To treat solid tumors lacking defined antigen targets, Vincent and Gurbatri et al. engineered tumor-colonizing E. coli to cyclically produce GFP fused to an ECM-binding domain, which activated anti-GFP CAR T cells and enabled cancer cell lysis. In a xenograft model, i.t. injection of engineered bacteria, followed by anti-GFP CAR T cells slowed tumor growth, superior to bacteria producing non-ECM-binding GFP. In syngeneic models, i.t. injection controlled both primary (treated) and contralateral (untreated) tumors. Engineering to also produce CXCL16 increased T cell tumor infiltration, and i.v. dosing also led to antitumor efficacy in a TNBC model.
Contributed by Alex Najibi
ABSTRACT: A major challenge facing tumor-antigen targeting therapies such as chimeric antigen receptor (CAR)-T cells is the identification of suitable targets that are specifically and uniformly expressed on heterogeneous solid tumors. By contrast, certain species of bacteria selectively colonize immune-privileged tumor cores and can be engineered as antigen-independent platforms for therapeutic delivery. To bridge these approaches, we developed a platform of probiotic-guided CAR-T cells (ProCARs), in which tumor-colonizing probiotics release synthetic targets that label tumor tissue for CAR-mediated lysis in situ. This system demonstrated CAR-T cell activation and antigen-agnostic cell lysis that was safe and effective in multiple xenograft and syngeneic models of human and mouse cancers. We further engineered multifunctional probiotics that co-release chemokines to enhance CAR-T cell recruitment and therapeutic response.
