Enhancing Solid Tumor Targeting with Probiotic-Guided CAR-T Cells

Overcoming the Challenges of Solid Tumor Targeting

For several years, scientists have successfully used Chimeric Antigen Receptor (CAR) T cells to target specific antigens on the surface of blood cells for the treatment of leukemia and lymphoma. However, the use of CAR-T cells for targeting solid tumors, such as breast and colon cancer, has proven particularly challenging due to the variety of antigens present in these tumor cells, which are also often carried by healthy cells in the body. This difficulty in identifying a consistent and safe tumor target has hindered the success of CAR-T cell therapies for solid tumors in most developmental stages.

Probiotic-guided CAR-T Cell Therapy

In a groundbreaking study, researchers have designed probiotics capable of locating and colonizing solid tumors, thereby enhancing CAR T cell immunotherapy. This two-step method involves modifying a strain of non-pathogenic E. coli to deliver synthetic antigens to the tumor microenvironment and "tag" the tumor. Subsequently, CAR T cells are generated, and programmed to recognize these synthetic antigen tags. Upon administration of the E. coli probiotics, the CAR T cells are guided to the solid tumor, orchestrating the eradication of tumor cells in both breast and colon cancer experimental models.

Unlike traditional CAR-T cell therapy, which relies on targeting natural tumor antigens, this new approach represents the first instance of combining genetically engineered T cells with genetically modified bacteria. This is to deliver synthetic antigens to solid tumors in a safe, systematic, and effective manner. This novel pairing is anticipated to have a major impact on the treatment of many types of cancer.

Fig.1 Engineered bacteria guide T cells to tumors.²

The Probiotic-guided CAR-T Cell Platform

The bacteria being programmed to locate tumors and apply synthetic antigens that CAR-T cells can recognize lays the foundation for a universal CAR-T cell that can effectively attack ubiquitous antigens. With further enhancements, this platform could potentially treat any type of solid tumor without needing to identify specific tumor antigens, ruling out the need to customize CAR-T cell products for every type of cancer and each patient.

This probiotic-guided CAR-T cell (ProCAR) platform successfully integrates genetically modified probiotics and CAR-T cells. It makes the first demonstration that CAR-T cells can respond to synthetic antigens generated directly within the tumor. This unique advantage of combining tumor-targeting bacteria and CAR-T cells offers a novel tumor identification strategy, laying the groundwork for the development of genetically modified bacteria for use in in vivo therapies. This optimally combines the strengths and compensates for the limitations of both therapies by utilizing bacteria to produce tumor targets and T cells to eliminate malignant tumor cells.

Research continues to show that this platform is safe and effective in various human and mouse cancer models both on immunocompromised and immunocompetent mice. Indeed, the new study indicates that human T cells particularly benefit from the presence of immunostimulatory bacteria within the tumor, boosting their tumoricidal functions.

The ProCAR platform represents a novel strategy to enhance the effectiveness of CAR-T cell therapy in solid tumors. Although it is still in the research phase, it might present a fresh path for cancer treatment, bringing renewed hope to many patients. Overall, the ProCAR platform showcases the unceasing march of human ingenuity in the fight against cancer.

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References

1. Vincent, Rosa L., et al. "Probiotic-guided CAR-T cells for solid tumor targeting." Science 382.6667 (2023): 211-218.
2. Bressler, Eric M., and Wilson W. Wong. "Engineered bacteria guide T cells to tumors." Science 382.6667 (2023): 154-155.

For Research Use Only. Not intended for use in food manufacturing or medical procedures (diagnostics or therapeutics). Do Not Use in Humans.