A new study published in the Journal of Clinical Investigation Insight (JCI Insight) suggests that combining focused ultrasound ablation with immunotherapy in the right order can produce a systemic attack on epithelial cancer in a mouse model. However, for the combination to be effective, the immunotherapy must come first using a technique called priming.
Katherine Ferrara, PhD, and her team at the University of California Davis achieved these results in a study that was partially funded by the Focused Ultrasound Foundation. They found the specific protocol to be the key to achieving their groundbreaking results.
“We discovered that priming with immunotherapy before applying a local treatment with focused ultrasound could enable a systemic effect,” said Dr. Ferrara. “The overall idea with cancer immunotherapy is to allow the immune system to see the tumor antigen and respond to it. When we released the antigen in a controlled aspect, we used focused ultrasound to transform what was initially a local treatment into a strong effect that spread to other tumor cells.”
When given in the correct order, the therapies had a profound impact on tumors, controlling systemic lesions, as well as those being targeted with ultrasound. In addition, treating multiple tumor sites sequentially with ultrasound ablation following immunotherapy was more effective than immunotherapy alone.
The team tested a combination of two immunotherapies (a PD-1 checkpoint inhibitor and TLR9 agonist) both before and after ultrasound to determine which protocol was more effective. They found that priming the immune response before ultrasound ablation was the best approach, and it lead to complete responses in 80 percent of mice after 90 days. This system of “primed ablation” also improved survival. In a group with increased tumor burden, successive primed ablation of two discrete lesions resulted in survival of 60% of treated mice as compared to 25% of mice treated with immunotherapy alone.
To prime the tumor cells, they used the PD-1 inhibitor to prime cytotoxic T-cells (allowing them to fight cancer with greater intensity) and the TLR9 agonist to boost dendritic cell action and other immune components. This was followed by application of focused ultrasound to shrink the tumor and make it more vulnerable to the immune attack. The researchers observed an abscopal effect wherein the dying cancer cells released antigens that propagated the immune response, focusing T-cells on the tumor and turning a local effect into a systemic one. The early immunotherapy both expanded the T-cell population and primed them to respond – like a swarm of angry bees waiting for a target.
“We are particularly excited about immunotherapy because the criticism of focal treatments in the past has been that people die of systemic disease, whereas local treatments like focused ultrasound won’t impact that,” added Ferrara. “Now that we see the ability to treat one lesion and see the effects throughout the body – that really changes the game.”