Breaking barriers: ECM-degrading CAR T cells for enhanced efficacy in solid tumors 4516

Abstract Description Chimeric antigen receptor (CAR) T cell therapy has transformed cancer treatment. Yet, its effectiveness against solid tumors is hindered by limited infiltration into the dense extracellular matrix (ECM) and the immunosuppressive tumor microenvironment (TME). To address these challenges, we developed Matrix-degrader Armored CAR T Cells Hacking Established Tumor microEnvironment (MACHETE), engineered to secrete ECM-degrading proteins. These proteins actively disrupt the ECM, enhance T cell infiltration, and mitigate fibrosis-associated immunosuppression. In vitro, MACHETE demonstrated superior cytotoxicity in both 2D and 3D tumor co-culture systems. In pancreatic cancer spheroid models, MACHETE exhibited significantly enhanced infiltration by effectively disrupting ECM architecture. Moreover, the secreted proteins exhibited intrinsic cytotoxic properties and antagonized TGF-β1, a key immunosuppressive cytokine in the TME, further boosting MACHETE’s efficacy. Importantly, we showed that this armoring strategy was broadly applicable across CAR/TCR platforms targeting diverse solid tumors, including breast, ovarian, and pancreatic cancers. In vivo study is ongoing to validate MACHETE’s ability to improve tumor infiltration, reprogram the TME, and enhance therapeutic efficacy. These findings underscore the potential of MACHETE as an innovative approach to overcoming the major barriers in CAR T cell therapy for solid tumors and support its translation into clinical applications. Funding Sources Supported by NIH R35241894. Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)