Overcoming Barriers: Enhancing CAR T-Cell Therapy Efficacy in brain tumors

Despite advances, conventional treatments for adult and pediatric high-grade gliomas (e.g. GBM, DMG, DIPG) still produce poor survival. This unmet medical need has prompted development of CAR T-cell therapies but applying them to aggressive brain tumors is hampered by tumor heterogeneity, anatomical barriers (e.g., blood–brain barrier), and an immunosuppressive tumor microenvironment (TME) that limits T-cell function and drives exhaustion.

We recently designed a CAR targeting a novel tumor-associated antigen. These CAR T cells recognize and kill tumor and tumor-derived endothelial cells, reducing blood vessel density and prolonging survival in murine and human GBM models. To address TME barriers, we are exploring combination strategies with immunomodulatory agents delivered via lipid-nanoparticle (LNP) mRNA for targeted, in vivo expression, showing promising preliminary results. Additionally, we are engineering "metabolically superior" CAR T cells capable of utilizing alternative energy sources to survive in nutrient-deprived environments, leading to improved T-cell persistence and antitumor activity in preclinical models.

By combining novel CAR T cells with superior metabolic fitness and advanced nanomedicines designed to remodel the hostile TME, this strategy aims to fundamentally transform the treatment landscape for these aggressive brain cancers.