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CANCER RESEARCH Endostatin Beads Pack Therapeutic PunchIn early clinical trials, the first question is always safety, and the second efficacy. Yet there is already a third question for endostatin, the first of a radically new kind of anticancer agent that interferes with tumor blood supply—that is, how do you deliver this potential therapy effectively? Even as closely watched Phase I human trials continue for endostatin, a team of HMS researchers headed by Peter Black, the Ingraham professor of neurosurgery at Children's Hospital, is tackling the delivery question in a novel way.
Rona Carroll, Nicholas Seyfried, and Peter Black (l to r) and their colleagues have devised and tested in mice implantable capsules that contain endostatin-producing cells whose product cuts off the blood supply of tumors. Photo by Steve Gilbert In the January Nature Biotechnology, Black and colleagues say they successfully microencapsulated producer cells genetically engineered to secrete biologically active endostatin and implanted them around a human-derived tumor grown on a mouse. For 21 days, these tiny "bioreactors" lived inside the mouse, cranking out endostatin and severely inhibiting the tumor's growth without provoking an immune response. The work was done by Marcelle Machluf, HMS research fellow in surgery at Children's; Tatsuhiro Joki, a visiting neurosurgical research fellow from the Jikei University School of Medicine in Tokyo; Rona Carroll, HMS instructor in surgery at Children's; Jianhong Zhu, a postdoctoral fellow; Nicholas Seyfried, a research associate; and Ian Dunn, an HMS student in Peter Black's lab. Anthony Atala, an HMS associate professor of surgery at Children's, was also a co-author on the paper. The plasmid containing an expression cassette for human endostatin was from the lab of Judah Folkman, the Andrus professor of pediatric surgery at Children's and the scientist most closely associated with anti-angiogenic cancer therapy. The capsules are made of an algae-derived natural polymer that shields the endostatin-secreting cells behind a fine molecular mesh. This allows nutrients in and endostatin out but bars the large antigen-seeking cells of the host's immune system. So the polymeric barrier enables the use of non-autologous cells in the patient. The microcapsules have an average diameter of 0.7 mm. As such, they cannot be filled but, instead, they form around the producer cells, which are derived from a baby hamster kidney cell line. The procedure takes place in aqueous solutions that use mild salts to avoid damage to the cells and the endostatin they secrete. The resulting capsules are finer than the finest grain of sand, according to Black. "They just look like a white emulsion and then you look at them with a microscope and can see that they have a complex structure." In HarnessThe encapsulated cells were injected near subcutaneous human glioma tumors. "For 21 days, these tiny bioreactors lived inside the mouse, secreting biologically active endostatin and inhibiting the tumors' growth by 72 percent compared to controls," Machluf explained. The microencapsulated cells were still thriving when they were removed for the final assay. The results match the findings from Folkman's group that endostatin is cytostatic.Microencapsulated bioreactors could address this and other unresolved practical problems facing all angiogenic inhibitors. "Theoretically, these bioreactors could be implanted near tumor sites and produce for months biologically active endostatin while the host provides nourishment to the cells," Black said. "This is a novel delivery method with some significant advantages. One is that you don't have to administer as much protein as needed when delivered intravenously because it won't get filtered out by the kidney or the liver." Tumor TargetThe advantages of this system particularly appeal to the Black lab, which focuses on brain tumors. "Malignant gliomas are important and often underappreciated brain tumors in adults," said Black. "They are so-called primary tumors of the brain, which don't come from anywhere else. They don't usually metastasize out of the nervous system, but they are very aggressive and have a median survival of maybe a year or 15 months with very aggressive therapy."One of the clinical characteristics of these tumors is that they are highly vascularized, making them excellent targets for angiogenesis inhibitors. "By putting delivery systems in the brain you can actually use the blood–brain barrier to your advantage because you can keep things in the brain that might otherwise induce toxicity in the rest of the body," Rona Carroll said. The lab's next experimental step is trying to implant endostatin bioreactors at the site of an intracranial tumor. Black's work with microencapsulated endostatin inside mice is, of course, a long way from Folkman's clinical trials using exogenous endostatin in humans. Those trials are proceeding in Boston, Houston, and Madison, Wis. Black points out that patients with malignant glioma of the brain were specifically excluded from the first human trials so endostatin's effect on them is still to be explored. Yet Black is cautiously hopeful. "I think this is the future—natural biological therapies for these tumors. Chemotherapy has not proved to be very efficacious. In biological therapies, you can use the body's own molecules and get cells to produce them." —John Fleischman |
