Ad-TD-nslL12

Gliomas are the most common central nervous system malignancies, with limited therapeutic options and poor prognosis, which are primarily attributed to the "immune desert" microenvironment. Previously, we constructed a three-gene-deleted oncolytic adenovirus (Ad-TD) loaded with non-secreting interleukin-12 (nsIL-12), which could be amplified in tumor cells and induce immunity to suppress tumors. However, the effects of this oncolytic virus on gliomas and their immune microenvironment remain unclear. There is an urgent need for further research.

We constructed a Syrian hamster brain tumor model and demonstrated the efficacy and mechanism of the novel oncolytic virus in treating brain tumors through a series of in vitro and in vivo experiments. We investigated the efficacy and safety (the number of hamsters in each group is either 5 or 10) of the oncolytic virus treatment in Syrian hamsters using a virus-treated group, a control virus-treated group, and a blank control group.

In vitro assays showed that Ad-TD-nsIL-12 could specifically proliferate in brain tumor cells which induce tumor cell apoptosis and intracellular expression of interleukin (IL)-12. Moreover, in vivo experiments demonstrated that Ad-TD-nsIL-12 could effectively inhibit the progression of brain tumors and prolong survival. Ad-TD-nsIL-12 significantly enhanced T-cell infiltration in the brain tumor microenvironment.

Ad-TD-nsIL-12 can inhibit glioma progression and increase T-cell infiltration in the tumor tissue, particularly infiltration by cytotoxic T cells (CD8+). Ad-TD-nsIL-12 can amplify and produce IL-12, inducing anti-glioma immune responses to inhibit tumor progression.

Glioblastoma (GBM) is a common malignant tumor of the central nervous system with a poor prognosis and a short survival period. A novel tumor oncolytic virus, Ad-TD-nsIL-12, has manifested anti-tumor properties in preclinical studies. However, the genetic changes caused by Ad-TD-nsIL-12 after GBM treatment are unclear. Therefore, we collected cerebrospinal fluid and tumor tissues from patients injected with Ad-TD-nsIL-12 at different time points and analyzed the methylation and expression profiles of cerebrospinal fluid-derived circulating tumor DNA (ctDNA). The differential genes were screened using the least absolute selection and shrinkage operator (LASSO) and Cox regression analyses. The CIBERSORT algorithm was used to assess the abundance of glioma immune cell infiltration in The Cancer Genome Atlas (TCGA) dataset. The role of hub genes in the diagnosis, prognosis, and immune cell correlation was analyzed using R software, SPSS software, and GraphPad Prism. The results showed that after Ad-TD-nsIL-12 injection, 3631 differential methylation regions (DMRs) were up-regulated and 497 DMRs were down-regulated. The methylation levels of these DMRs recovered within 70 to 82 days. Combined with the TCGA dataset, 8 key genes were selected for the construction of diagnostic and prognostic models. There was a significant correlation between core genes and immune cells. The results revealed that the hub genes in CSF could be used as a biomarker for the diagnosis and prognosis of GBM and led us to speculate the effect of the hub gene on the immune mechanism underlying Ad-TD-nsIL-12.