Imagine a super-charged immune cell that can launch a focused attack on stubborn solid tumors — a smart fighter that destroys cancer cells for days without tiring. USC biomedical engineers have made this concept a reality, crafting what they have named the "EchoBack CAR T-cell," which could soon be a game changer in the field of cancer immunotherapy.
The work, published in the scientific journal Cell , is a groundbreaking new approach that could overcome major obstacles in treating tumors that are not usually candidates for immunotherapy, while keeping healthy tissue safe.
Chimeric antigen receptor (CAR) T-cell therapy is a promising field of cancer treatment that has shown great success in treating bloodborne cancers such as leukemia. It is a highly customized therapy in which cancer-fighting T-cells are drawn directly from the blood of a patient and given genetic modifications to enhance their ability to target and kill cancerous cells. The USC Alfred E. Mann Department of Biomedical Engineering conducts pioneering research in the field, under the leadership of Peter Yingxiao Wang, the Dwight C. and Hildagarde E. Baum Chair in Biomedical Engineering.
The Wang Lab 's latest discovery demonstrates that these powerful new EchoBack-CAR T-cells can attack tumor cells for five times longer than regular CAR T-cells, in technology that is ready for medical applications. The cells can be remotely controlled to target tumors using focused ultrasound, potentially making treatments safer yet more effective.
Lead author Longwei Liu , an assistant professor at the USC Viterbi School of Engineering , said that while first-generation, ultrasound controllable CAR T-cells demonstrated significantly enhanced safety compared to the standard therapy, they usually only attack cancer cells for up to 24 hours before expiring. In contrast, the team's EchoBack CAR T-cells function by being activated by ultrasound in the tumor location. From there, the CAR T-cells continue to seek and destroy cancer cells for at least five days without fatiguing.
"You can imagine that when patients come to the hospital using the first-generation cells, the patient may need to come in every day for treatment. But using the new generation, the treatment now requires far fewer visits, such as once every two weeks, or even less frequently," Liu said.
"It's definitely a breakthrough," added Wang. "It will make the whole ultrasound-controllable CAR T practically useful for real medical applications."
The Wang Lab's focused ultrasound technology works as an "on switch" for the CAR T-cells, which have been engineered to respond to a short 10-minute pulse of ultrasound. That then triggers the cells to sense cancer cells in their surroundings.
"They also have this long-lasting function upon the ultrasound short transient stimulation, and therefore, they can do a much better job in killing the tumor in the local region. So that's definitely a milestone and a breakthrough in the field. To really, you know, migrate from the conceptional design to a real practical application system," Wang said.
The team named the cells 'EchoBack-CAR' due to unique mechanisms that echo the ultrasound stimulation that activates them. The cells have a unique call-and-response-like feedback function (the 'back' in EchoBack) allowing them to react to tumor cells, which triggers the CAR T-cells to activate and attack.
"Whenever there is a tumor cell nearby, the tumor cell sends a signal to our CAR T-cell, which will then produce more killing molecules to kill those tumor cells," Liu said. "That's also why it's safe, because when those CAR T-cells migrate out of the tumor, the CAR molecule will gradually degrade, so they won't kill the normal tissue. We've engineered them to be smart CAR T-cells."
The Results
The research team conducted lab-based experiments in mouse models to test the new CAR T-cells on a selection of tumor cells including prostate cancer and glioblastoma.
"We can clearly see that the ultrasound controllable CAR plus two rounds of ultrasound stimulation outperformed the standard CAR T-cells," Liu said. "Also, when we kept challenging our CAR T-cells with tumor cells, the standard CAR was already exhausted and in a dysfunctional state, but our ultrasound controllable CAR has a better function, less exhaustion and more enhanced killing."
USC Viterbi PhD students, Peixiang He and Yuxuan Wang contributed significantly to the project. The research team worked in close collaboration with colleagues in Yale University's Department of Biomedical Engineering and the University of North Carolina at Chapel Hill on single cell sequencing for the study. USC's Zohrab A. Kaprielian Fellow in Engineering Qifa Zhou also provided insight into the ultrasound technology used for the development of the cells.
This breakthrough opens the door to more powerful, precise and patient-friendly cancer treatments. Liu said that the EchoBack CAR-T cells are not just an idea — they are a real step toward the future of safe and efficient immunotherapy, offering new hope to patients with difficult-to-treat tumors. The team now hopes this new technology could be a modular tool that can be successfully adapted to other types of solid tumors for immunotherapy, such as breast cancer and retinoblastoma.
"The most exciting part is that the CAR T-cells are smart. They can listen to the ultrasound and sense the tumor cells. These types of CAR T-cells have never been developed previously, and we are looking forward to its benefits for patients in the future." Liu said.
