Biotech Values

[DewDiligence]

Immune System Might Be Revived to Fight AIDS, Cancer, HCV

[This research is relevant to a wide array of biotech companies, in particular MEDX.]

http://online.wsj.com/article/SB115611916112240632.html

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By MARK SCHOOFS
August 21, 2006

A spirited race between top immunology teams is set to culminate today with the publication of two scientific papers reaching broadly similar conclusions about the AIDS virus: It exploits the human body's natural mechanism for shutting down the immune system, and the process can be reversed.

The findings raise the tantalizing possibility that doctors one day could switch a patient's immune system back on, so that it could resume its fight against HIV, or even cancer cells, certain parasites or the virus that causes hepatitis C. Those very different diseases "have one common denominator," says Anthony Fauci, director of the National Institute for Allergy and Infectious Diseases. "They persist. They're chronic."

The studies, published in the journal Nature and its sister journal, Nature Medicine, build on almost 15 years of work by other researchers, including Kyoto University Prof. Tasuku Honjo, who in the early 1990s discovered a molecule, which he named PD-1, on the surface of disease-fighting T-cells. Subsequent research revealed that PD-1 is a natural regulator of the human immune system, acting like a brake on rampaging T-cells and potentially preventing them from attacking the body itself.

The latest findings are preliminary, and there isn't any way to predict whether this avenue of research will ever yield new treatments. And there's one more blazing caveat: Switching the immune system back on -- the most obvious treatment strategy -- might trigger autoimmune disease. Scientists currently studying PD-1 are sobered by the shocking experience of a German drug company's clinical trial conducted in London in March, in which six healthy volunteer patients received an experimental drug to stimulate the immune system and landed in intensive care, their lives in the balance, because the drug sent their immune systems into massive overdrive.

Nevertheless, research in this area is exploding. The Bill and Melinda Gates Foundation is funding a team researching how to turn the immune system back on in hepatitis C patients. Researchers at the National Institutes of Health are studying PD-1 in tuberculosis, one of the world's leading killers.

"This isn't just HIV," says Harvard University immunologist Bruce Walker, the lead researcher on the study published in Nature. "This is much broader."

Research has progressed furthest in cancer, where scientists have shown that PD-1 can shut down immune responses when it is activated by certain types of tumor cells. Last month, the U.S. Food and Drug Administration approved human testing of an experimental antibody designed to reverse the shutdown and permit the immune system to resume fighting cancer cells. The experimental drug is being developed by Medarex Inc., of Princeton, N.J., and Ono Pharmaceutical Co., of Japan.

When a virus or other pathogen enters the body, immune-system cells multiply furiously and send out potent chemicals, called cytokines, which cause inflammation. "When you get the flu, for example, you feel sick not so much because of the virus, but because of the immune system -- that's what gives you the aches and fevers," explains Drew Pardoll, an immunologist at Johns Hopkins University who has studied PD-1. Left unchecked, the raging immune response, including an excess of cytokines, could damage the body.

In a simple infection, such as the flu, the immune system apparently does its job and subsides. But if a pathogen isn't quickly cleared out, as in the case of chronic disease, then PD-1 goes to work and shuts down production of key types of immune-system cells. Much of this basic understanding was achieved only late last year in a study published in Nature and led by Emory University Prof. Rafi Ahmed and a student of his at the time, Daniel Barber.

The research being published today goes further to address one of the most vexing mysteries in the biology of AIDS. Key immune-system cells known as HIV-specific CD8 killer T-cells exist in high numbers in many HIV-infected patients. Early in the course of the infection, these cells kill other cells carrying the virus. But in long-term patients, these cells barely fight the virus at all. The reigning theory was that HIV somehow disabled them. That may still be true in part, but today's studies reveal that HIV actually exploits the body's own mechanism for shutting the cells down.

The PD-1 molecule buds on the surface of the killer T-cells that target HIV. By itself, PD-1 is inert and does nothing. But when PD-1 encounters a partner molecule, or ligand, the interaction sets off a chain reaction inside the killer T-cells. The T-cells multiply much more slowly or not at all, and overall they secrete far less of their powerful cytokines, the researchers found. Essentially, they abandon the fight.

The most dramatic finding is that the process can be reversed, at least in a test tube. When researchers added an antibody that blocked the interaction between PD-1 and its ligand, then the killer T-cells revived. They started multiplying again, and cytokine production increased. "I've never seen something as black and white," said Rafick Sékaly, a professor at Canada's Université de Montréal and a leader of the team whose study was published today in Nature Medicine.

The team, led by Harvard's Dr. Walker and researchers Cheryl Day and Daniel Kaufmann, made a further finding: Not only can PD-1 shut down the killer CD8 T-cells, but it also can affect command-and-control cells, known as CD4 cells. In other words, PD-1 acts on both the infantry and the generals. In one particularly striking bit of research, Dr. Kaufmann revived CD4 cells in five of six AIDS patients whose CD4 cells had shown zero activity against HIV.

Taken together, today's studies suggest that two critical types of immune system cells -- CD8 and CD4 -- can in most patients be rescued and remobilized to fight HIV.

The Walker and Sékaly research teams both are keen to test the hypothesis by giving patients an antibody that blocks the interaction between PD-1 and its ligand. The two researchers have initiated discussions with Medarex, developer of the experimental antibody about to be tested in cancer patients. Dr. Sékaly has even sent blood samples to Medarex so that it can run laboratory experiments on them.

In addition, Harvard University researcher Gordon Freeman has made his own antibodies to PD-1 and its ligands. He is busy planning tests of them in monkeys, with an eye to testing them in humans infected with HIV and hepatitis C.

Recently, Dr. Walker launched a new study of what he terms "elite controllers," the 0.33% of HIV patients who keep the virus in check for many years without drugs [#msg-12722870]. Dr. Walker believes that one reason these rare patients stay healthy may be that their immune cells lack PD-1, or that the interaction between PD-1 and its ligand might somehow be short-circuited. He has already begun to test these theories but doesn't yet have results.

A third scientific team, led by Richard Koup, chief of the immunology laboratory at the National Institutes of Health's Vaccine Research Center, also has been researching PD-1 in HIV. That study is scheduled to be published Sept. 5 in the online edition of the Journal of Experimental Medicine. Dr. Koup's team found that the interaction between PD-1 and its ligand appears to cause CD8 cells to die, not merely to stop functioning.
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