A New Frontier in Immunotherapy

Imagine an immune cell, supercharged and ready to launch a focused assault on the most stubborn of solid tumors. this is the vision that biomedical engineers at the University of Southern California (USC) have turned into reality with the creation of “EchoBack CAR T-cells.” This innovation promises to be a game-changer in cancer immunotherapy, offering a smarter, more effective way to target and destroy cancer cells.

Published in the journal Cell, this research details a novel approach designed to overcome important hurdles in treating tumors that are typically resistant to immunotherapy, all while safeguarding healthy tissue.

CAR T-Cell Therapy: A Primer

Chimeric antigen receptor (CAR) T-cell therapy represents a significant advancement in cancer treatment, especially for bloodborne cancers like leukemia. This highly personalized therapy involves extracting cancer-fighting T-cells directly from a patient’s blood. These cells then undergo genetic modification to enhance their ability to target and eliminate cancerous cells. Peter Yingxiao Wang, the Dwight C. and Hildagarde E.Baum Chair in Biomedical Engineering,leads pioneering research in this field at USC’s Alfred E.Mann Department of Biomedical Engineering.

EchoBack CAR T-Cells: Enhanced power and Control

The Wang Lab’s latest breakthrough demonstrates that EchoBack CAR T-cells can attack tumor cells for five times longer than conventional CAR T-cells. This technology is now poised for medical applications.The key innovation lies in the remote control capability, using focused ultrasound to target tumors. This approach has the potential to make treatments both safer and more effective.

Longwei Liu, an assistant professor at the USC Viterbi School of Engineering and lead author of the study, explains the advantage of this new generation of cells: 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.

The Ultrasound “On Switch”

The focused ultrasound technology developed by the Wang Lab acts as an “on switch” for the CAR T-cells.These cells are engineered to respond to a brief, 10-minute pulse of ultrasound, which then triggers them to identify and attack cancer cells in their vicinity.

It’s definitely a breakthrough. It will make the whole ultrasound-controllable CAR T practically useful for real medical applications.

Peter Yingxiao Wang, the Dwight C.and hildagarde E. Baum Chair in Biomedical Engineering

Wang further elaborated, They also have this long-lasting function upon the ultrasound short transient stimulation, and thus, 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.

EchoBack: A Unique Mechanism

The team named these cells ‘EchoBack-CAR’ due to their unique mechanism that echoes the ultrasound stimulation. This creates a call-and-response-like feedback function, allowing the cells to react to tumor cells, triggering activation and attack.

Liu explains,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. 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.

Promising Results in the Lab

the research team conducted lab-based experiments using mouse models to test the new CAR T-cells against a variety of tumor cells, including prostate cancer and glioblastoma.

According to Liu, We can clearly see that the ultrasound controllable CAR plus two rounds of ultrasound stimulation outperformed the standard CAR T-cells. Also, when we kept challenging our CAR T-cells with tumor cells, the standard CAR was already fatigued and in a dysfunctional state, but our ultrasound controllable CAR has a better function, less exhaustion and more enhanced killing.

Collaboration and Expertise

The project benefited from the contributions of USC Viterbi PhD students Peixiang He and Yuxuan Wang. the research team also collaborated with colleagues at Yale University’s Department of Biomedical Engineering and the University of North carolina at Chapel Hill for single-cell sequencing.qifa Zhou, USC’s Zohrab A. Kaprielian Fellow in Engineering, provided valuable insight into the ultrasound technology used in the development of these cells.

Looking Ahead: A Modular Tool for Cancer Immunotherapy

This breakthrough paves the way for more powerful, precise, and patient-friendly cancer treatments. Liu emphasizes that EchoBack CAR-T cells are not just a concept but a tangible step toward the future of safe and efficient immunotherapy, offering renewed hope for patients with tumors that are difficult to treat. The team envisions this new technology as a modular tool that can be successfully adapted to other types of solid tumors for immunotherapy,including breast cancer and retinoblastoma.

Liu concludes, 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.