Bioengineers at the University of California, San Diego have developed cancer immunotherapy that combines ultrasound with cancer-killing immune cells to destroy malignant tumors while sparing normal tissue.
The new experimental therapy significantly slowed the growth of solid cancerous tumors in mice.
The team, led by the labs of UC San Diego bioengineering professor Peter Yingxiao Wang and emeritus bioengineering professor Shu Chien, detailed their work in an article published Aug.12 at Nature Biomedical Engineering.
The work addresses a long-standing problem in cancer immunotherapy: how to make chimeric antigen receptor (CAR) T cell therapy safe and effective for treating solid tumors.
CAR T-cell therapy is a promising new approach to treating cancer. This involves collecting a patient’s T cells and genetically modifying them to express special receptors, called CARs, on their surface, which recognize specific antigens on cancer cells. The resulting CAR T cells are then injected back into the patient to find and attack cells that have cancer antigens on their surface.
This therapy has worked well for treating some blood cancers and lymphomas, but not for solid tumors. This is because many of the target antigens on these tumors are also expressed on normal tissues and organs. This can cause toxic side effects which can kill cells – these effects are known as target and non-tumor toxicity.
“CAR T cells are so potent that they can also attack normal tissues that express target antigens at low levels,” said lead author Yiqian (Shirley) Wu, project scientist in Wang’s lab.
“The problem with standard CAR T cells is that they’re always active – they always express the CAR protein, so you can’t control their activation,” Wu explained.
To combat this problem, the team took standard CAR T cells and redesigned them so that they only express the CAR protein when ultrasound energy is applied. This allowed researchers to choose where and when the genes in CAR T cells are turned on.
“We use ultrasound to successfully monitor CAR T cells directly in vivo for cancer immunotherapy,” said Wang, a faculty member at the Institute of Engineering in Medicine and the Center for Nano-ImmunoEngineering, both at UC San Diego. What’s interesting about the use of ultrasound, Wang noted, is that it can penetrate tens of inches below the skin, so this type of therapy has the potential to non-invasively treat tumors buried deep within. inside the body.
The team’s approach is to inject the reconfigured CAR T cells into tumors in mice, then place a small ultrasound transducer over an area of the skin above the tumor to activate the CAR T cells. The transducer uses what are called focused ultrasound beams to focus or concentrate short pulses of ultrasound energy at the tumor. This causes the tumor to warm moderately – in this case, to a temperature of 43 degrees Celsius (109 degrees Fahrenheit) – without affecting the surrounding tissue. The CAR T cells in this study are equipped with a gene that only produces the CAR protein when exposed to heat. As a result, CAR T cells only light up where ultrasound is applied.
The researchers tested their CAR T cells against standard CAR T cells. In mice treated with the new CAR T cells, only tumors exposed to ultrasound were attacked, while other body tissues were left alone. But in mice treated with standard CAR T cells, all tumors and tissues expressing the target antigen were attacked.
“This shows that our CAR T cell therapy is not only effective, but also safer,” Wu said. “It has minimal side effects on target and off tumor.”
The work is still in its early stages. The team will perform more preclinical testing and toxicity studies before they can reach clinical trials.
Reference: Wu Y, Liu Y, Huang Z. et al. Monitoring of CAR-T cell activity in tumors by focused ultrasound. Nat Biomed Ing (2021). doi: 10.1038 / s41551-021-00779-w
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