Thalidomide’s promise provides a double bonus
May decrease symptoms as it speeds cure
In a research lab at Rockefeller University in New York City, an old villain is making a comeback — but with its reputation newly burnished.
Banned from pharmacy shelves worldwide in the 1960s because it was causing birth defects, thalidomide seems to hold exciting new promise as a weapon against TB, says Gilla Kaplan, PhD, associate professor at the laboratory of cellular physiology and immunology at the university.
Thalidomide, used as a sedative decades ago, is now being studied for potential beneficial effects on diseases as diverse as AIDS, breast cancer, and multiple myeloma. In the field of TB research, work on immune system modulation is among the most exciting. Within that sphere, Kaplan’s work has been pegged as edge-of-the-seat stuff. "She’s definitely the one to watch," says Clifton Barry III, chief of the mycobacterial research unit at the National Institute for Allergy and Infectious Diseases in Bethesda, MD.
Drug could boost immunity against TB
One of thalidomide’s many puzzles is its ability to hide one effect inside another, like nested boxes. To begin with, the drug exerts certain effects on the cytokine known as tumor necrosis factor alpha, or TNF-A. That cytokine is thought to be responsible for most of the pathology associated with TB: the wasting, tissue damage, night sweats, fevers, and weakness. Thalidomide appears to reduce the soluble molecules associated with those symptoms, Kaplan says.
Thalidomide doesn’t reduce cytokine too much, which is a good thing Kaplan adds. "Without TNF-A, we don’t get the recruitment of white blood cells to the site of infection, or the walling off the infection. With insufficient TNF-A, we’d get disseminated, or miliary, TB. So it’s a fine balance."
Thalidomide also appears to boost the immune system by acting as a co-stimulatory molecule to increase the level of activation of T-cells, which play an important role in immunity against TB, says Kaplan. That may be the reason TB infection never becomes active in some people.
It’s too soon to tell for sure, but thalidomide may have two important roles in the fight against TB. "First, it may help protect the body against infection," she says. "Second, it may attenuate the immune response that drives the pathology."
Kaplan’s work could provide a much-needed key to unlock the intricacies of how TNF-A works in humans. In animal models, its role is fairly well-understood, she explains, but in people, that relationship needs further elucidation. "So part of what we’re doing is seeking proof of concept as a way to understand and analyze the pathology of TB. And another part is to see if we can intervene in a way to improve outcome."
Her work in small trials involving humans already has begun to show that using thalidomide to improve therapy’s outcome may indeed be possible. In pilot studies with patients co-infected with HIV and TB, Kaplan has shown that thalidomide stimulates T-cells. The next challenge is to prove that a beneficial effect is likewise produced in patients contending only with TB.
The relationship between the drug’s ability to cause birth defects and its promise as an ally in the fight against TB is another puzzle, Kaplan adds. "We don’t know how thalidomide causes birth defects — whether it has to do with the same properties that impact the immune system or with different ones, and whether its ability to cross the placenta is key to the damage it does or not."
With researchers striving to find analogs of thalidomide that don’t cause birth defects, some of those questions soon may be answered as well.