Engineered bacteria guide CAR-T cells to poorly infiltrated solid tumors

A new probiotic-guided chimeric antigen receptor (CAR)-T platform uses engineered bacteria to infiltrate and produce synthetic antigen targets, enabling CAR-T cells to find, identify, and destroy tumor cells in situ, according to a new study. The combined cell therapy platform expands the scope of CAR-T cell therapy to include difficult-to-target solid tumors. Immunotherapies using CAR-T cells have proven successful in treating some types of blood cancers. However, their efficacy against solid tumors remains elusive. A key challenge facing tumor-antigen targeting immunotherapies like CAR-T is the identification of suitable targets that are specifically and uniformly expressed on solid tumors. Solid tumors express heterogeneous and nonspecific antigens and are poorly infiltrated by T cells. As a result, the approach carries a high risk of fatal on-target, off-tumor toxicity, wherein CAR-T cells attack the targeted antigen on healthy vital tissues with potentially fatal effects. Previous studies have shown that, unlike CAR-T cells, some species of bacteria can selectively colonize the hostile microenvironments of immune-privileged tumor cores and can be engineered as antigen-independent platforms for therapeutic delivery. In this study, Rosa Vincent, Candice Gurbatri, and colleagues combine probiotic therapy with CAR-T cell therapy to create a two-stage probiotic-guided CAR-T cell (ProCAR) platform, whereby T cells are engineered to sense and respond to synthetic CAR targets that are delivered by solid tumor-colonizing probiotic bacteria. Using synthetic gene circuit engineering on a well-characterized non-pathogenic strain of E. coli, Vincent et al. created a probiotic that could infiltrate and cyclically release synthetic CAR targets directly to the tumor core, effectively “tagging” the tumor tissue. Then, generated CAR-T cells that were programed to recognize the probiotic-delivered synthetic antigen tags could be used to “home in” on the tagged solid tumors and kill tumor cells in situ. What’s more, the authors also engineered probiotics that co-release chemokines in addition to synthetic targets to further enhance CAR-T cell recruitment to the tumor, boosting therapeutic response. Vincent et al. demonstrate the platform in humanized and immunocompetent mouse models of leukemia, colorectal cancer, and breast cancer and show that it resulted in the safe reduction of tumor volume. “The study of Vincent et al. is an important proof-of-concept for a potential approach to treating heterogeneous, immunologically cold, and poorly infiltrated solid tumors,” write Eric Bressler and Wilson Wong in a related Perspective.