With technical improvements over the last several years, molecular imaging--positron emission tomography (PET) in particular--now has the capacity to begin to answer important unknowns in gene therapy trials, such as whether the transgene gets to the tumor site and whether it expresses and for how long it expresses.1 By its very nature, PET has the capacity to move seamlessly into clinical use. "One of the nice things about PET is that the probes are used in near-'mass-less' quantities--meaning they don't alter the system at all --so we can and do the same types of studies in patients as in mice, and it's very easy to move back and forth between them," explains Michael E. Phelps, co-developer of PET, and a principal investigator at the ICMIC at the University of California, Los Angeles.
Imaging gene therapy in ongoing cancer trials is exactly what investigators at UCLA and Memorial Sloan-Kettering Cancer Center in New York are setting out to do, hot on the heels of researchers at the University of Cologne in Germany who have already demonstrated retroviral transduction using a radiolabeled probe--124I-FIAU--developed at Sloan-Kettering for PET imaging of HSV1-tk expression. In fact, Sloan-Kettering and UCLA appear to be in something of a race to be the first to image adenoviral transduction in cancer patients. "Nobody is saying very much," says Ronald G. Blasberg, head of the NeuroOncology PET program at Sloan-Kettering. But, says Sanjiv S. (Sam) Gambhir, director of the Crump Institute for Molecular Imaging at UCLA, stating the obvious: "None of us are working toward curing disease in mice."
|Courtesy of University of California, Los Angeles|
At Sloan-Kettering, in addition to its translational study of imaging the expression of the androgen receptor gene in prostate cancer (one of its primary ICMIC projects), investigators are collaborating with Savio Woo and Max Sung and colleagues at Mt. Sinai Hospital in New York to determine efficacy of gene therapy in the treatment of hepatic metastasis in colorectal cancer. "We're going to be supplying the radiopharamceutical--the new probe we developed, 124I-FIAU," says Blasberg. Although getting Food and Drug Administration approval for a new radiopharamceutical to put into patients has not been the easiest task, "especially for one with an unconventional isotope such as 124I," Blasberg adds, "hopefully, we'll be able to finally do this trial this summer."
Meanwhile, at UCLA, Gambhir recently completed studies on normal human volunteers at UCLA Medical Center and is now coordinating its efforts with a number of ongoing gene therapy trials.2 "We've shown that the probes behave properly in humans, that the probes don't find anything because the [transferred or therapeutic] genes don't exist there, and now that we have that information, we're working with several groups to image genes being delivered in human patients," Gambhir says.
One project, Gambhir adds, will be a collaboration with Steven Albelda and Abass Alavi at the University of Pennsylvania in a gene therapy trial treating mesothelioma, a form of lung cancer. Despite the "heavier bureaucracy" involved, the UCLA team is also in negotiations with U.S. Oncology and other companies that conduct a variety of different gene therapy trials.
While PET is directly applicable to humans and the crossover from animal--MicroPET studies--to human is relatively simple, the technology remains expensive. Optical probes, on the other hand, are less expensive and getting better all the time. At Massachusetts General, Ralph Weissleder and colleagues are preparing to use the optical near infrared tomography they developed to image endogenous gene products--specifically proteases (e.g. cathepsins)--in a Phase 1 clinical trial with a cohort of about 20 patients.
As the results of these translational studies come in, these researchers will, no doubt, write a new chapter in cancer research.
1. M.E. Phelps, "Positron emission tomography provides molecular imaging of biological process," Proceedings of the National Academy of Sciences, 16:9226-33, Aug. 1, 2000.
2. S. Yaghoubi et al., "A reporter probe for imaging herpes simplex virus type 1 Thymidine Kinase (HSV1-tk) Reporter Gene Expression," Journal of Nuclear Medicine, in press.