OH2 oncolytic virus: A novel approach to glioblastoma intervention through direct targeting of tumor cells and augmentation of anti-tumor immune responses.

Glioblastoma (GBM), the deadliest central nervous system cancer, presents a poor prognosis and scant therapeutic options. Our research spotlights OH2, an oncolytic viral therapy derived from herpes simplex virus 2 (HSV-2), which demonstrates substantial antitumor activity and favorable tolerance in GBM. The extraordinary efficacy of OH2 emanates from its unique mechanisms: it selectively targets tumor cells replication, powerfully induces cytotoxic DNA damage stress, and kindles anti-tumor immune responses. Through single-cell RNA sequencing analysis, we discovered that OH2 not only curtails the proliferation of cancer cells and tumor-associated macrophages (TAM)-M2 but also bolsters the infiltration of macrophages, CD4+ and CD8+ T cells. Further investigation into molecular characteristics affecting OH2 sensitivity revealed potential influencers such as TTN, HMCN2 or IRS4 mutations, CDKN2A/B deletion and IDO1 amplification. This study marks the first demonstration of an HSV-2 derived OV's effectiveness against GBM. Significantly, these discoveries have driven the initiation of a phase I/II clinical trial (ClinicalTrials.gov: NCT05235074). This trial is designed to explore the potential of OH2 as a therapeutic option for patients with recurrent central nervous system tumors following surgical intervention.

Unravelling the role of immune cells and FN1 in the recurrence and therapeutic process of skull base chordoma.

BACKGROUND: Skull base chordoma is a rare and aggressive tumour of the bone that has a high likelihood of recurrence. The fundamental differences in single cells between primary and recurrent lesions remain poorly understood, impeding development of effective treatment approaches. METHODS: To obtain an understanding of the differences in single cells between primary and recurrent chordomas, we performed single-cell RNA sequencing and T-cell/B-cell receptor (BCR) sequencing. This allowed us to delineate the differences between the two types of tumour cells, tumour-infiltrating lymphocytes, myeloid cells, fibroblasts and B cells. Copy number variants (CNVs) were detected and compared between the tumour types to assess heterogeneity. Selected samples were subjected to immunohistochemistry to validate protein expression. Fluorescence in situ hybridisation experiments, Transwell assays and xenograft mouse models helped verify the role of fibronectin 1 (FN1) in chordoma. RESULTS: Promoting natural killer (NK) cell and CD8_GZMK T-cell function or inhibiting the transformation of CD8_GZMK T cells to CD8_ZNF683 T cells and promoting the transformation of natural killer T (NKT) cells to NK cells are promising strategies for preventing chordoma recurrence. Additionally, inhibiting the M2-like activity of tumour-associated macrophages (TAMs) could be an effective approach. Antigen-presenting cancer-associated fibroblasts (apCAFs) and dendritic cells (DCs) with high enrichment of the antigen-presenting signature were enriched in primary chordomas. There were fewer plasma cells and BCR clonotypes in recurrent chordomas. Remarkably, FN1 was upregulated, had more CNVs, and was more highly secreted by tumours, macrophages, CD4 T cells, CD8 T cells and fibroblasts in recurrent chordoma than in primary chordoma. Finally, FN1 enhanced the invasion and proliferation of chordomas in vivo and in vitro. CONCLUSION: Our comprehensive picture of the microenvironment of primary and recurrent chordomas provides deep insights into the mechanisms of chordoma recurrence. FN1 is an important target for chordoma therapy.

Multimodal MRI-based radiomic nomogram for predicting telomerase reverse transcriptase promoter mutation in IDH-wildtype histological lower-grade gliomas.

The presence of TERTp mutation in isocitrate dehydrogenase-wildtype (IDHwt) histologically lower-grade glioma (LGA) has been linked to a poor prognosis. In this study, we aimed to develop and validate a radiomic nomogram based on multimodal MRI for predicting TERTp mutations in IDHwt LGA. One hundred and nine IDH wildtype glioma patients (TERTp-mutant, 78; TERTp-wildtype, 31) with clinical, radiomic, and molecular information were collected and randomly divided into training and validation set. Clinical model, fusion radiomic model, and combined radiomic nomogram were constructed for the discrimination. Radiomic features were screened with 3 algorithms (Wilcoxon rank sum test, elastic net, and the recursive feature elimination) and the clinical characteristics of combined radiomic nomogram were screened by the Akaike information criterion. Finally, receiver operating characteristic curve, calibration curve, Hosmer-Lemeshow test, and decision curve analysis were utilized to assess these models. Fusion radiomic model with 4 radiomic features achieved an area under the curve value of 0.876 and 0.845 in the training and validation set. And, the combined radiomic nomogram achieved area under the curve value of 0.897 (training set) and 0.882 (validation set). Above that, calibration curve and Hosmer-Lemeshow test showed that the radiomic model and combined radiomic nomogram had good agreement between observations and predictions in the training set and the validation set. Finally, the decision curve analysis revealed that the 2 models had good clinical usefulness for the prediction of TERTp mutation status in IDHwt LGA. The combined radiomics nomogram performed great performance and high sensitivity in prediction of TERTp mutation status in IDHwt LGA, and has good clinical application.