(H-296) Heat-Inducible CAR-T Overcomes Adverse Mechanical Tumor Microenvironment in 3DBioprinted Glioblastoma Model.

Glioblastoma (GBM) presents a significant therapeutic challenge due to the limited efficacy of existing treatments and the complex tumor microenvironment. Chimeric antigen receptor (CAR) T-cell therapy offers promise, but its potential in solid tumors like GBM is undermined by the physical barrier posed by the extracellular matrix (ECM). Particularly, the stiffening of ECM impairs the function and infiltration of cytotoxic T cells. Conventional 2D models and animal models are deficient in accurately replicating the intricate tumor ECM. We addressed this gap by employing digital light processing-based 3D bioprinting to fabricate biomimetic tumor models, enabling precise control over matrix composition and stiffness. Our findings revealed that ECM stiffness impeded CAR-T cell penetration and cytotoxicity in GBM models. Notably, we developed a heat-inducible CAR-T cell therapy that effectively navigated through the stiff tumor microenvironment, increasing T cell infiltration and cytotoxicity. This study presented the first 3D bioprinted models to examine ECM stiffness effects on CAR-T cell therapy, introducing a more clinically-relevant evaluation model for CAR-T development against solid tumors.