By using MRI to detect magnetic probes of tiny
iron oxide particles, an international research team
for the first time has successfully tracked immune-stimulating
cells implanted into cancer patients for treatment
"In four of the eight patients, MRI revealed that
the implanted cells weren't where they needed to
be to be effective for treatment," says Jeff Bulte,
Ph.D., an associate professor of radiology at Hopkins'
Institute for Cell Engineering who developed methods
to optimally label cells with the clinically approved
iron oxide particles.
This new application of the probes -- already clinically
approved for MRI scanning of the liver -- could dramatically
improve efforts to test and use cellular therapies
such as vaccines to treat cancer or prevent its recurrence
or stem cells to repair damaged organs, say the researchers.
Bulte and a team of Dutch researchers used MRI and
a magnetic probe approved by both European and U.S.
agencies to locate therapeutic cells injected into
eight melanoma patients.
"Our results show that the MRI-based technique was
more accurate than tracking the cells using radioactivity
and that ultrasound failed to accurately guide injection
of the cells into lymph nodes in half of the patients," says
Bulte, an author on the report, which appears in
the November issue of Nature Biotechnology.
cells used in the current study, so-called dendritic
cells, are the immune system's own "most wanted posters" because
they take up and display foreign proteins that tell
the immune system's fighters what cells to look for
Since the mid-1990s, clinical trials have been testing
dendritic cells to see whether they can stimulate
the immune system to kill cancer cells. In these
trials, dendritic cells from patients are exposed
to proteins from the patients' cancer cells and then
returned to the patients.
some of the clinical trials of such "cancer
vaccines" have been disappointing, with some patients
responding very well but others not at all. A critical
issue behind each patient's success on the treatment,
however, is whether the cells get to the lymph nodes,
where the immune system's fighters are normally "trained" by
dendritic cells. Until now, there's been no accurate
way to know where the cells end up.
It's thought, but not proven, that the best way
to get the cells where they need to be is to inject
them directly into the lymph nodes that drain the
area containing a tumor. Currently, doctors use ultrasound
to guide the needle, and dendritic cells carrying
a radioactive tag are sometimes used to try to double-check
the cells' final resting place.
However, in this study, the Dutch team discovered
that using MRI and iron oxide particles was able
to track the cells' location much more accurately
than the radioactive tracking method and provided
anatomic detail simultaneously -- structural detail
not possible by tracking radioactivity.
"On the MR images, we can see the lymph nodes, and
we can see the magnetically labeled dendritic cells,
and we can tell very clearly whether they are in
the same place," says the study's first author, Jolanda
de Vries, an assistant professor at the Nijmegen
Center for the Molecular Life Sciences (NCMLS) of
the Radboud University Nijmegen Medical Center in
The Netherlands. "The cells can't get from the fat
into the lymph nodes by themselves, so injecting
them properly is very important."
Bulte says he, Dara Kraitchman, Ph.D., D.V.M., and
colleagues at Hopkins are already testing magnetically
labeled stem cells with MRI-compatible injection
systems to allow MRI guidance of injection in large
The current clinical trial builds on Bulte's earlier
work tracking magnetically labeled cells in animals.
Four years ago, he and colleagues reported that stem
cells containing so-called magnetodendrimers could
be followed by MRI.
But to advance to clinical trials, the research
team switched from the experimental magnetic tags
to formulations of iron oxide already approved for
clinical use in Europe (as Endorem) and the United
States (as Feridex). Because immature dendritic cells
naturally take up materials around them, they simply
absorbed, or ingested, the iron oxide particles when
exposed to them in the lab. The magnetically labeled,
cancer-primed cells were then returned to the patients,
all of whom had stage III melanoma.
"Although dendritic cell therapy is used in clinical
trials to treat patients with melanoma, in this study
we wanted to see whether the magnetically labeled
cells could be tracked by MRI, to study their migratory
behavior in more detail," says Carl Figdor, principal
investigator of the study, of the NCMLS. "We were
very pleased that they showed up clearly. With the
anatomic information from the MRI, we could see precisely
where they were -- inside or outside of the lymph
The research was funded by The Dutch Cancer Society,
the Netherlands Organization for Scientific Research,
the Dutch Program for Tissue Engineering, the TIL-foundation
and the NOTK-foundation. Bulte is supported by the
United States National Institute of Neurological
Disorders and Stroke.
Authors on the study are Bulte of Johns Hopkins;
and de Vries, Joost Lesterhuis, Jelle Barentsz, Pauline
Verdijk, Han van Krieken, Otto Boerman, Wim Oyen,
Johannes Bonenkamp, Jan Boezeman, Gosse Adema, Tom
Scheenen, Cornelis Punt, Arend Heerschap and Figdor,
all of the Radboud University Nijmegen Medical Center,
Nijmegen, The Netherlands.
On the Web:
Contact: Joanna Downer
Johns Hopkins Medical Institutions