Disease Prevalence and Grim Outcome
Glioblastoma (GBM) is the most common primary brain cancer in adults and is nearly always fatal. Between 2001 and 2020, there were 168,030 GBM diagnoses and 151,023 deaths in the United States alone. Despite aggressive treatments combining surgery, radiotherapy, and temozolomide, most patients relapse within a year of diagnosis. For recurrent GBM, standard therapies (lomustine, bevacizumab, re-irradiation) result in a median overall survival (OS) of just 6–10 months, and no intervention has ever extended OS in this setting in randomized trials.
Historically, chimeric antigen receptor (CAR) T cell therapy has shown striking success only against hematologic cancers. Solid tumors, including GBM, have proven resistant due to factors like heterogeneous antigen expression, poor immune infiltration, and a highly immunosuppressive tumor microenvironment. However, recent early-phase studies in high-grade gliomas have shown signs of efficacy and have paved the way for more advanced CGT approaches.
Reported Work
The referenced phase 1 clinical trial tested the safety and activity of intracerebroventricular (ICV) infusion of bivalent CAR T cells targeting both EGFR (epitope 806) and IL-13Rα2 in patients with recurrent, EGFR-amplified GBM. Eighteen adult patients participated; the maximum tolerated dose was determined as 2.5 × 10⁷ cells. The therapy was feasible with no manufacturing failures. Although 56% experienced grade 3 neurotoxicity, these events were mostly reversible; there were no grade 4–5 events. Sixty-two percent of patients with measurable disease showed radiographic tumor regression, and one achieved a partial response. Durable disease control was limited—median progression-free survival was only 1.9 months, although some patients experienced extended periods of disease stability and CAR T cell persistence.
Conclusions
While most patients relapsed within a few months, bivalent CAR T therapy showed clear signs of bioactivity in this aggressive disease, with occasional durable responses and significant immune changes in the tumor environment. The safety and feasibility profile supports further investigation. CGT approaches like these offer a glimmer of hope for otherwise untreatable cancers, representing a long-sought potential for transformative, precision therapy in GBM.
Reference: Bagley SJ, Desai AS, Fraietta JA, Silverbush D, Chafamo D, Freeburg NF, et al. "Intracerebroventricular bivalent CAR T cells targeting EGFR and IL-13Rα2 in recurrent glioblastoma: a phase 1 trial." Nature Medicine. 2025 Aug;31:2778–2787. DOI: 10.1038/s41591-025-03745-0.