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BACKGROUND: Immune checkpoint inhibitors (ICIs) have shown limited success in glioblastoma due to the tumor's profoundly immunosuppressive microenvironment. Tumor treating fields (TTFields), a non-invasive electric field therapy, activate the type I interferon (T1IFN) pathway via DNA sensor-dependent inflammasomes, promoting in situ immunization against glioblastoma. METHODS: In this phase 2 study (this study was registered at ClinicalTrials.gov: NCT03405792), 31 newly diagnosed glioblastoma patients were enrolled post-chemoradiation to evaluate synergy between TTFields, pembrolizumab, and temozolomide. The primary endpoint was progression-free survival (PFS) compared to case-matched controls treated with TTFields and temozolomide alone. Secondary endpoints included overall survival (OS), response rate, safety, and immune correlates assessed through single-cell transcriptomics and T cell clonotyping of blood and tumor samples. FINDINGS: Among 26 patients treated per protocol, the median PFS was 12.0 vs. 5.8 months in controls (HR 0.377, 95% CI 0.217-0.653; p = 0.0026), and the median OS was 24.8 vs. 14.6 months (HR 0.522, 95% CI 0.301-0.905; p = 0.0477). Patients undergoing biopsy had longer PFS (27.2 vs. 9.6 months; HR 0.37, 95% CI 0.16-0.85; p = 0.014) and OS (31.6 vs. 18.8 months; HR 0.4, 95% CI 0.17-0.92; p = 0.023) compared to maximal resection. Severe adverse events constituted 7.5% of treatment-related toxicities. TTFields promoted clonal T cell expansion via a T1IFN-driven trajectory, while pembrolizumab supported adaptive replacement of these clones, sustaining T cell activation and memory formation, especially in biopsy-only patients. CONCLUSIONS: These findings demonstrate synergy between TTFields and ICIs, particularly in patients with high tumor burden, and support further study in larger trials. FUNDING: This work was supported by a grant from Novocure.
Chen et al. (Tue,) studied this question.