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Photo of Craig Jordan and John YannelliCreating Cancer Killers

by Debbie Gibson

Knowing the enemy's location is critical to winning any war. In the war against cancer, the enemy—cancer cells—have a distinct advantage. These errant cells are able to exact serious damage because they frequently go undetected and, therefore, do not trigger an alarm to activate the body's immune system.

Two scientists at the UK College of Medicine, however, may have found a way to help the immune system detect these destructive cells so the body's natural defense system can marshal its forces and destroy the cells. Craig Jordan, an assistant professor of medicine in the UK College of Medicine, and John Yannelli, an associate professor of internal medicine, are putting the finishing touches on a new gene therapy that holds promise for cancer patients, particularly those with acute myeloid leukemia, a form of cancer which has been particularly difficult to treat with traditional therapies.

An update from the front lines
"People once thought that cancer occurred because of a weakness in the body's immune system," says Yannelli, "but we have known for years that overall that is not the case. The immune system in cancer patients actually works quite well. Otherwise, they could not survive the disease for long periods of time nor could they fight off other viruses, which they routinely do. The problem is not that the immune system doesn't work; it is that the immune system doesn't recognize the tumor."

According to Yannelli, for the body's defense system to work properly, key antigens must be presented in a specific way to lymphocytes, the cellular mediators of the immune system, which then kill the cancerous cells. Normally, antigens are tipped off by co-stimulating molecules. When the co-stimulating molecules are not present, the immune system does not "see" the cancer cell, and therefore does not act to destroy it.

Scientists have discovered that lymphocytes have very narrow job descriptions, each one designed to attack only a specific molecule. The researchers have also discovered a wide range of co-stimulating molecules. A critical co-simulating molecule is CD80. Because cancer cells do not express CD80, they are invisible to the lymphocytes responsible for destroying them.

Enter Jordan, a molecular biologist educated at Princeton University and the University of California, and Yannelli, an immunologist educated at the Medical College of Virginia.

In 1998, the two scientists received a $321,459 grant from the Leukemia Society of America. Their major goal is to develop genetically modified tumor vaccines for treatment of acute myeloid leukemia (AML). They believe this gene-therapy-based treatment will help leukemia patients avoid recurrence of the disease, which today is a common and frequently fatal problem.

"In essence, we are putting a billboard on the tumor cells which says, 'Here I Am.'" —John Yanelli

Currently, oncologists treat leukemia by attacking the tumor with chemotherapy. Three-quarters of all patients can be successfully brought into remission (an absence of cancer cells in the body) with chemotherapy. However, three-quarters of those relapse later, meaning tumor cells make a comeback. This can happen because cancer cells often travel throughout the body, and some malignant cells may escape chemical or surgical removal. When cancer recurs, chemotherapy is used again, but with each relapse the patient's long-term prognosis worsens.

The gene therapy developed by Jordan and Yannelli will work in concert with chemotherapy, giving oncologists a new strategy to beat this deadly disease.

"It is important to note that we are not replacing traditional chemotherapy," Jordan says. "We are trying to augment it. At first, we hope to help patients stay in remission longer and have a better quality of life. In the long-term, we hope that this therapy is so effective that the tumor never comes back."

Invisible no more
The key to this new approach is making the cancer cells visible.

"We are making tumor cells more recognizable," says Yannelli, who conducted similar work as head of the Cellular Immunotherapy Laboratory for the National Cancer Institute before he joined UK in 1996. "In essence, we are putting a billboard on the cells which says, 'Here I Am.'"

Erecting this billboard begins when the patient enters the hospital for treatment. As always, the patient will undergo a standard course of chemotherapy, designed to eliminate, or at least minimize, the number of cancer cells. Prior to administering the drugs, physicians will draw 250 milliliters of blood from the patient, a sample which is typically loaded with tumor cells.Cells from this blood sample are then subjected to a procedure that isolates the cancer cells. Once isolated, the cells are genetically engineered so that they express the co-stimulating antigen and can be recognized by the body's immune system. To perform this gene transfer, a common virus—an adenovirus which has been disabled so it will cause no harm—is used as the vehicle for the transfer process. This process takes from 12 to 24 hours.

The re-engineered cells are then crippled by radiation. They will not die but will lose the ability to reproduce. Once chemotherapy is complete, the patient receives a vaccine containing the cells—his or her own cells—which have been re-engineered. The scientists hope that the genetically engineered cells will "rev up" the patient's immune system so that it seeks and destroys any remaining cancer cells, thus preventing a relapse of the cancer.

Another benefit of the approach is that the treatment is almost completely non-toxic.

"Ever since doctors began treating cancer, there has been a basic strategy—give people a very toxic drug that's more toxic to cancer cells than normal cells," Jordan says. "The unfortunate drawback is that the normal cells are affected, and this causes people to be sick."

The gene-transfer process has no such effect, which is no doubt one reason it is so appealing. Gene transfer gained national attention when physicians used the technique to treat the "bubble boy," a child who had to live in an enclosed area because he had no immune system. Since then, it has become one of the hottest subjects in science, and research is being done across the country using this process. However, the gene therapies developed to date have not been effective on AML cells.

"A large technical problem arises from AML cells," says Jordan. "They tend to be different, and traditional gene transfer does not work with them."

Jordan and Yannelli's technique for performing the gene transfer does appear to be effective with AML. Furthermore, the researchers believe that the technique may be useful with other forms of cancer. Yannelli is planning to use the same technique in his current research on lung cancer, for example.

Photo of Dianna HowardDianna Howard believes that clinical trials involving this new gene-transfer process will begin within a year.

The two scientists hope to begin Phase I clinical trials of the process soon and will be working closely with Dianna Howard in this endeavor. Howard, a clinical faculty member in UK's Blood and Marrow Transplant Program, has focused her work for the past 18 months on the care of leukemia and bone-marrow transplant patients. Under Jordan's guidance, she has also participated in the laboratory research, infecting primary human leukemia cells with viruses to encode gene expression.

"We would like to think our work may be ready for a Phase I trial within six months to a year," says Howard, who is board certified in pediatrics and internal medicine. "Typically, this type of trial would be limited to the University of Kentucky and perhaps a few collaborating institutions."

Meanwhile, their technique will go through the approval process at the Food and Drug Administration (FDA). "One of our first hurdles is obtaining FDA permission for use of an investigational new drug," Howard says. "Patient participation is also a challenge—letting patients know about the new therapies that are available and educating them to the value of clinical trials."

After the initial tests are complete, Jordan and Yannelli hope to get a second grant to do the next phase of trials, which will run from four to five years. These trials would determine the effectiveness of the vaccine as well as such variables as the proper dosage.

For now, the scientists have filed a patent on their technique and have caught the attention of the scientific community with an article about their research that appeared in the October 1998 issue of the journal Leukemia.