Dual Immune Checkpoint Blockade Shows Promise Against Recurrent Glioblastoma
A phase 1 trial finds relatlimab plus nivolumab is safe in recurrent GBM, with 52% one-year survival and measurable immune activation in tumors.
Summary
Glioblastoma is one of the deadliest brain cancers, with very few effective treatments after initial therapy fails. This multicenter phase 1 trial tested relatlimab, an antibody blocking the LAG-3 immune checkpoint, alone or combined with nivolumab, which blocks PD-1. Both checkpoints suppress T cell activity and allow tumors to evade the immune system. Forty-six patients with recurrent glioblastoma received treatment. The combination was manageable in terms of safety, and neoadjuvant dosing before surgery increased tumor-infiltrating CD8+ T cells — a sign of immune activation inside the tumor. Twelve-month overall survival reached 52% with combination therapy versus 35% with monotherapy. Patients with higher baseline interferon signaling and T cell diversity appeared more likely to benefit. While not designed to prove efficacy, this trial offers early immunological and survival signals that support further investigation.
Detailed Summary
Glioblastoma (GBM) remains one of the most lethal cancers, with median survival under 15 months even with standard treatment. Recurrent GBM offers virtually no curative options, making novel immunotherapy strategies urgently needed. LAG-3 is an immune checkpoint that, like PD-1, drives T cell exhaustion and helps tumors hide from immune surveillance. Blocking LAG-3 alone or alongside PD-1 may restore anti-tumor immune responses in the brain.
This multicenter, open-label phase 1 trial enrolled 46 patients with recurrent GBM across two sequential cohorts of 23 each. One cohort received relatlimab (anti-LAG-3) monotherapy; the other received relatlimab combined with nivolumab (anti-PD-1). The primary goal was to establish safety and maximum tolerated doses, with exploratory analyses examining tumor immunology and clinical outcomes.
The safety profile was acceptable. Maximum tolerated doses were 800 mg relatlimab alone and 160 mg relatlimab plus 240 mg nivolumab in combination. Grade 3–4 treatment-related adverse events occurred in 6 of 23 patients on combination therapy and none on monotherapy. Critically, neoadjuvant administration — giving the drugs before surgical resection — was associated with increased CD8+ T cell infiltration into the tumor in both cohorts, indicating that immune checkpoint blockade can activate tumor-infiltrating lymphocytes in glioblastoma.
Exploratory biomarker analyses identified patients with elevated baseline interferon signaling and higher T cell clonal diversity as more likely to achieve durable responses with combination therapy. Twelve-month overall survival was 52.2% with combination therapy and 34.8% with monotherapy — noteworthy figures given the grim prognosis of recurrent GBM, though the trial was not powered to demonstrate efficacy.
These results position LAG-3 blockade as a credible immunotherapeutic target in GBM and provide a biological rationale for selecting patients based on tumor immune signatures. Larger, randomized trials are warranted to confirm efficacy and refine patient selection.
Key Findings
- Combination relatlimab plus nivolumab was tolerable; grade 3-4 events occurred in 6 of 23 combination patients.
- Neoadjuvant dosing increased CD8+ T cell infiltration in tumors for both monotherapy and combination arms.
- Twelve-month overall survival was 52% with combination therapy versus 35% with monotherapy.
- Tumors with higher baseline interferon signaling and T cell clonality were enriched among durable responders.
- Maximum tolerated doses established: 800 mg relatlimab alone; 160/240 mg relatlimab/nivolumab combined.
Methodology
This was a multicenter, open-label, sequential-allocation phase 1 trial enrolling 46 patients with recurrent GBM (23 per cohort). The primary endpoint was safety; efficacy, biomarker, and survival analyses were exploratory and not powered for statistical inference. Neoadjuvant administration before surgical resection allowed intratumoral immune profiling.
Study Limitations
The trial was not designed or powered to assess efficacy, so survival figures are hypothesis-generating only. Competing interests among multiple authors and the absence of a control arm limit interpretability of clinical outcomes. The full paper is not open access; this summary is based on the abstract only.
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