Ad-TD-nslL12

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.

Two single-center Phase I trials evaluated safety (primary endpoint) and preliminary efficacy (secondary endpoint) of oncolytic adenovirus Ad-TD-nsIL12 in primary (Group A, NCT05717712) and progressive (Group B, NCT05717699) pediatric patients with IDH wild-type (WT) diffuse intrinsic pontine glioma (DIPG). Studies employed single-arm and 3 + 3 dose-escalation design. 9 patients were enrolled in Group A and 6 in Group B. Group A completed the dose escalation, and no severe adverse events were observed. Enrollment in Group B was halted after Group A completed escalation. All patients experienced drug-related adverse events. In Group A, three partial responses and five stable diseases were documented, with a median overall survival (mOS) of 10.3 months after the first virus and 11.3 months after onset. In Group B, three patients had stable diseases, and three had progressive disease, with an mOS of 6.4 months after the first virus and 12.7 months after onset. Both groups demonstrated improved mOS from onset compared to the DIPG patients in our center's retrospective study (mOS, 8.3 months). Both groups showed increased lymphocytes post-treatment, but only Group A decreased after radiotherapy. These trials confirmed the safety of Ad-TD-nsIL12 and provided preliminary efficacy evidence, offering insights for future clinical applications in DIPG.