UVA School of Medicine

12 VIRGINIA MEDICINE vaccines against melanoma has led to insights about how tumor cells hide from the immune system, keeping the body's natural defense system from clearing them. Much of the center's work will involve trying to create changes in the tumor microenvironment that will make those cells more receptive to immune therapy. Other research will focus on developing ways to deliver immune and other therapies directly to the tumor in a more effective way. Exploring Forms of Sonic Energy "Focused ultrasound is appealing, because there are different modalities for how it can affect the tissue, but it's noninvasive," says Slingluff. These different modalities depend on the different properties of ultrasound used. When applied continuously, a high-intensity, focused beam of this acoustic energy can destroy a tumor or other tissue by heating it. This process also elicits certain forms of tumor cell death that may be responsible for at least some of the immune response to the treatment. When applied in a pulsed form with different settings, focused ultrasound can mechanically destroy tissue through cavitation, which also induces an immune response. Three exploratory clinical trials supported by the center are now leveraging these various modalities to bring new cancer therapies out of the lab and into the clinic for breast cancer as well as other solid tumors. They all use FUS ablation in combination with either an immune checkpoint inhibitor or a chemotherapeutic agent that, at low doses, has an immune effect. The hope is these combinations will decrease the tumor's immune suppression and increase a T-cell response that will control the cancer both locally and at more distant sites. "The FUS technology has high precision and is well tolerated," says medical oncologist Patrick Dillon, MD, Res '07, the principal investigator on two of these trials. "Our biggest hope in all these studies is that by generating a system-wide response we have the exciting potential to control disease throughout the body without having to use such toxic therapies. Eventually we may be able to control early-stage breast cancer without even needing surgery or radiation." While the thermal effects of FUS ablation are the most well-researched at this time, others are trying to understand what level of energy can best induce an immune response. Histotripsy, for example, which uses lower intensity FUS to mechanically destroy tissue through cavitation, may be more effective. The concern is that thermal heating may denature proteins to the point that the T cell response against them is not adequate to produce systemic immune suppression. Solid tumors are fairly adept at evading immune recognition, so there's a lot of interest in trying to disrupt that environment within the tumor." C R A I G S L I N G L U F F, M D D I R E C T O R O F U V A C A N C E R C E N T E R ' S H U M A N I M M U N E T H E R A P Y C E N T E R A N D C O - D I R E C T O R O F T H E F O C U S E D U L T R A S O U N D C A N C E R I M M U N O T H E R A P Y C E N T E R

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