Ultrasound-guided SHIFTERS could expand CAR-T therapy for solid tumors

For more than a decade, CAR-T cell therapy has been one of the biggest breakthroughs in cancer medicine. By reprogramming a patient's own immune cells to attack cancer, doctors have produced remarkable results against certain blood cancers, offering hope to patients who once had few treatment options.

But that success has largely stopped at solid tumors, including cancers of the brain, liver, lung, breast and pancreas. Unlike blood cancers, these tumors often lack a clear target for CAR-T cells, making the therapy far less effective.

Researchers at the USC Viterbi School of Engineering believe they have found a new approach that offers hope.

Their solution is called SHIFTERS. Instead of searching for a naturally occurring marker that may not even exist, the researchers developed a way to temporarily create one. Using focused ultrasound, physicians prompt tumor cells to briefly display CD19, a marker CAR-T cells already recognize. The work is described in the study,"Ultrasound Priming Gated by Solid Tumor Hallmarks to Guide CAR-T Therapy" in Science Advances.

"I think this is revolutionary," said Peter Yingxiao Wang, the Dwight C. and Hildagarde E. Baum Chair in Biomedical Engineering and professor in the Alfred E. Mann Department of Biomedical Engineering, of the work taking place in his lab. 

A lock with two keys

The idea behind SHIFTERS is surprisingly straightforward.

Most solid tumors have characteristics that healthy tissue does not. One of those characteristics is low oxygen. As tumors grow rapidly, they often outgrow their blood supply, leaving pockets of cancer cells starved for oxygen.

The USC researchers designed SHIFTERS to recognize that condition. But low oxygen alone isn't precise enough to activate the system. Doctors must also apply focused ultrasound, a noninvasive technology that can precisely target tissue deep inside the body without surgery.

Think of it as a lock that requires two keys. One key comes from the tumor. The other comes from the physician. Only when both keys are present do tumor cells briefly display CD19. That temporary marker tells the engineered immune cells, "Attack here."

"The goal is to make solid tumors easier to recognize while giving doctors control over where and when treatment switches on," Tianze Guo, a doctoral student advised by Wang, said.

The marker remains for about a week, allowing physicians to control where and when the immune attack begins.

A different way of thinking

The approach challenges an assumption that has guided cancer immunotherapy for years.

Researchers around the world have spent decades searching for a marker that appears only on solid tumors and nowhere else in the body. Finding one has proven extraordinarily difficult because solid tumors arise from normal tissue and often share many of the same surface features as healthy cells.

"Instead of trying to search for a perfect antigen, we basically force them to produce one," Wang said.

The researchers evaluated SHIFTERS one step at a time. They first tested the system in cancer cells grown in the laboratory. Next came three-dimensional tumor models that more closely resemble real tumors. Finally, they tested the technology in animal models carrying human brain and liver tumors.

Across every stage, the results pointed in the same direction. Once ultrasound activated the temporary marker, CAR-T cells mounted a much stronger attack than they normally achieve against solid tumors. Tumors treated with ultrasound shrank dramatically, while untreated tumors continued to grow.

Small changes, big impact

The team also uncovered an unexpected finding. They discovered they didn't need every tumor cell to display the temporary marker. Even a relatively small number of cells was enough to launch a much broader immune attack.

Those cells became what the researchers call "training centers." Rather than serving as the final target, they activated CAR-T cells to recognize and destroy neighboring cancer cells throughout the tumor, including cells that never displayed the marker.

"We expected to need a high density of target-positive cells, but in our lab models even 10% to 25% carrying the initiating target was enough to drive substantial killing across the whole tumor," Guo said.

Solid tumors on the run

The work builds on years of research in Wang's laboratory using focused ultrasound to control engineered immune cells. Earlier studies showed ultrasound could activate CAR-T cells at specific locations. SHIFTERS goes a step further by creating the target those immune cells need to recognize.

This technology is still experimental and hasn't been tested in people yet. The biggest hurdle is finding a practical way to deliver the SHIFTERS genetic program directly into tumors. Researchers are currently comparing two delivery methods, lipid nanoparticles and modified viruses, before moving on to larger animal studies and, eventually, human trials.

Wang estimates the technology is still years from the clinic and will require further technical advances and significant funding. Still, he believes it opens a promising new direction for treating solid tumors.

"We're continuing to rewire the tumor, rewire the T cell, and improve recognition and killing," Wang said.