Combining a modified version of a commonly used chemotherapy medication with Positron Emission Tomography (PET), researchers at UCLA have achieved a breakthrough in immune system modeling and treatment response monitoring.
In the past, oncologists have been forced to wait weeks and often months to determine whether a patient is responding to a therapy. Currently, physicians use conventional imaging methods such as CT and MRI to scan tumors before and during treatment to measure tumor size and determine how it is responding to treatment. However, because of the time lag involved, patients who don’t respond to treatment are exposed to toxic therapies for longer than necessary, and precious time is wasted during which another, more effective therapy could have been administered. That may change soon.
Researchers at UCLA’s Jonsson Comprehensive Cancer Center
(JCCC) have modified a common chemotherapy drug to create a new probe for Positron Emission Tomography (PET), an advance that will allow them to model and measure the immune system in action and monitor response to new therapies. The probe can monitor immune and treatment response much more quickly than conventional imaging techniques—within a week or two—thereby sparing patients from prolonged exposure to therapies that aren’t working. The results of the study, published online June 8 in the peer-reviewed journal Nature Medicine
, reveal how this new development will enable scientists to monitor the immune system three-dimensionally as it tries to fi ght some cancers, or when it goes awry, as it does in autoimmune diseases.The pathway to success
Researchers created the small molecule, called FAC, by slightly altering the molecular structure of gemcitabine. They then added a radiolabel so the cells that take in the probe can be seen during PET scanning. Because the probe is labeled with positron-emitting particles, cells that take it in glow “hot” under PET scanning. Th e probe is based on a fundamental cell biochemical pathway called the DNA Salvage Pathway, which acts as a recycling mechanism that helps with DNA replication and repair. The pathway is activated at very high levels in lymphocytes and macrophages, causing the probe to accumulate at high levels in those cells.
“This will help us to more eff ectively model and measure the immune system,” said Dr. Owen Witte, a researcher at UCLA’s Jonsson Comprehensive Cancer Center and senior author of the study. “Monitoring immune function using molecular imaging could significantly impact the diagnosis and treatment evaluation of immunological disorders, as well as evaluating whether certain therapies are effective.” The work, done in animal models, will be further evaluated in subsequent studies. Eventually, Witte said, researchers hope to monitor the immune systems of patients with FAC and other PET probes.Probing immune response
Understanding the role of immune response in fighting or, in some cases, possibly stimulating tumor growth is a dilemma faced by many cancer researchers, says Kevin Shannon, MD, the Auerback Distinguished Professor of Molecular Oncology at the University of California, San Francisco. “Dynamic probes like the one developed by UCLA scientists will allow researchers to learn more about the role of the immune response in cancer, how current treatments aff ect immune cells, and will allow them to quantitatively monitor responses to new modalities such as tumor vaccines,” says Shannon. “Probes of this type may also help oncologists more rapidly identify tumors that will respond to certain drugs so treatments can be made more patient-specific.” In previous studies, UCLA researchers were able to track the immune system as it recognized and responded to cancer. But in those studies, the cells had to be modifi ed with “reporter” genes that sequestered a specifi cally designed PET probe that allowed scientists to monitor them. The new probe doesn’t require modifi ed cells, making it easier and less expensive to use and giving it far broader applications than existing probes. In addition to modeling and measuring the immune system, those applications include stratifying diff erent types of cancers and their response to therapy, defi ning the level of immune response and helping to determine whether new drugs prompt an immune response to cancer and other diseases. “This probe will tell us things about the immune system that existing probes can’t,” says Caius Radu, a Jonsson Cancer Center researcher and the first author of the study.Kim Irwin is director of media relations for the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA’s Jonsson Comprehensive Cancer Center.