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Natural killers. Immune system's own cells may be best hope against some cancers. By Sally Bell

Imagine a future just a decade or so hence when a man hears the devastating diagnosis that he has leukemia.

But instead of being told he faces long months of debilitating chemotherapy and possible death, his doctor says, "Don't worry. We can cure you in a few days."

Porunelloor Mathew views cancer cells on a lightbox  
Porunelloor Mathew, associate director for basic research at the UNT Health Science Center's Institute for Cancer Research, views cancer cell data on a light box.    

That's what Porunelloor Mathew, Ph.D., is working toward. An associate professor in the Department of Molecular Biology and Immunology at the University of North Texas Health Science Center at Fort Worth, Mathew believes his work activating the immune system's "natural killer" cells could someday lead to treatments that quickly hunt down and assassinate several kinds of cancers.

"All our work so far points to using one's own immune system to kill cancer cells relatively safely and without side effects," he says.

Mathew is associate director for basic research with the Health Science Center's Institute for Cancer Research. His work has been supported since 1992 by grants from the National Cancer Institute.

He also was named the Health Science Center's Outstanding Graduate Faculty member for 2000 by the Graduate School of Biomedical Sciences and the Graduate Student Association. It's the honor of which he's most proud.

"By inspiring students to do cancer research, they'll do much more than we can today," he says.

A new cancer weapon

Mathew focuses on the 2B4 molecule, a receptor located on the surface of the natural killer, or NK, cells. NK cells are one of the three kinds of lymphocytes, the white blood cells that are a major component of the body's immune system. (The other two are T cells, which also kill virus-infected and tumor cells, and B cells, which produce antibodies.)

He learned that when the antibody to the 2B4 molecule activates the NK cell, the pumped-up killer cell suddenly can attack leukemia, lymphoma and melanoma — in mice and in human tissue cultures, anyway.

He expects to get patent approval for the single B cell antibody in early 2003 and then begin working with pharmaceutical companies on the three to five years of large-scale clinical trials that he hopes will result in NK cell mediated therapy to kill the three forms of cancers.

While emphasizing that nothing is certain until after clinical trials, John Ortaldo, Ph.D., chief of the experimental immunology laboratory at the National Cancer Institute, calls Mathew's work "an interesting approach."

"If it works, it would be a very significant advance in leukemia and lymphoma treatment," Ortaldo says.

Knocking out ‘bad guys'

The immune system normally operates quickly and efficiently. NK cells constantly cruise the body, seeking out and destroying viruses, bacteria and parasites. When that isn't enough, backup T cells soon adapt to finish the job.

Swapnil Vaidya examines a	cancerous tumor
Graduate student Swapnil Vaidya examines a cancerous tumor.  

But cancer grows and spreads because the rogue cells are the body's own cells gone awry — native-born terrorists able to establish beachheads without suspicion, if you will — so the immune system doesn't always recognize them as it does outside invaders. By the time symptoms appear, cells often have spread, or metastasized, to distant parts of the body where they beget new cancers.

"Metastasis is the big problem in cancer," points out Kenneth Brunson, Ph.D., ICR director and research professor in the Health Science Center's Department of Molecular Biology and Immunology. "Very often, the patient already has undetectable spread of the cancer at diagnosis. More cancer patients die of the metastasis than the initial tumor."

Doctors strike back with the blunt weapon of chemotherapy, slaughtering healthy cells along with cancerous; surgery to excise the tumor, hoping cells don't escape; or relatively new anti-angiogenic drugs, which slow the growth of new blood vessels that the cancer needs to nourish itself.

And that's fine, for a while. The patient often goes into remission, but the few remaining cancer cells — those resistant to chemotherapy or those surgery didn't get — may grow to attack again in a few months or years. As Mathew explains, "Surgery or chemotherapy is rarely complete. About 70 percent of the time, you'll get the cancer again."

In fact, some 70 percent (about 21,700 people) of the approximately 30,800 Americans diagnosed with all forms of leukemia each year eventually succumb to the disease, according to American Cancer Society figures. In lymphoma, about 42 percent eventually die, or 25,800 of the 60,900 people diagnosed with new cases each year. Perhaps because it's more easily seen and removed promptly, only about 7,400 people die of melanoma yearly, or approximately 14 percent of roughly 53,600 new cases.

If Mathew's work holds up in clinical trials, his activated natural killer cells "have the potential to help us use the immune system to knock out not only the primary cancer, but also the metastatic cancers, which are the really bad guys of tumors," notes Brunson. The need for chemotherapy and radiation would be greatly reduced.

Of course, that potential is years away. Mathew to date has identified the critical 2B4 molecule, cloned human 2B4, generated an antibody to it and located the receptor molecule, or ligand, on the cancer cell, with which the antibody interacts like a key turning in a lock.

Once 2B4 and its antibody bind, "the NK cell becomes activated and kills cancer cells it normally cannot kill," Mathew says. "It kills quickly, wherever the cancer has spread."

Killing within hours

By "quickly" he means literally a few hours.

Porunelloor Mathew and graduate student Jae-Kyung Lee  
Mathew and graduate student Jae-Kyung Lee examine cancer cells at the institute.    

"In tissue cultures, the cells are killed in four hours, but the body is much more complex, so it would take longer. It could kill most of the cancer cells in two to three days in a person. This is realistic for some — but not all — cancers."

In practice, he envisions, doctors would draw blood to isolate the patient's own natural killer cells. The 2B4 antibody would be added to the NK cells and the two would be allowed to incubate for several hours so they would bind. The newly activated killer cells then would be injected into the patient on their seek-and-destroy mission.

"The beauty of our method is that it kills hidden cancer cells, and there are no side effects because you use the patient's own cells," Mathew says.

He works with leukemia, lymphoma and melanoma because they have the ligand to which 2B4 binds.

"If the cancer doesn't normally express the ligand for 2B4, this treatment doesn't work," he stresses.

Leukemia and lymphoma are also blood system cancers. Ortaldo says previous clinical studies showed activated killer cells have "minimal effect" on solid tumors, but "very possibly" the effect might be different in the blood system.

Mathew has also cloned two additional NK receptors, dubbed CS1 and LLT1, but hasn't yet identified their ligands and the activation mechanism. The goal is a treatment that targets every necessary cancer receptor.

He's confident his techniques will produce some cures before the decade is out because activated NK cells from healthy people wipe out cancers in human tissue culture.

Brunson adds, "Mathew has identified receptors that may be very effective in turning NK cells on. If you turn on the appropriate receptors, you can make the NK cells much better killers. It's fair to say that his lab is on the cutting edge of research today."































































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