This study is the first to evaluate the safety and feasibility of intracranial administration of anti-PD-1 with or without anti-CTLA-4 in humans for treating recurrent high-grade gliomas (rHGG). It further explores the therapeutic potential of autologous CD1c+/CD141+ myeloid dendritic cells (myDC) combined with immune checkpoint blockade, providing novel directions for glioma immunotherapy.
Literature Overview
This article reviews three clinical and preclinical studies focused on recurrent high-grade gliomas (rHGG). The research examines intracranial delivery strategies for immune checkpoint inhibitors (e.g., nivolumab and ipilimumab) and investigates the therapeutic potential of autologous CD1c+/CD141+ myeloid dendritic cells (myDC) combined with nivolumab/ipilimumab. Additionally, it explores the role of TGFβ in mitochondrial transfer within the glioblastoma (GBM) tumor microenvironment (TME) and its impact on tumor invasiveness. These studies provide preliminary safety and efficacy data for rHGG immunotherapy strategies while revealing connections between mitochondrial metabolism and invasiveness. End of paragraph
Background Knowledge
Recurrent high-grade gliomas (rHGG) are highly malignant central nervous system tumors with poor prognosis and limited therapeutic options for survival extension. Systemic administration of immune checkpoint inhibitors (e.g., anti-PD-1 and anti-CTLA-4 antibodies) has shown limited efficacy; thus, researchers are testing direct intracranial injection to enhance localized antitumor immune responses. Dendritic cells (myDC), as critical antigen-presenting cells, can amplify antitumor immune responses by activating T cells. The TGFβ signaling pathway is highly expressed in GBM and plays a key role in tumor invasion-related microtubule formation. This study further investigates its regulatory function in mitochondrial transfer within the TME. Current research challenges include the immunosuppressive tumor microenvironment, therapeutic resistance, and uncontrolled tumor invasiveness. By addressing delivery routes, cellular therapy, and metabolic regulation, this study aims to elucidate the relationship between localized immune activation, mitochondrial metabolism, and tumor invasiveness, offering new insights for rHGG treatment. End of paragraph
Research Methods and Experiments
The study comprises three clinical trial cohorts: (1) Preoperative intravenous administration of nivolumab (10 mg), followed by postoperative local injection of nivolumab and ipilimumab into resection cavities or brain tissue; (2) Preparation of autologous myDC combined with intracranial injection of nivolumab/ipilimumab; (3) In vitro and in vivo experiments to evaluate the impact of TGFβ signaling on mitochondrial transfer and tumor invasiveness. Methods included glioma models, flow cytometry, confocal imaging, and collagen invasion assays. End of paragraph
Key Conclusions and Perspectives
Research Significance and Prospects
This study establishes the clinical safety of intracranial immune checkpoint blockade and suggests localized delivery may enhance immune responses. Additionally, the discovery of TGFβ-regulated mitochondrial transfer provides a novel therapeutic target for GBM invasiveness, with future strategies potentially combining inhibitors of mitochondrial transfer or TGFβ pathway to improve outcomes. End of paragraph
Conclusion
This study provides initial safety data for intracranial immunotherapy in recurrent high-grade gliomas and demonstrates the potential of autologous dendritic cell therapy combined with immune checkpoint blockade to sustain postoperative antitumor immunity. Furthermore, the TGFβ-mediated mitochondrial transfer mechanism offers a new metabolic control perspective for GBM invasiveness, suggesting future strategies targeting TGFβ or mitochondrial transfer mechanisms could yield more effective therapies. These findings expand treatment options for rHGG and open new research avenues in tumor immunotherapy and metabolic intervention, warranting further clinical evaluation and mechanistic studies.
