Under the Microscope: A New Technology for a Better Treatment

More than 60,000 people in the U.S. are diagnosed with kidney cancer each year, and chemotherapy and radiation therapy are largely ineffective. Immunotherapy—which uses a patient’s immune cells to fight cancer—has been a significant step forward, but only about 50-60 percent of patients benefit. Now, researchers at the University of Texas Southwestern Medical Center Kidney Cancer Program are closer to understanding why.

“We need to develop better tools to be able to predict who is and isn’t going to respond to immunotherapy,” said James Brugarolas, M.D., Ph.D., professor at UT Southwestern Medical Center and Director of the Kidney Cancer Program at the Harold C. Simmons Comprehensive Cancer Center. “Pinpointing that will maximize the likelihood of treatment success.”

Brugarolas and his colleagues, Drs. Alex Bowman and Xiankai Sun, have developed a tool using positron emission tomography (PET) imaging technology to track how immunotherapies behave inside a patient’s body. Their approach, called iPET, could give doctors a unique window into patients’ likelihood of success with immunotherapy and help them to find the best treatment for each patient.

Brugarolas was named a V Foundation Scholar in 2007. In 2018, he and his team were awarded a Translational Grant to advance the use of their iPET technology in the clinic.

Following the drugs to understand the disease

Brugarolas and his colleagues study the behavior of a specific type of kidney cancer known as renal cell carcinoma (RCC). RCC tumors express a surface protein, PD-L1, that sabotages incoming immune cells sent to destroy it, making immunotherapy ineffective. Drugs that mask PD-L1, whose discovery and development were recognized by the 2018 Nobel Prize, enable the immune cells to evade this defense and destroy the tumor.

Brugarolas and his team came up with a creative way to figure out whether PD-L1 masking immunotherapies are likely to work for patients with RCC: They added a tracer to the immunotherapy drug using their cyclotron, making it visible on a PET scan. By combining immunotherapy and PET technology, iPET can be used to follow the drug’s pathway and see how much of it reaches the tumor. If iPET shows the drug doesn’t reach the tumor, doctors will know the treatment is unlikely to work.

Why iPET?

Studying tumors with iPET has many advantages. First, seeing the presence of the target on a PET scan gives a more comprehensive view than testing biopsies, which offer only a narrow glimpse of a tumor. PD-L1 expression can vary substantially, even within the same tumor, and iPET is able to show PD-L1 levels across an entire tumor. In addition, iPET is dynamic, showing how different interventions induce or suppress PD-L1, which can have a significant impact on treatment decisions.

iPET also makes it possible to better match patients with the right therapy. Unfortunately, not all RCCs use the PD-L1 defense mechanism. Identifying patients whose tumors use different mechanisms, and therefore won’t benefit from a PD-L1 masking drug, is essential to using the immunotherapy where it is needed but avoiding unnecessary expense and side effects where it is not. Understanding which tumors don’t use this mechanism could also enable researchers to uncover, and perhaps overcome, other immunotherapy-blocking mechanisms.

Moving forward

After a successful trial in mice last year, the UT Southwestern team is now bringing their iPET technology to kidney cancer patients with a clinical trial. “The results look promising,” Brugarolas said. “We are seeing a lot of variability in PD-L1 levels across patients.”

It takes a large team of dedicated researchers to translate innovations like iPET into successful therapies to treat difficult cancers. Brugarolas said the V Foundation has been instrumental in moving his team’s research forward.

“Translational grants enable a team of investigators to accelerate innovation and bring it directly to the patient,” Brugarolas said. “The V Foundation’s support has the potential to be very impactful.”