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
purposes.
"In four of the eight patients, MRI revealed that the
implanted cells weren't where they needed to be to be
effective for treatment," said Jeff Bulte, an associate
professor of
radiology at Johns
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, the
researchers said.
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," said
Bulte, an author on the report, which appears in the
November issue of Nature Biotechnology.
The 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 and destroy.
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.
However, 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
the technique using MRI and iron oxide particles was able
to track the cells' location much more accurately than the
radioactive tracking method and also 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,"
said the study's first author, Jolanda de Vries, an
assistant professor at the Nijmegen Center for the
Molecular Life Sciences 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 said that he, Dara Kraitchman and colleagues at
Johns Hopkins are already testing magnetically labeled stem
cells with MRI-compatible injection systems to allow MRI
guidance of injection in large animals.
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," said principal investigator Carl Figdor, of
the Nijmegen Center for the Molecular Life Sciences. "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
nodes."
The research was funded by the Dutch Cancer Society,
Netherlands Organization for Scientific Research, Dutch
Program for Tissue Engineering, TIL-foundation and
NOTK-foundation. Bulte is supported by the U.S. National
Institute of Neurological Disorders and Stroke.