Neuro-Oncology | Study on Tumor Dormancy, Senescence, and Their Interactions with the Immune System

This study demonstrates the safety and feasibility of intracranial administration of anti-PD-1 and anti-CTLA-4 monoclonal antibodies alone or in combination for recurrent high-grade gliomas. It also investigates mitochondrial transfer mechanisms in glioblastomas and their interactions with the immune microenvironment. These findings provide novel insights into immune therapy strategies for brain tumors.

 

Literature Overview
This article series 'OS03 EXPLOITING DORMANCY, SENESCENCE AND THEIR LINKS WITH THE IMMUNE SYSTEM IN BRAIN TUMORS' published in Neuro-Oncology comprehensively reviews the interactions between tumor dormancy, senescence, and the immune system in brain tumors. The series covers safety evaluations of anti-PD-1 and anti-CTLA-4 monoclonal antibodies in recurrent high-grade gliomas, and explores relationships between mitochondrial transfer in glioblastomas and TGF-β signaling pathways.

Background Knowledge
Recurrent high-grade gliomas (rHGG) represent one of the most challenging diseases in neuro-oncology due to their poor prognosis and lack of effective life-prolonging therapies. PD-1 and CTLA-4 are critical immune checkpoint proteins whose blockade can enhance anti-tumor immune responses. However, systemic administration shows limited efficacy, prompting exploration of local and postoperative intracranial injection strategies. Glioblastomas (GBMs) exhibit aggressive invasiveness and metabolic adaptability that hinder treatment. Mitochondrial transfer has been identified as an energy-support mechanism for GBMs to exploit their tumor microenvironment, while the TGF-β/SMAD signaling pathway shows hyperactivation in GBMs and may correlate with mitochondrial transfer and tumor invasiveness. This study further examines these mechanisms to provide novel insights for combined immunotherapy and metabolic targeting approaches.

 

 

Research Methods and Experiments
In the Glitipni Phase I clinical trial, 61 patients were enrolled across three cohorts: 43 received brain parenchymal injections of NIVolumab (NIVO) and Ipilimumab (IPI) following maximal safe resection (MSR), while 22 received postoperative intracavitary (iCav) injections of varying NIVO±IPI doses. Additionally, 21 patients received autologous CD1c+/CD141+ dendritic cell (myDC) therapy combined with NIVO/IPI to assess survival and toxicity impacts. In vitro experiments utilized co-culture systems and collagen invasion assays with TGF-β treatments and SMAD pathway analysis to investigate mitochondrial transfer mechanisms and invasion enhancement.

Key Conclusions and Perspectives

• Intracranial and postoperative iCav administration of NIVO±IPI in rHGG patients demonstrated safety with no unexpected adverse events, though fatigue was the primary adverse effect (80% incidence)
• Patients receiving maximal safe resection showed improved overall survival compared to stereotactic biopsy, but iCav combination with IPI didn't further extend survival
• Autologous myDC combined with IPI/NIVO showed feasible and safe intracranial administration, with some patients achieving progression-free survival exceeding 2 years and 1-year overall survival rate reaching 50%
• In vitro studies demonstrated TGF-β promotes mitochondrial transfer and microtubule formation, with SMAD signaling serving as the critical downstream mediator
• Glioblastoma cells exhibit enhanced mitochondrial acquisition capability under mitochondrial-depleted conditions, dependent on TGF-β/SMAD signaling
• Research identifies mitochondrial transfer as a key mechanism for GBM invasiveness and drug resistance, suggesting targeting this process could improve therapeutic outcomes

Research Significance and Prospects
This series represents the first systematic evaluation of intracranial immune checkpoint inhibitors combined with dendritic cell therapy in rHGG. It also reveals TGF-β's novel role in regulating mitochondrial transfer in GBMs. Future research should focus on combining TGF-β inhibitors with mitochondrial transfer blockers, and optimizing postoperative local immunotherapy protocols.

 

 

Conclusion
This literature series establishes two critical research directions: first, demonstrating local immunotherapy's safety and survival benefits in recurrent high-grade gliomas; second, elucidating the TGF-β/SMAD signaling pathway's role in glioblastoma mitochondrial transfer mechanisms. These findings provide new perspectives for brain tumor immunotherapy and metabolic targeting, with potential clinical value to be validated in future phase II trials.

 

L Lescrauwaet, I Dirven, J Del’haye, B Neyns, and J Duerinck. OS03.4.A REPEATED INTRACRANIAL ADMINISTRATION OF ANTI-PD-1 ALONE OR IN COMBINATION WITH ANTI-CTLA-4 IMMUNE CHECKPOINT-BLOCKING MONOCLONAL ANTIBODIES IN PATIENTS WITH RECURRENT HIGH-GRADE GLIOMA. Neuro-Oncology.