Proffered paper session on CNS

In this video, Prof Bart Neyns, a medical oncologist at the University Hospital Brussels and Dr Pierre Frères, a medical oncologist at CHU Liège, discuss the most essential studies from the proffered paper session on Central Nervous System malignancies. 

The Phase 1 trial for intracranial immunotherapy in recurrent glioblastoma, presented by Prof Neyns during this proffered paper session, represents a significant shift from previous efforts using intravenous anti-PD-1 and anti-PD-L1 therapies, which have largely failed to yield positive results. The rationale for this study is based on the idea that systemic immunotherapy might not achieve adequate drug concentration in the brain due to a plasma-to-cerebrospinal fluid ratio of approximately 1:100. This may limit the effectiveness of therapies like nivolumab. Additionally, systemic administration of CTLA-4 inhibitors, such as ipilimumab, is constrained by toxicity, particularly at the doses required to affect the tumour microenvironment.

In the present trial, checkpoint inhibitors were administered directly into the brain tissue surrounding the resected tumour cavity in conjunction with autologous dendritic cells derived from the patient’s blood. This strategy is based on prior encouraging results in melanoma, where intratumoral dendritic cell injections yielded positive outcomes, even in patients resistant to systemic checkpoint inhibitors. This approach in glioblastoma was tested following tumour resection, with the dendritic cells injected into the brain alongside ipilimumab and nivolumab. The early results from cohorts 5 and 6, presented at ESMO, indicate promising efficacy in recurrent glioblastoma, a notoriously difficult-to-treat cancer. In terms of survival outcomes, this trial has shown an unprecedented PFS rate at one year of nearly 50%, a marked improvement over historical data. Among the patients treated in the initial dose-escalation phase, three out of eleven remained recurrence-free at two years, and two patients maintained this status at three and a half years. This durability of response stands out, given that previous treatments for glioblastoma typically showed universal disease progression by the two-year mark. Regarding safety, the study found that direct intracerebral injection of checkpoint inhibitors was well-tolerated, with surprisingly low toxicity. The only dose-limiting toxicity occurred at higher doses (5-10 mg) of ipilimumab in the resection cavity, leading to an inflammatory response and increased neutrophils in the cerebrospinal fluid. In contrast, combining dendritic cells with nivolumab and ipilimumab showed no adverse events. The only notable complication associated with the trial design was the risk of bacterial colonisation due to the repeated use of an Ommaya reservoir inserted postoperatively to allow for intracavitary drug administration. One case of bacterial meningitis occurred, caused by Staphylococcus aureus, although it was treatable and reversible.

Overall, the trial demonstrates safety and efficacy for this novel approach to treating recurrent glioblastoma. The ability to achieve long-term remission in some patients and the relatively manageable toxicity profile provide strong justification for continued investigation. These results highlight the potential of intratumoral immunotherapy to overcome the challenges that have plagued systemic approaches in this particular cancer, and future work will likely focus on optimising the delivery method to minimise infection risks while maintaining therapeutic benefits.

The session presented the first results of a novel approach using messenger RNA (mRNA) vaccination as part of the first-line treatment for glioblastoma, administered immediately after radiochemotherapy. The rationale behind this timing is the hypothesis that the tumour environment may become more immunogenic post-radiotherapy due to prior radiation and chemotherapy. This could provide a window of opportunity to maximise the benefits of immunotherapy by leveraging the altered tumour microenvironment, which may be more receptive to immune interventions.

The use of mRNA vaccines in cancer immunotherapy, which have shown promise in other malignancies like melanoma, is exciting for glioblastoma patients, a group with historically poor outcomes and limited treatment options. The immunostimulatory properties of RNA itself serve as an adjuvant, enhancing the immune response, and early data from this trial are encouraging. Preliminary results indicate that 70% of the treated population developed a measurable immune response to at least one of the antigens present in the vaccine. Although this phase of the study primarily focuses on safety and immune response rather than long-term survival outcomes, these early signals suggest the potential for a meaningful impact on disease progression.

In terms of future therapeutic strategies, mRNA vaccination alone is likely not sufficient to significantly improve survival. As seen in other solid tumours, combining vaccines with other immunotherapies, such as checkpoint inhibitors, may be necessary to optimise the immune system’s ability to target and eliminate glioblastoma cells. This combined approach could enhance the durability and effectiveness of the immune response initiated by the vaccine.

While still in its early stages, this trial represents an important step forward in treating glioblastoma. The results are particularly significant given the lack of progress in this field over the past two decades. The ongoing investigation and further trials could pave the way for more effective treatment regimens incorporating advanced technologies like RNA-based vaccines. The glioblastoma community, which has long-awaited new therapeutic options, may benefit from this innovation, and future studies must continue to explore this promising avenue