Researchers at the Stanford University School of Medicine in California have devised a way to obtain repeated snapshots of the location and survival of infected or diseased cells in a living human patient months and possibly years later, according to a case study published online Nov. 18 in Nature Clinical Practice Oncology.
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, according to senior author of the research, Sanjiv Gambhir, MD, PhD, director of Stanford's molecular imaging program.
"This has never before been done in a human," said Gambhir. "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 and his colleagues tested the technique in a middle-aged man with an aggressive brain tumor who was enrolled in a clinical trial of cell-based therapy at City of Hope Clinical Research Hospital in Los Angeles.
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 researchers said.
In the current study, Gambhir and colleagues worked to remove cytotoxic T cells, which 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 wrote.
Gambhir and colleagues 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.
PET/CT results showed that the T cells had found the tumor, he said. However, they also migrated through the patient's brain to highlight a second, previously unsuspected tumor site. Although the 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.
Gambhir pointed out that the same technique could be used to follow other immune cells or eventually stem cells throughout the body.
The Doris Duke Charitable Foundation, the National Institutes of Health and the National Cancer Institute funded the research.