New PET imaging chemical gives 3-D image of immune response in
action
29 June 2008
A new molecular probe developed at the University of California, Los
Angeles (UCLA) Jonsson Comprehensive Cancer Center enables scientists to
monitor the immune system at the whole body level in 3D, as it tries to
fight some cancers or when it goes awry as it does in autoimmune
diseases. The advance will allow scientists to model and measure the
immune system in action and monitor response to new therapies.
The discovery, published June 8, 2008 in the early online edition of
the journal Nature Medicine.
|
Autoimmune syndrome visualised
with new molecular probe |
The researchers obtained the molecular probe, by modifying a common
chemotherapy drug to create a new probe for Positron Emission Tomography
(PET). Researchers created the small molecule, called FAC, by slightly
altering the molecular structure of one of the most commonly used
chemotherapy drugs, gemcitabine. They then added a radiolabel so the
cells that take in the probe can be seen during PET scanning.
The probe is based on a fundamental cell biochemical pathway called
the DNA Salvage Pathway, which acts as a sort of recycling mechanism
that helps with DNA replication and repair. All cells use this
biochemical pathway to different degrees.
But in lymphocytes and macrophages, the cells of the immune system
that initiate immune response, the pathway is activated at very high
levels. Because of that, the probe accumulates at high levels in those
cells, said Dr. Owen Witte, a researcher at UCLA’s Jonsson Cancer Center,
a Howard Hughes Medical Institute investigator and senior author of the
study.
“This is not a cure or a new treatment, but it will help us to more
effectively model and measure the immune system,” said Witte, who also
serves as director of the Eli and Edythe Broad Center of Regenerative
Medicine and Stem Cell Research at UCLA. “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.”
Because the probe is labeled with positron emitting particles, cells
that take it in glow 'hot” under PET scanning, which operates as a
molecular camera that enables visualization of biological processes in
living organisms. The work, done in animal models, will be further
evaluated in subsequent studies. Eventually, Witte said, researchers
hope to be able to monitor the immune systems of patients with FAC and
other PET probes.
“This measurement is not invasive — it involves a simple injection of
the probe,” Witte said. “We could do repetitive scans in a single week
to monitor immune response.”
Using conventional methods, oncologists are forced to wait weeks and
often months to determine whether a patient is responding to a therapy.
CT and MRI scans are taken before and during treatment and the size of
the tumour is measured to determine response — if the tumour is
shrinking, the patient is responding. However, patients that don’t
respond are exposed to potentially toxic therapies for longer than
necessary. If the new PET probe can monitor immune response and response
to treatment much more quickly — within a week or two — patients would
be spared from therapies that aren’t working.
One frustrating aspect for many cancer researchers is understanding
the role of the immune response in fighting or, in some cases, possibly
stimulating tumour growth, said Dr Kevin Shannon, 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 affect immune cells, and will allow them
to quantitatively monitor responses to new modalities such as tumour
vaccines,” Shannon said. “Probes of this type may also help oncologists
more rapidly identify tumours that will respond to certain drugs so
treatments can be made more patient-specific.”
Witte said the type of multidisciplinary research that led to
development of the probe is uniquely suited to UCLA’s collaborative
strengths. Researchers from the cancer center, the Broad stem cell
center and the Crump Institute for Molecular Imaging took part in the
study. The PET scanner was invented by UCLA’s Michael Phelps, also a
co-author on this study.
The work by Witte and his colleagues was prompted by the desire to
add to a short list of probes now used in PET scanning and to develop
new probes that monitor different molecular functions than the current
probes.
“What we wanted to do was to develop new ways to look inside a living
organism and gather as much information as we can about the immune
system,” said Caius Radu, an assistant professor of molecular and
medical pharmacology, a Jonsson Cancer Center researcher and the first
author of the study. “We wanted to know how cells move from one site in
the body to another and find a way to trace them to tumours.”
In previous studies, Witte and other 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 modified with 'reporter' genes that
sequestered a specifically designed PET probe that allowed scientists to
monitor them.
The new probe doesn’t require modified 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 different types of
cancers and their response to therapy, defining the level of immune
response in both normal and pathological situations 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,” said Radu, who also is a member of the Crump Institute
for Molecular Imaging.