por Lynn Shapiro
, Writer | November 19, 2008
"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.
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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.