Currently, HIFU is only used clinically to induce thermal ablation of the target site. But ultrasound can also cause mechanical damage by shaking the tumour until its cell membranes rupture, releasing intracellular proteins - or danger signals - which then trigger an immune response. What's more, the Duke researchers' findings suggest that once activated by the ultrasound, the immune system may even seek out and destroy cancer cells that have spread to other parts of the body.

"HIFU in the current form can only be used to treat the primary tumour," explained Pei Zhong, an associate professor in Duke University's department of mechanical engineering and materials science. "We now think that HIFU delivered in a different mode, with emphasis on using mechanical vibration to break apart the tumour cells, may have an even more significant impact in suppressing cancer metastasis by waking up the immune system."

Raised response
To determine the therapeutic effects of thermal and mechanical HIFU, the researchers performed in vivo experiments on mice bearing colon tumours in their hindlegs. For thermal HIFU, the ultrasound transducer was used in continuous-wave mode at a comparatively low pressure and with an exposure time of 3 s. This set-up caused a rapid temperature rise in the tumour tissue to above 70°C, and resulted in regular and well-defined thermal lesions.

For mechanical HIFU, the transducer was operated in burst mode with a duty cycle of 2%, a higher pressure and a 30 s exposure. In this case, the focal temperature increased slowly, reaching just less than 55°C in the full exposure time. The treatment generated strong cavitation (formation and collapse of microbubbles), resulting in lysis of the tumour cells.

Both thermal and mechanical HIFU impaired primary tumour growth. On average, a thermally-treated tumour was 85% smaller in volume than an untreated lesion, while tumours treated with mechanical HIFU were, on average, 43% smaller than those observed in control experiments. In terms of immune response, however, it was mechanical HIFU that showed the most striking effects.

To compare the contributions of thermal and mechanical damage to anti-tumour response, the researchers assessed the effects of HIFU on dendritic cell activity. Dendritic cells are the main initiators of anti-tumour immunity, but in order to mount an effective response they need to be activated by danger signals released from ruptured cancer cells. Both HIFU schemes significantly enhanced the infiltration of dendritic cells into the tumour, with mechanically-lysed tumour cells causing a more pronounced effect then the thermally-ablated cells.

The team also examined HIFU-induced systemic immunity by injecting cancer cells into the mouse's healthy hindleg the day after treatment. Mechanical HIFU showed a stronger retarding effect on growth of the second tumour. It also produced a larger increase in cytotoxic T-cell activity than thermal ablation.

"Our results show that while mechanical HIFU is not as effective as thermal HIFU in killing tumour cells directly, it has the potential to induce a stronger anti-tumour immune response," said Zhong. "These preliminary findings open up the possibility that we could use heat from HIFU to treat the primary tumour and HIFU-boosted immunotherapy for combating any residual and metastatic tumour cells."

• See also: HIFU alliance has Europe in its sights, Ultrasound therapy: why standards matter and Different takes on prostate cancer on medicalphysicsweb.