Intrathecal iPSC-derived natural killer cells combined with the Stupp regimen for newly diagnosed WHO grade 4 glioma: A phase I trial.

Abstract

2072 Background: WHO grade 4 glioma has a poor prognosis despite standard Stupp therapy. Induced pluripotent stem cell–derived allogeneic natural killer cells (iPSC-NK) represent a standardized and scalable cellular immunotherapy with consistent cytotoxic potential. This Phase I study evaluated intrathecal iPSC-NK cells combined with the Stupp regimen in newly diagnosed WHO grade 4 glioma. Methods: Thirteen newly diagnosed WHO grade 4 glioma patients (median age 46 years; IDH-wildtype n=11; MGMT-methylated n=6) received standard chemoradiotherapy followed by intrathecal iPSC-NK cell infusions. iPSC-NK cells were administered at escalating doses (2×10⁷, 6×10⁷, 2×10⁸ cells/cycle) via lumbar puncture (n=8) or Ommaya reservoir (n=5) over four 28-day cycles, with temozolomide priming 5 days before each infusion. The primary endpoint was safety (serious adverse events, ≥Grade 3 toxicities); secondary endpoints included progression-free survival and pharmacokinetic/pharmacodynamic immune analyses. Results: Across 54 intrathecal iPSC-NK infusions, treatment-related toxicities were predominantly low grade: fever occurred as Grade 1 in 35 (64.8%) and Grade 2 in 9 (16.7%) infusions; headache as Grade 1-2 in 19 (35.2%) and Grade 3 in 1 (1.9%) infusion; and cytokine release syndrome was limited to Grade 1 events (44/54, 81.5%), with no ≥Grade 2 CRS or ICANS. Median PFS was 17.41 months, while median OS was not reached at a median follow-up of 22.47 months (data cutoff: January 18, 2026). PK analysis showed detectable iNK cells in CSF on Days 1–3 post-infusion, peaking on Days 1–2 and declining by Day 3. PD analyses demonstrated rapid activation of CD4⁺/CD8⁺ T cells (CD69⁺) and expansion of myeloid populations. Olink proteomics revealed consistent upregulation of cytotoxic (GZMA/B), chemokine (CXCL/CCL), and inflammatory cytokines (TNF, IFN-γ). Conclusions: iPSC-NK cells combined with the Stupp regimen demonstrated a favorable safety profile, induced early immune activation within the central nervous system, and showed encouraging preliminary efficacy in patients with WHO grade4 glioma. Clinical trial information: NCT06147505 .