A small study investigating tumor treating fields—an antimitotic electric fields therapy—in combination with pembrolizumab and temozolomide for the treatment of patients with glioblastoma was found to be a promising strategy, especially in patients with substantial residual tumor, according to the study abstract. The study by Chen et al (Abstract 591) was presented during the Society for Immunotherapy of Cancer (SITC) 2024 Annual Meeting & Pre-Conference Programs, in Houston, and simultaneously published in the Journal for ImmunoTherapy of Cancer.
Study Methodology
The researchers enrolled 26 patients newly diagnosed with glioblastoma with either a bulky, biopsy-only, or maximally resected tumor. They were treated with adjuvant tumor treating fields plus concomitant pembrolizumab and temozolomide. To distinguish the immune effects of tumor treating fields from those of pembrolizumab, the tumor treating fields therapy was started at cycle 1 of temozolomide, and pembrolizumab (200 mg every 3 weeks) was started at cycle 2.
The primary endpoint was progression-free survival. Secondary endpoints included overall survival, toxicity, and mechanism of treatment response and failure using a combination of bulk RNA-seq of enriched T cells and single-cell RNA-seq and T-cell receptor clonotyping of primary and recurrent tumors and peripheral blood mononuclear cells.
Results
The researchers found that while no significant disparity was demonstrated in the tumor microenvironment of primary biopsy-only vs maximally resected tumors, patients with biopsy-only tumors displayed a marked improvement in both progression-free survival (27.2 months vs 9.6 months; hazard ratio [HR] = 0.37, 95% confidence level [CI] 0.16–0.85; P = .014), overall survival (31.6 months vs 18.8 months; HR = 0.4, 95% CI 0.17–0.92; P = .023), and response rates (66.6% vs 25%), when compared to those with maximally resected tumors.
The researchers tracked the clonal evolution of T cells and confirmed that adaptive immune activation of tumor treating fields followed a type 1 interferon trajectory (T1IFN) specifically through the dendritic cells compartment in patients with biopsy-only tumors. From dendritic cells, the T1IFN pathway engaged the adaptive immune system, highly correlated with T-cell activation (Pearson r = 0.81; P = .000027), and strongly predicted for extended survival (HR = 0.3; P = .034) in a Cox proportional hazard model.
Importantly, the researchers discovered the adaptive replacement of expanded T-cell clones induced by tumor treating fields and enhanced by pembrolizumab predicted for prolonged survival (P = .031), leading to sustained T-cell activation (Pearson r = 0.72; P = .0018) and robust generation of central memory CD4-positive and CD8-positive T cells, especially in responders with biopsy-only tumors. In recurrent tumors, the PD-1/PD-L1 axis was suppressed, while concurrent upregulation of alternative immune checkpoints was observed in the periphery and in the tumor microenvironment. This was coupled with ineffective compensatory T-cell activation, suggesting potential mechanisms of resistance.
“These findings highlight the potent in situ vaccination effects of [tumor treating fields] and support its co-application with immune checkpoint inhibitors as a promising strategy for [glioblastoma], especially in patients with substantial residual tumor,” concluded the study authors.
Disclosure: For full disclosures of all study authors, visit SITC.
