Combining CAR-T Therapy with Tumor-Seeking Bacteria

T cells engineered to express a chimeric antigen receptor (CAR) aggressively attack other cells bearing surface markers that match that receptor. This approach is expensive, as it requires engineering cells taken from a patient, and developing CARs specific to each cancer subtype, but has so far proven effective against a number of forms of cancer. Not all cancers are consistent in markers expressed by cancer cells, however, and many cancers exhibit rapid evolution of tumor cell characteristics - only a marginal slowing of progress is achieved when much of the cancer can quickly become immune to a therapeutic approach.

In today's research materials, scientist report on an interesting and novel way to make CAR-T therapies both more effective and logistically efficient. The researchers used engineered, tumor-seeking bacteria to introduce consistency into the markers found on cancerous cells, allowing engineered immune cells to more efficiently destroy tumor tissue. Targeting different cancers then becomes a matter of picking the right bacterial species to engineer, most of which are quite capable of seeking out many different types of cancer, as well as adapting to the evolution of a tumor, rather than having to develop new CARs.

Engineered Bacteria Paint Targets on Tumors for Cancer-killing T Cells to See

For several years, researchers have been successfully using chimeric antigen receptor (CAR) T cells to target specific antigens found on blood cells as a cure for patients with leukemia and lymphoma. But solid tumors, like breast and colon cancers, have proven to be more difficult to home in on. Solid tumors contain a mix of cells that display different antigens on their surface - often shared with healthy cells in the body. Thus, identifying a consistent and safe target has impeded the success of most CAR-T cell therapy for solid tumors at the first phase of development.

Researchers have now engineered tumor-colonizing bacteria (probiotics) to produce synthetic targets in tumors that direct CAR-T cells to destroy the newly highlighted cancer cells. "Traditional CAR-T therapies have relied on targeting natural tumor antigens. This is the first example of pairing engineered T cells with engineered bacteria to deliver synthetic antigens safely, systemically, and effectively to solid tumors. This could have a significant impact on the treatment of many cancers."

This probiotic-guided CAR-T cell (ProCAR) platform is the first time that scientists have not only successfully combined engineered probiotics with CAR-T cells, but have also demonstrated the first evidence of CARs responding to synthetic antigens produced directly within the tumor. "Combining the advantages of tumor-homing bacteria and CAR-T cells provides a new strategy for tumor recognition, and this builds the foundation for engineered communities of living therapies. We chose to bridge the individual limitations of these two cell therapies by combining the best features of each - using bacteria to place the targets, and T cells to destroy the malignant cells."

Probiotic-guided CAR-T cells for solid tumor targeting

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.