Probiotic-guided CAR-T cells for solid tumor targeting


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.

Synthetic biologists report a new approach to attacking tumors. They have engineered tumor-colonizing bacteria (probiotics) to produce synthetic targets in tumors that direct CAR-T cells to destroy the newly highlighted cancer cells.   

“Our probiotic platform enables CAR-T cells to attack a broad range of tumor types,” said the study lead. “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.”

The lab has essentially created a universal CAR-T cell that attacks a universal antigen, by programming the tumor-seeking bacteria to paint solid tumors with a synthetic marker that the CAR-T cells can recognize. The researchers expect that, with further refinements, this platform will enable the treatment of any solid tumor type without the need to identify a specific tumor antigen -  thus bypassing the need to generate a custom CAR-T cell product for each cancer type and each patient. 

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,” said the study’s co-lead author. “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.”

The platform has proven to be safe and effective across multiple models of human and mouse cancers in both immunocompromised and immune-healthy mice. In fact, the study shows that human T cells in particular benefit so much from the presence of immunostimulatory bacteria within the tumor that their tumor-killing functions are further enhanced.

“Overall, our ProCAR platform represents a new strategy for enhancing the effectiveness of CAR-T cell therapy in solid tumors,” said the senior author. “While we’re still in the research phase, it could open up new avenues for cancer therapy.” 

https://www.science.org/doi/10.1126/science.add7034

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