Source: Stanford University Medical Center
Tuesday, November 18, 2008
STANFORD, Calif. — Coaxing a patient's own cells to hunt down and tackle
infected or diseased cells is a promising therapeutic approach for many
disorders. But until now, efforts to follow these specially modified
cells after their reintroduction to the body have relied on short-term
monitoring techniques that don't give a complete picture of the cells'
status.
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Now, for the first time, researchers at the Stanford University School
of Medicine have devised a way to obtain repeated "snapshots" of the
location and survival of such cells in a living human patient months and
possibly years later. This is good news for individual patients and
clinicians who may want to assess the cells' disease-fighting
performance over time, as well as for researchers trying to design more
effective cell-based therapies.
"This has never before been done in a human," said the senior author of
the research, Sanjiv Gambhir, MD, PhD, director of Stanford's Molecular
Imaging Program. "Until now, we've been shooting blind—never knowing why
failed therapies didn't work. Did the cells die? Did they not get where
we wanted them to go? Now we can repeatedly monitor them throughout
their lifetime." Gambhir is a professor of radiology and a member of
Stanford's Cancer Center. He collaborated with researchers at City of
Hope in Los Angeles and at UCLA to conduct the research.
Gambhir and his colleagues tested the technique in a middle-aged man
with an aggressive brain tumor (called a glioblastoma) who was enrolled
in a clinical trial of cell-based therapy at City of Hope. However, they
believe similar strategies will work to monitor cell-based therapies for
many disorders. The results of the case study will be published online
Nov. 18 in Nature Clinical Practice Oncology.
The new approach relies on a two-step process: first, the therapeutic
cells are modified to express a unique reporter gene shared by no other
cells in the body. Second, an imaging agent that is trapped only in
cells expressing the reporter gene is injected into the patient. The
unbound imaging agent is otherwise quickly cleared from the body. Each
time the imaging agent is used, the researchers get a new, up-to-date
map showing the cells' locations.
The technique has several advantages over previous tracking methods.
Unlike an external radioactive tag, which decays over a short time and
does not indicate whether a cell is living or dead, the reporter gene is
expressed throughout a cell's lifetime, but not beyond. Furthermore,
unlike an external tag, the reporter gene is duplicated and passed along
if the original cell divides. Finally, different reporter genes can be
used that could indicate not only the location of the cells, but also
what they're up to.
"In this patient, the reporter gene was always on," said Gambhir. "But
the beauty of this approach is that we could make it so the reporter
gene is expressed only if the cell differentiates, or finds a certain
target. Has the T cell found a tumor? Has it activated its cell-killing
machinery?"
In the current study, Gambhir collaborated with Michael Jensen, MD,
associate chair of the cancer immunotherapeutics & tumor immunology
program at City of Hope, and others to remove cytotoxic, or "killer," T
cells from the man with glioblastoma. These cells naturally seek out and
destroy infected or dysfunctional cells in the body. The researchers
then inserted a circle of DNA encoding two key genes into these T cells.
One endowed the cells with the ability to home in on the cancer cells.
The other encoded a gene from a herpes simplex virus called thymide
kinase, or HSV1-tk. The product of the HSV1-tk gene traps a
radioactively labeled imaging molecule that can be visualized on a PET
scan. Any imaging molecule that is not trapped in the modified T cells
is eliminated from the body. A clinical PET-CT scanner tracks the
locations of the imaging molecule and therefore the modified T cells.
The researchers then returned the modified T cells to the site of the
patient's brain tumor over a period of five weeks. The patient received
the imaging agent three days after the last infusion of cells. As the
researchers had hoped, the subsequent PET-CT scan showed that the T
cells had homed in on the tumor. However, they also migrated through the
patient's brain to highlight a second, previously unsuspected tumor
site. Although this study did not assess the ability of the T cells to
kill the tumor cells, the imaging results suggested they at least got to
their targets.
"The cells were actually good at finding the tumor," said Gambhir, who
pointed out that the same technique could be used to follow other immune
cells or eventually stem cells throughout the body. He plans to
collaborate with other researchers at Stanford and elsewhere to not only
continue his study with T cells and other tumor types, but also to
investigate the movement of therapeutic cells in patients with arthritis
and diabetes.
The study could not have been done without the concerted efforts of
researchers at Stanford, UCLA, City of Hope and the Food and Drug
Administration, Gambhir emphasized. Genetically modifying cells for
re-infusion into a human patient requires rigorous quality-control
measures and extensive ethical review. The researchers selected the
glioblastoma patient for their first attempt because this cell-based
therapy trial was already approved by the FDA. Gambhir also had FDA
approval on the PET imaging agent.
"It took all of the institutions to come together to make such a complex
trial work," said Gambhir, "but, because we're not limited to just one
cell population, the results are tremendously exciting."
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In addition to Gambhir, other Stanford researchers involved in the work
were Shahriar Yaghoubi, PhD, senior research scientist; Shradha
Budhiraja, PhD; and David Paik, PhD, assistant professor of diagnostic
radiology. Nagichettiar Satyamurthy, PhD, and Johannes Czernin, MD, at
UCLA were also pivotal to the study's success.
The research was funded by the Doris Duke Charitable Foundation, the
National Institutes of Health and the National Cancer Institute.
Stanford University Medical Center integrates research, medical
education and patient care at its three institutions — Stanford
University School of Medicine, Stanford Hospital & Clinics and Lucile
Packard Children's Hospital at Stanford. For more information, please
visit the Web site of the medical center's Office of Communication &
Public Affairs at http://mednews.stanford.edu.