumor. Even with progressive combination treatment that includes surgery, radiotherapy, and chemotherapy, the prognosis for GBM patients is still extremely poor. Oncolytic adenovirus (OAd) can specifically replicate in GBM cells, permitting the rapid copy of the therapeutic genes it carries. Moreover, E1A is an essential gene in adenoviral replication and is the first gene expressed upon viral infection. E1A expression can be regulated by the Ki67 promoter, while the CMV promoter drives therapeutic gene expression. However, the efficacy of a double-controlled OAd driven by the Ki67 core promoter and armed with IL-15 against GBM cells has not been investigated. Methods Fluorescence microscopy was performed to evaluate infection ability in the viruses. Cell viability was detected by CCK-8 assay. Levels of cytokines in different supernatants were determined by ELISA, and IL-15 gene expression was measured by RT-PCR. Angiogenic capacity was analyzed by tube formation assay. Results We successfully constructed a double-controlled oncolytic adenovirus driven by the Ki67 core promoter and armed with IL-15 that selectively infected and killed GBM cells while sparing normal cells. The adenoviruses prime IL-15 gene expression to significantly enhance anti-GBM efficacy through effective activation of microglial cells. Moreover, OAd not only directly inhibits angiogenesis but exhibits potent antiangiogenic capacity mediated by the reduction of VEGF secretion. Conclusions These results provide new insight into the effects of a novel double-controlled OAd driven by the Ki67 core promoter and armed with IL-15 in glioblastoma treatment, which may help in the development of novel therapies in solid tumors.

Enriched Environment Cues Suggest a New Strategy to Counteract Glioma: Engineered rAAV2-IL-15 Microglia Modulate the Tumor Microenvironment

“…In the last 10 years, few pharmacological approaches have been tested to take advantage of IL-15 for the treatment of GBM patients: a novel double-controlled oncolytic adenovirus driven by the Ki67 promoter and armed with IL-15 selectively infects and kills GBM cells, while sparing normal cells, and significantly enhances the activation of microglial cells (45). Furthermore, the administration of an IL-15 superagonist complex (ALT-803) leads to long-term survival and antitumor immune response in murine models of GBM (41).…”

The War Is on: The Immune System against Glioblastoma—How Can NK Cells Drive This Battle?

“…In glioblastoma, IL-15 can have effects in different types of therapy [296][297][298], and regarding its effects in NK cells, Ma et al (2021) [299] saw that the in vitro administration of a herpes-simplex-1-based oncolytic virus (OV) expressing the human IL-15/IL-15Rα sushi domain fusion protein (named OV-IL15C) was able to promote the secretion of soluble IL-15/IL-15Rα complexes by the infected GBM cells, inducing tumor cytotoxicity and greater survival of NK and TCD8 + cells. In animal models, this therapy led to increased survival and inhibition of tumor growth in the presence of TCD8 + cells.…”

Targeting Tumor-Associated Antigen: A Promising CAR-T Therapeutic Strategy for Glioblastoma Treatment

“…Moreover, the drug was able to pass through the blood-brain barrier (BBB) and was used in a phase I clinical trial of patients with chemo-resistant glioma ( Hu H. et al, 2018 ). We designed a novel Ki67-expressing oncolytic adenovirus to target glioma and showed potent oncolytic efficacy ( Zhang Q. et al, 2020 ). These studies underscore the possibility of targeting specific antigens for GBM therapy.…”

“…OVs can specifically infect and kill tumor cells and have become an attractive treatment choice ( Fang et al, 2014 ; Martikainen and Essand, 2019 ; Zhang W. et al, 2020 ). Our research team has showed that OVs have potent therapeutic efficacy and safety to treat malignant brain glioma and uveal melanoma ( Zhang J. et al, 2020 ; Liu et al, 2020a ; Zhang Q. et al, 2020 ; Liu et al, 2020b ; Liu et al, 2021 ). Previous studies confirm that intratumoral OV injection can enhance anti-tumor immunity and eliminate contralateral tumors ( Lun et al, 2005 ; Saha et al, 2018 ; Martinez-Velez et al, 2019 ; Liu et al, 2021 ).…”