The use of focused ultrasound to control CAR-T cells led to suppression of solid tumours and mitigated off-target activity in mice.
Cancer treatment involves the use of surgery, chemotherapy or radiotherapy but in recent years, interest has grown in the use of immunotherapy which utilises a patient’s own immune system to fight cancer. One particular form of immunotherapy, Chimeric Antigen Receptor (CAR) T-cell therapy involves the genetic modification of a patient’s T cells to express a specific tumour antigen. Once modified, these T cells are infused back into the patient and attack and destroy chemotherapy-resistant cancer cells by recognising the specific surface antigen. However, whilst this is an important development in cancer therapy, a major limitation is that the specific tumour antigen can also be expressed by normal, healthy cells. Thus, the modified T cells are often unable to differentiate between malignant and benign cells. This problem led a team from the Department of Bioengineering, University of California, US, to use a different approach. They created CAR-T cells that were engineered to express the surface protein, but only in response to short-pulsed, focused ultrasound stimulation.
The team subcutaneously injected the specific CAR-T cells at the site of a tumour in mice, followed by three 5-minute pulses of focused ultrasound at 43 degrees centigrade. This led to a significant reduction in tumour size. To ensure that it was the combination of the CAR-T cells and focused ultrasound that were shrinking the tumour, the team used two control groups of mice with tumours. In one group, the pulsed ultrasound was directed at the tumour in the absence of the specific CAR-T cells, which had no impact on tumour growth. The second group again received the focused ultrasound but this time in the presence of naïve T cells, as opposed to the CAR-T cells and again, there was no effect on tumour growth. Finally, the researchers examined whether localised, pulsed ultrasound was effective using mice with both a local and distal tumour. Injection of standard CAR-T cells reduced the size of both the local and distal tumour. However, after injection of the CAR-T cells and directing the ultrasound only at the local tumour, there was a dramatic reduction in size of the local, but not distal tumour.
Discussing their findings, the authors noted the use of the targeted pulsed ultrasound was a potentially effective approach to the treatment of localised tumours. They added the local administration of the CAR-T cells has already been tested in animals and patients and a further advantage of their technique was the potential for a reduction in off-target activity, i.e., where the CAR-T cells affected healthy tissue. While this novel approach appeared to be effective, further work is required to ensure that the method represents a much safer form of cell therapy.
Wu Y et al. Control of the activity of CAR-T cells within tumours via focused ultrasound. Nat Biomed Eng 2021