A new positron emission tomography (PET) probe that models and measures the immune system may help physicians more quickly determine how patients are responding to treatment.

Owen N. Witte, M.D., and Caius Radu, M.D., of the University of California, Los Angeles, led the team that developed a way to noninvasively monitor the immune system using PET.

A team at the University of California, Los Angeles, Jonsson Comprehensive Cancer Center, has altered the chemotherapy drug gemcitabine to create the molecule fluoracetate (FAC), which in turn can be used as a probe monitoring the immune system with 3D PET. Owen N. Witte, M.D., and Caius Radu, M.D., led the team, which published its findings in the July 1, 2008, issue of the journal Nature Medicine.

"The challenge that motivated me was to develop a new way to visualize the immune system in a noninvasive way using PET," said Dr. Radu, an assistant professor of molecular and medical pharmacology at UCLA. "One of the first ideas we had was developing such imaging drugs by using a very simple screening strategy."

Dr. Witte, director of the Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at UCLA, described how he had gotten to know Michael Phelps, Ph.D., a UCLA colleague and pioneer in modern PET scanning. "I began asking him about the potential for PET to evaluate immune function," explained Dr. Witte. "We came about this not by taking anything that anyone else had done, but by working with the principles, to try to understand how cells involved in an immune response could be potentially imaged."

Focusing on how immune response cells behave, the team looked at DNA salvage pathways—the scavenger mechanism that takes up DNA building blocks that have been degraded as cells died during immune response. The team knew that gemcitabine and related molecules are efficiently picked up by the DNA salvage pathway. According to Dr. Witte, with some modification of the gemcitabine molecule, the newly created FAC molecule "goes through the salvage pathway and is taken up quite beautifully in lymphoid cells, particularly when they're in an activated state." The result, he said, is vivid PET imaging of the probe and thus the immune system response.

Dr. Radu said he sees this imaging development in the larger picture of personalized medicine. "Doctors need to start treating individual patients rather than generic diseases," he said. New ways to image the immune system, he said, will allow doctors to both predict how a specific patient would respond to a drug and to quickly determine whether patients are responding to the drug once treatment begins.

"You can measure antibodies, the soluble protein components of the immune system, quite well," said Dr. Witte. "But the cellular immune system is very poorly monitored by modern technology. We take cells out of the peripheral blood, but you have to realize there's only a tiny, tiny fraction of the cells in the peripheral blood and they're only there transiently. In order to think about cells that are actually functioning, we would have to take cells out of a place where they're carrying out a function—for example, attacking a tumor."

With FAC and similar PET probes, said Dr. Witte, doctors will soon be able to look for "abnormal accumulation of lymphoid cells in places they shouldn't be, indicating an autoimmune disease or a response to another pathological process. It's really a completely different way of measuring."

Researchers altered the chemotherapy drug gemcitabine to create the molecule fluoroacetate (FAC), which can be used as a probe for monitoring the immune system with 3D PET. Researchers are using the probe and its derivatives to look at different aspects of immune response, including cases of autoimmune disease.

The research required a multidisciplinary team. "You have to think about everything from fundamental physics all the way to the immune system and the whole body, so it covers a lot of turf," said Dr. Witte. "You need people who are both synthetic chemists as well as radiochemists, you need people who are trained in the physics and mathematics of image construction. You need engineers who build and design the latest varieties of PET scanners."

Moving ahead, the UCLA team will be testing FAC in humans to see if it works as well as it has in mice. The researchers are also actively seeking more PET probes. "We are trying to take the lessons we learned from developing FAC and apply them to the discovery of other probes," said Dr. Radu. "We believe that probably the most important implication of this study is that one can see it as a pathway to developing other PET imaging probes."

Added Dr. Witte: "There's a whole collection of relatives that we're working on. They are being evaluated in a broad range of experimental models that look at different aspects of the immune response, some against cancer in terms of cellular therapies and some against infectious agents and in cases of autoimmune disease. There's quite a bit of work to do in characterizing FAC."

The team is committed to moving ahead into the clinic with the agents, said Dr. Witte. "We want to see which, if any, of these compounds has any value in the clinic for diagnosis or prognosis of autoimmune disease or cellular therapeutics for cancer," he said.

Because FAC and its derivatives are related to a family of cancer chemotherapy agents like gemcitabine, researchers hope to be able to use the probes to predict which patients would respond to the chemotherapy agents, said Dr. Witte. "Some patients really do respond to the chemotherapy agent and you know you're having a therapeutic effect," he said. "In other patients, there's remarkably little response and it's not clear why. It can be for lots of reasons, such as the drug wasn't taken up or it's metabolized differently. What we hope to do is use a probe like FAC to identify patients who are taking up a lot of this class of compound because we believe they'd be the ones who are more likely to have a favorable chemotherapy response. We may have a way of predicting how patients with a certain types of cancer will respond best to a selected, more targeted therapy."

Both Drs. Radu and Witte are excited about expanding their diagnostic toolbox. "What's important is I don't think we're finished finding good, new, effective probes," said Dr. Witte. "We're not looking at a single molecule perspective; we're looking at a pathway perspective."