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 tumour 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 tumours.
Immunotherapies using CAR-T cells have proven successful in treating some types of blood cancers.
However, their efficacy against solid tumours remains elusive.
A key challenge facing tumour-antigen targeting immunotherapies like CAR-T is the identification of suitable targets that are specifically and uniformly expressed on solid tumours.
Solid tumours 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-tumour 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 colonise the hostile microenvironments of immune-privileged tumour 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 tumour-colonising probiotic bacteria.
Using synthetic gene circuit engineering on a well-characterised non-pathogenic strain of E. coli, Vincent et al. created a probiotic that could infiltrate and cyclically release synthetic CAR targets directly to the tumour core, effectively “tagging” the tumour tissue.
Then, generated CAR-T cells that were programed to recognise the probiotic-delivered synthetic antigen tags could be used to “home in” on the tagged solid tumours and kill tumour 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 tumour, boosting therapeutic response.
Vincent et al. demonstrate the platform in humanised and immunocompetent mouse models of leukaemia, colorectal cancer, and breast cancer and show that it resulted in the safe reduction of tumour 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 tumours,” write Eric Bressler and Wilson Wong in a related perspective.