Chimeric antigen receptor (CAR)-T cell therapy is a promising new approach to treat cancer and researchers are finding new ways to make CAR-T cell therapy safe and effective at treating solid tumors. The therapy has worked well for the treatment of some blood cancers and lymphoma, but not against solid tumors. Now, bioengineers at the University of California, San Diego (UCSD), have developed a cancer immunotherapy that pairs ultrasound with cancer-killing immune cells to destroy malignant tumors without harming normal tissue in mice.

The new experimental therapy significantly slowed down the growth of solid cancerous tumors in mice. The findings are published in the journal Nature Biomedical Engineering in a paper titled, “Control of the activity of CAR-T cells within tumors via focused ultrasound,” and led by the labs of UCSD bioengineering professor Peter Yingxiao Wang, PhD, and bioengineering professor emeritus Shu Chien, PhD.

“Focused ultrasound can deliver energy safely and non-invasively into tissues at depths of centimeters,” wrote the researchers. “Here we show that the genetics and cellular functions of CAR-T cells within tumors can be reversibly controlled by the heat generated by short pulses of focused ultrasound via a CAR cassette under the control of a promoter for the heat-shock protein.”

“CAR-T cells are so potent that they may also attack normal tissues that are expressing the target antigens at low levels,” said first author Yiqian (Shirley) Wu, PhD, a project scientist in Wang’s lab.

“The problem with standard CAR-T cells is that they are always on—they are always expressing the CAR protein, so you cannot control their activation,” explained Wu.

The researchers took standard CAR-T cells and re-engineered them so that they only express the CAR protein when ultrasound energy is applied.

“We use ultrasound to successfully control CAR-T cells directly in vivo for cancer immunotherapy,” said Wang, who is a faculty member of the Institute of Engineering in Medicine and the Center for Nano-ImmunoEngineering, both at UCSD. What’s exciting about the use of ultrasound, noted Wang, is that it can penetrate tens of centimeters beneath the skin, so this type of therapy has the potential to non-invasively treat tumors that are buried deep inside the body.

The team’s approach involves injecting the re-engineered CAR-T cells into tumors in mice and then placing a small ultrasound transducer on an area of the skin that’s on top of the tumor to activate the CAR-T cells.

In mice that were treated with the new CAR-T cells, only the tumors that were exposed to ultrasound were attacked, while other tissues in the body were left alone. However, all tumors and tissue expressing the target antigen were attacked.

“This shows our CAR-T cell therapy is not only effective, but also safer,” said Wu. “It has minimal on-target, off-tumor side effects.”

The researchers will be performing more preclinical tests before they can reach clinical trials.

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