Therapeutic Targeting of the TGFβ Pathway Augments CAR T cell Efficacy in Glioblastoma

Lower TGFβ levels in tumor cavity fluid after CAR T treatment are linked to improved responses in high-grade glioma patients, with baseline TGFβ stratifying outcomes.

• Why it matters: Variable clinical responses to CAR T therapy in high-grade gliomas leave a need to identify tumor microenvironment factors that predict and improve efficacy.
• What they did: Patients were stratified by baseline TGFβ in tumor cavity fluid, and single-cell RNA sequencing compared TGFβ high versus TGFβ low tumor tissues; preclinically, syngeneic murine glioma models received a TGFβR1 inhibitor.
• The result: TGFβR1 inhibition in mice and TGFβ pathway blockade in CAR T cells (TGFβR1 inhibitor or TGFβR2 CRISPR/Cas9 knockout) significantly enhanced CAR T expansion and antitumor activity, aligning with tumor microenvironment changes.