Novel 'Theranostic' Screening Tool Shows Promise in Determining Kidney Cancer Treatment

A novel imaging test may help to determine which patients with kidney cancer would benefit from treatment with immunotherapy, according to preclinical findings published in the Journal for ImmunoTherapy of Cancer.

Currently, patients with kidney cancer are typically treated with a class of drugs called immune checkpoint inhibitors, which target PD-1 and CTLA-4. However, an efficient way to predict who would and would not respond is lacking.

“In other kinds of cancer, the level of (PD-L1) expression in biopsies is predictive of response to checkpoint inhibitors,” principal investigator Dr. Isaac Bowman, an assistant professor of internal medicine at UT Southwestern Medical Center in Dallas, said in an interview with CURE. “In kidney cancer, there is some association, but it is not a reliable way of predicting who is going to respond.”

Therefore, researchers from UT Southwestern’s Kidney Cancer Program developed a new screening tool, called immuno-PET (iPET) — designed to illuminate the tumors using a “theranostic” to demonstrate who may respond to checkpoint inhibitors.

“‘Thera’ comes from therapeutic drugs and ‘nostic’ comes from diagnostic testing. So, theranostic is a drug turned into a diagnostic.,” explained corresponding author Dr. James Brugarolas, director of the UT Southwestern Kidney Cancer Program and principal investigator of the clinical trial. “So, that is what we are doing with Tecentriq (atezolizumab). We are using the immunotherapy drug and turning it into a diagnostic test to look for PD-L1 expression.”

The process involves transforming Tecentriq, which binds to and disables PD-L1 (a protein on the surface of cancer cells that serves as an “off-switch” to immune cells) into a diagnostic tracer. The drug was labeled with zirconium-89 — a radioactive metal generated using a cyclotron. With the PET scan, a very small dose of zirconium-89 plus Tecentriq can be used to evaluate whether tumors express PD-L1 to suppress immune cells and whether drugs that disable this pathway, like Opdivo (nivolumab) or Tecentriq, may be effective.

“That will provide a comprehensive picture of PD-L1 expression throughout the entire body, whereas a tissue biopsy only tells us about PD-L1 at the site of the biopsy,” Bowman said, adding that biopsies are also invasive and cannot be easily repeated during the course of treatment. “We can’t see how PD-L1 expression has changed during treatment just by relying on biopsies.”

In addition, the screening tool could help oncologists to home in on a smaller group of individuals who would benefit from immunotherapy. “Instead of having 100 patients and only 25 who will respond to treatment, maybe we can take 40 patients and 25 of those 40 would benefit,” Brugarolas said. “This would allow us to tailor the treatment for patients who are most likely to respond.”

Bowman added that the test enables the potential of reducing unnecessary toxicity as well. “This helps us to make sure the patient gets the most effective treatment, but it also makes sure we don’t expose patients to toxicity from medications which aren’t going to benefit them.”

In the preclinical study, the researchers transplanted tumors from two patients — one with high PD-L1 expression and one with low expression – into mice. The mice were injected with the theranostic, and the iPET showed that it was able to illuminate kidney tumors with high levels of PD-L1.

As predicted, the patient with the high PD-L1 tumor, Robert Tokarczyk, had substantial regression of his metastases when treated with Opdivo — an agent that targets the PD-L1 pathway.

Tokarczyk admitted that, prior to his diagnosis, he was unaware of what PD-L1 was and the effects the protein had on his cancer diagnosis. “I had no idea if you had asked me before I had cancer. I learned I had high PD-L1 expression and went from there. So, I started learning from that point forward.”

“I feel so fortunate to be part of such a cutting-edge program,” he added. “Hopefully with this discovery, they’ll be able to identify other kidney cancer patients who are candidates for immunotherapy. That’s my goal. I want other people to benefit from what I’m going through.”

Next, the researchers are moving forward with a clinical trial to be conducted at UT Southwestern’s Harold C. Simmons Comprehensive Cancer Center, where they will be evaluating the iPET strategy in a broader group of patients with the added hope that one day it could be used in more than just kidney cancer. “There is really a need for the development of iPET tests across cancer types,” Brugarolas said.