Researchers at the University of Wisconsin–Madison (UW) have developed a novel focused ultrasound procedure that successfully treated tumors, increased chemotherapy uptake and altered the tumor immune microenvironment in a mouse model of breast cancer.
Their findings will be presented as a featured abstract, “Histoplasty Modification of the Tumor Microenvironment in a Murine Preclinical Model of Breast Cancer,” during Sunday’s Scientific Session 2, New Frontiers in IR, from 3–4:30 p.m. MT.
The abstract will be presented by Alexander Pieper, MD, PhD, now a first-year radiology resident at University of Pennsylvania. Dr. Pieper was a part of the UW research team when he was completing his MD/PhD program.
Histotripsy is a noninvasive, nonthermal targeted ultrasound technique that could improve and expand cancer treatment administered by IRs. Histotripsy controls and directs cavitation without damage to surrounding structures.
The idea for a less-intense form of histotripsy, dubbed “histoplasty,” started from conversations between Dr. Pieper and his mentor, J.P. Yu, MD, PhD, an associate professor of radiology and leader of a systems neuroscience laboratory at UW.
The two were discussing how some tumors could be located adjacent to more delicate structures in which a slightly off-target histotripsy could cause death or significant injury. In addition, physicians who have performed histotripsy have mentioned anecdotally that when they do histotripsy on only a part of a tumor, they achieve a stronger antitumor immune response, Dr. Pieper said.
“That got us thinking that maybe there is something to be said about having an intact extracellular matrix within the tumor in order to get an optimal antitumor immune response,” he said.
The team used a mouse model of breast cancer to deliver 15-second subcavitation nonablative acoustic pulses at a single spherical focal point to ex vivo tumors. The researchers used a histotripsy device but used levels of acoustic energy below what is needed to create cavitation for histotripsy.
Separately, mice with bilateral 4T1 tumors were injected with the chemotherapy drug liposomal doxorubicin (Doxil at 16 mg/kg), and the right flank tumor was treated with histoplasty. Mice were fluorescently imaged to detect Doxil uptake following treatment.
The results showed that histoplasty altered the tumor microenvironment by decreasing tumor collagen length and density by nearly 30%. This allowed for significantly increased Doxil uptake.
In a separate experiment, 4T1 tumor-bearing mice were randomized into two treatment groups: histoplasty treatment and sham. The tumor immune microenvironment was analyzed with flow cytometry. Compared to control tumors, histoplasty-treated tumors demonstrated a significant increase in tumor macrophage frequency and a significant decrease in myeloid-derived suppressive cell frequency 2 days after histoplasty. In addition, mice treated with histoplasty survived longer than untreated mice (median survival of 33 days compared with 26.5 days).
If ongoing studies continue to show the success of histoplasty, it could provide exciting implications for cancer patients, Dr. Pieper said. Currently, “we can identify which chemotherapy a patient may or may not need based upon the genetics of the tumor, but one significant barrier to the efficacy of chemotherapy right now is getting the chemotherapy actually into the tumor so that it can do its job in killing tumor cells.”
Beyond breast cancer, histoplasty could be used in tumors demonstrating significant fibrosis, such as liver cancer and pancreatic cancer, Dr. Pieper said. For nonsurgical pancreatic cancer candidates, histoplasty could potentially improve the effect of chemotherapy, shrinking the tumor enough so that surgery would be an option, he explained.
Dr. Pieper said he believes the field of IR is only starting to understand how IRs can play a role in assisting oncologists in dosing or utilizing cancer immunotherapies. Activating a strong systemic antitumor immune response requires a three-step treatment process. The first step is a “spark,” followed by applying gas to the immune system and then removing the brakes of the immune system.
Dr. Pieper said IRs can provide that initial spark through combination treatments such as histoplasty and histotripsy. “Within tumor immunology, in the tumor microenvironment it’s like this teeter-tottering balance of protumor immune cells and antitumor immune cells,” he said. “What we found was that histoplasty can actually tilt the balance in favor of an antitumor immune microenvironment.”
