Abstract
The ProCAR platform was developed in which tumor-colonizing probiotics label tumor tissue for CAR T-cell lysis.
Major Finding: The ProCAR platform was developed in which tumor-colonizing probiotics label tumor tissue for CAR T-cell lysis.
Concept: This system demonstrated CAR T-cell activation and antigen-agnostic lysis in multiple cancer models.
Impact: Use of this platform can improve the tumor-specific delivery and efficacy of CAR T-cell therapy.
Chimeric antigen receptor (CAR) T cells have demonstrated success in hematologic malignancies, but their efficacy in solid tumors is limited due to challenges in identifying specific and uniformly expressed targets. Contrarily, certain bacterial species can selectively colonize and grow within the immune-privileged tumor core and can be used as antigen-independent therapeutic delivery platforms. To bridge these two approaches, Vincent, Gurbatri, and colleagues developed the ProCAR platform in which T cells are engineered to sense and respond to synthetic CAR targets that are released by tumor-colonizing, probiotic bacteria. Specifically, the colonizing probiotic bacteria, Escherichia coli Nissle 1917, was engineered to produce and release synthetic CAR targets (Tags) that label ubiquitous cell surface and matrix proteins found in the tumor microenvironment for de novo CAR T-cell lysis. In this case, Tags were designed as dimers of superfolder GFP fused to a heparan-binding domain and were found to robustly and specifically coat the surface of cancer cells as well as facilitate synapse formation between the GFP-targeting CARs and the target cell. Moreover, target cell lysis was observed in a Tag dose-dependent manner across multiple human cancer cell lines. Additional investigation of the ProCAR platform in vivo revealed that treatment significantly reduced tumor growth and improved survival while having no effects on weight. Moreover, the ProCAR platform was found to have antigen-agnostic capabilities and therapeutic efficacy using human xenograft models with treatment also demonstrating systemic therapeutic benefit in immune competent mouse models of colorectal carcinoma. Further engineering of probiotics to corelease an activating CXCL16 mutant that directly recruits circulating ProCAR T cells to the tumor exhibited enhanced therapeutic benefit in an orthotopic model of breast cancer. In summary, the results of this study show that the ProCAR platform can promote antigen-agnostic tumor cell death and suggests that use of this platform can improve tumor-specific targeting and therapeutic efficacy of CAR T cells in solid tumors.
Note:Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.
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