"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.
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 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 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," 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 nodes."
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.