American Neurological Association (ANA) 30-Dec-99
Keywords: CANCER BREAST OVARIAN PARANEOPLASTIC NEUROLOGICAL DISEASE TACROLIMUS NY
Description: "Killer" cells called into action by the immune system to fight breast and ovarian cancer can find their way into the nervous system and attack the body's own brain cells, a finding that suggests new ways to fight cancer and even MS.
EMBARGOED UNTIL DECEMBER 29
For more information, contact: Beckie Smith
American Neurological Association
CANCER COMPLICATIONS HINT AT TREATMENTS
"Killer" cells called into action by the immune system to fight breast and ovarian cancer can find their way into the nervous system and attack the body's own brain cells, according to a report in this month's Annals of Neurology, the scientific journal of the American Neurological Association. This finding points the way to a treatment for these relatively rare neurological symptoms, say the authors, but it may also provide a way to tweak the immune system to help fight other cancers, and it may even open new avenues of research into neurological diseases such multiple sclerosis.
The immediate consequences of the study concern treatment for a condition called paraneoplastic cerebellar degeneration (PCD), which can accompany breast, ovarian, lung, and several other types of cancer. PCD patients experience balance, speech, and movement problems as cells in a part of the brain called the cerebellum are destroyed.
"The syndrome . . . is a devastating one, producing a cerebellar deficit whose severity is seen in few other conditions," writes John Greenlee, MD, a neurologist at the University of Utah, in an editorial in the same issue of the journal. There is no treatment that can reverse or slow the progression of the disorder.
The present study was inspired by evidence that the body has unexpected ways of fighting tumors. That such "tumor immunity" exists has, by its very nature, been difficult to prove.
"Tumor immunity is inherently difficult to detect and study, because people in whom it is working efficiently would be healthy and would not go to see their doctors. Such an immune response could be rare, or it could occur in nearly all people all of the time," said Robert B. Darnell, MD, PhD, a neurologist at Rockefeller University in New York, and senior author of the report.
One of the rare occasions when physicians can spot an immune response to tumors appears to be when it has disastrous consequences for the brain. Researchers have found that certain tumor cells produce proteins that are normally only found in cells in the nervous system. The immune system, which is designed to identify and destroy unwanted objects, views these proteins as tags indicating that the tumor cells should be destroyed.
Normally, this would have no effect on the nervous system, because the nervous system is essentially off limits to white blood cells such as the aptly named "killer T cells" that are among the foot soldiers of the immune system. The problem in PCD, as Darnell and his colleagues show in their study of three patients (one woman with breast cancer and two with ovarian cancer), is that some killer T cells find their way past the elaborate barrier that insulates the nervous system from the rest of the body.
All of the women in the study suffered from PCD, and spinal taps revealed killer T cells in their cerebrospinal fluid. These immune cells were the type that react to the brain proteins found both on tumor cells and cells in the cerebellum. The presumption is that once these efficient, but not very discerning, killer cells find themselves in the unfamiliar environment of the nervous system, they cause PCD by finding cerebellar cells tagged with the appropriate protein markers and destroying them.
In the second part of their study, the researchers tried to treat the neurological symptoms with tacrolimus, a drug that selectively kills the type of killer T cells they had found in the women's cerebrospinal fluid. The danger, though, was that by incapacitating the killer T cells in the nervous system they would also interfere with the desirable immune response against tumor cells, allowing the tumors to recur.
The short courses of tacrolimus did indeed eradicate the immune cells from the cerebrospinal fluid and, fortunately, the treatment did not lead to recurrences of cancer. On the other hand, the drug did not significantly improve the women's neurological conditions, though this may be because the damage to the nervous system was already done in these cases.
With evidence in hand that the approach is at least safe, Darnell and his colleagues hope that they can assemble a sufficiently large group of patients to allow them to determine whether tacrolimus can be effective earlier in the disease.
Understanding how immune cells can reach the brain to cause disease, and possessing tacrolimus or similar drugs to eliminate them if they do, opens an additional line of research. Ultimately, Darnell said, researchers would like to be able to intentionally trigger immune responses, while keeping immune cells out of the brain.
Finally, there is a hope that these results will offer ideas to scientists who have been searching, without much luck, for a way to treat multiple sclerosis (MS). Many scientists think MS occurs in a similar way--the immune system is triggered to call out its defenses (against cancer cells in PCD, against a virus or bacterium in MS), and those immune system defenders also find their way into the nervous system, where they attack a substance called myelin that coats nerve fibers.
"Our findings suggest tools to study this phenomenon, and a potential treatment to suppress such errant immune cells in the brain," said Darnell.
Other authors of the report were Matthew L. Albert, PhD, and Lisa M. Austin, PhD, also of Rockefeller University.
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