How to Improve the Efficacy of Cancer Immunotherapies

Combination therapy targets tumors in epithelial cancer.

Epithelial cancer mouse models treated with a combination of high-intensity focused ultrasound and 2 immunotherapies achieved a complete response.

In a study published in JCI Insight, investigators found that the treatment combination produced excellent response rates, and had greater efficacy when the immunotherapy combination (PD-1 checkpoint inhibitor and TLR9 agonist) was used first.

“This combination protocol can achieve a complete response in a large fraction of solid tumors,” said senior author Katherine Ferrara. “We found that we could achieve responses in distant lesions, but the specific protocol is really important.”

High-intensity focused ultrasound is a relatively new approach to reduce or eliminate malignant tumors. Although the beam can kill cancer cells in minutes, the effect is purely localized. For the study, investigators sought to gain more systemic tumor control by combining the approach with immunotherapies.

The investigators tested the immunotherapies before and after the ultrasound to determine which protocol was more efficacious. Priming the immune response before ultrasound was found to be the best approach, resulting in complete responses in 80% of mice after 190 days.

“We were surprised the protocol made such a difference,” said first author Matthew Silvestrini. “For the immunotherapy to be successful, it’s particular important to start it first. We found the focal therapy could have negative consequences if the immunotherapy wasn’t started first.”

The results of the study showed that early immunotherapy expanded the T cell population and primed them to respond.

“You get the immune response going, and then you deliver the focal therapy,” Ferrara said.

Overall, when immunotherapy was given first, it had a profound impact on tumors by controlling systemic lesions, as well as those targeted with ultrasound. Furthermore, multiple tumors sites treated sequentially with ultrasound following immunotherapy was more efficacious than immunotherapy alone.

Currently, the investigators are developing imaging probes to help track the efficacy of the therapies and quickly identify the most beneficial protocols.

“We know we need to personalize these therapies,” Ferrara said. “We’re developing the tools that will help us do that.”