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.
Author Info: (1) Department of Biomedical Engineering, Columbia University, New York, NY 10027, USA. (2) Department of Biomedical Engineering, Columbia University, New York, NY 10027, USA. (3)
Author Info: (1) Department of Biomedical Engineering, Columbia University, New York, NY 10027, USA. (2) Department of Biomedical Engineering, Columbia University, New York, NY 10027, USA. (3) Department of Microbiology and Immunology, Vagelos College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA. (4) Department of Biomedical Engineering, Columbia University, New York, NY 10027, USA. (5) Department of Biomedical Engineering, Columbia University, New York, NY 10027, USA. (6) Department of Biomedical Engineering, Columbia University, New York, NY 10027, USA. (7) Department of Biomedical Engineering, Columbia University, New York, NY 10027, USA. Department of Microbiology and Immunology, Vagelos College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA. (8) Department of Microbiology and Immunology, Vagelos College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA. Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA. (9) Department of Microbiology and Immunology, Vagelos College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA. (10) Department of Microbiology and Immunology, Vagelos College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA. (11) Department of Biomedical Engineering, Columbia University, New York, NY 10027, USA. Department of Microbiology and Immunology, Vagelos College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA. (12) Department of Microbiology and Immunology, Vagelos College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA. (13) Department of Biomedical Engineering, Columbia University, New York, NY 10027, USA. (14) Department of Microbiology and Immunology, Vagelos College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA. Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA. (15) Department of Biomedical Engineering, Columbia University, New York, NY 10027, USA. Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA. Data Science Institute, Columbia University, New York, NY 10027, USA.
