Initial analysis of adoptive neoantigen-specific T-cell immunotherapy for MGMT-unmethylated glioblastoma (TVI-AST-008): Signals amid control arm attrition.

Abstract

2042 Background: MGMT-unmethylated (MGMT-u) glioblastoma (GBM) confers resistance to alkylating agents and poor overall survival (OS). Limited options beyond Standard of Care (SOC) drive patient pursuit of experimental therapies, complicating randomized controlled trials (RCTs). TVI-AST-008 evaluates safety and efficacy of adding autologous neoantigen-specific T-cell immunotherapy to SOC in this high-risk population. Methods: In this prospective RCT, newly diagnosed MGMT-u GBM patients were randomized 1:1 post-resection to Immunotherapy + SOC or SOC alone, stratified by age, residual tumor, and sex. The investigational arm used patient tissue to manufacture an autologous vaccine and undergo tumor cell vaccination to induce antigen-specific priming. Following leukapheresis, harvested lymphocytes undergo ex vivo T-cell activation/expansion (TVAX). On completion of SOC (radiation/temozolomide), manufactured cells undergo adoptive transfer with low-dose IL-2. Primary endpoint: OS. Results: As of September 2025, 21 subjects (median age 60) were randomized: Treatment (n=11) or Control (n=10). Control arm retention was challenging: 4/10 withdrew post-randomization to pursue other experimental therapies, leaving 6 evaluable Controls. Six Treatment subjects completed infusion. Despite limited statistical power, survival divergence emerged: mean OS for Controls (n=6) was 6.6 months versus 10.6 months for infused Treatment patients (n=6), with survivors followed at a median of 14 months (2 died at 9 and 10 months). Safety was favorable; adverse events were Grade 1–2 (pyrexia, rash) consistent with immune activation. No SAEs attributed to the investigational product. Conclusions: Early TVI-AST-008 data suggest adoptive neoantigen-specific immunotherapy is feasible, safe, and early signals suggest possible improved survival in MGMT-u GBM. High post-randomization withdrawal in Controls highlights challenges of SOC-controlled trials in this setting. Future validation may require synthetic controls or crossover allowances to ensure trial viability. Clinical trial information: NCT05685004 .