By Robert Sanders, Public Affairs
Posted October 13, 1999

A promising new cancer therapy developed at Berkeley has caught the eye of cancer researchers, who are readying it for human trials sometime next year.

Unlike other immune therapies that stimulate the body's immune system to attack tumors, this technique releases a natural brake on the immune system to unleash an assault on the cancer.

So far, the therapy has been tried with impressive results in animals with melanoma and prostate cancer. The drug company Medarex Inc., of Annandale, N.J., announced last week that it will make the drug and spearhead human trials to treat these cancers. It signed a sublicensing agreement with Gilead Sciences Inc., of Foster City, which has a license to the patent covering the technology from Berkeley.

"This agreement is an exciting transfer of basic research into the private sector to hopefully lead to the development of drugs useful for the treatment of human disease," said immunologist James Allison, professor of molecular and cell biology and developer of the technology. The drug is an antibody that blocks a receptor called CTLA-4 on T cells, the cancer-killing cells of the immune system.

"We have shown that CTLA-4 blockade can elicit a potent anti-tumor effect in many different mouse tumor models and seems to be generally useful in enhancing immune response," Allison said.

"CTLA-4 blockade could be used therapeutically by itself or in combination with other approaches, such as vaccines."

Medarex has used its patented technique for creating antibodies to make fully human, high-affinity antibodies that inhibit the receptor. The company hopes to test the antibodies not only against cancer, but also against infectious diseases and autoimmune conditions.

"There are a lot of ways to turn on or stimulate the immune system, but this approach focuses on a switch that's not being turned off," said Eric Small, an associate professor of urology at UC San Francisco who plans to conduct preliminary prostate cancer trials. "In terms of immune therapies against cancer, this is the hottest thing going."

Allison thinks that the receptor is important in shutting down the body's autoimmune response -- that is, making sure the body doesn't attack its own tissues. Since cancers arise from a person's own cells, they survive because of the body's reluctance to attack itself.

"The immune system develops tolerance to the body's own tissue through the thymus gland, which takes care of recognizing the molecules that deal with routine chores common to all cells in the body -- nutrient uptake and metabolism, energy production , and cell division -- and preventing an immune attack against them," Allison explained.

"However, the thymus doesn't see much of the peripheral tissue, the more specialized tissues like the skin. We think that the immune system is capable of reacting against these tissues, though normally they are below the immune system's radar. We are bringing them onto the radar screen."

When the receptor is blocked, the T cells of the immune system suddenly begin to chip away at tumors. In 1996, Allison and his team reported in Science that injection of antibodies to CTLA-4 led mice to reject tumors.

"In general, we can't launch an immune response against cancer -- the cancer is ourselves," Small said. "But Allison's work shows that our body does have the capacity to do so, and his therapy makes this more robust."

In the August issue of the Journal of Experimental Medicine, Allison and his colleagues reported that injection of anti-CTLA-4 antibodies together with a tumor cell vaccine genetically engineered to produce a growth factor that stimulates the immune system was effective 80 percent of the time in curing mice with experimentally created melanomas, an often deadly type of skin cancer. A tumor cell vaccine is created by surgically removing tumor cells, inactivating them, and then reinjecting the cells to stimulate rejection of the tumor, much like someone can be vaccinated against chicken pox. The cells also had a gene inserted in them to produce the hormone granulocyte-macrophage colony stimulating factor, which boosts the immune system.

"It seems that T cells are trying to make an effective immune response, but can't," Allison said.

Cancer cells that had migrated to the lung also were taken out by the combination therapy, indicating that the technique may help deal with metastases, that is, cancers that spread from the original site. Interestingly, the mice who survived subsequently were immunized against a second injection of melanoma cells, indicating that the treatment has a protective effect as well.

Similarly, preliminary results suggest that blocking CTLA-4 may be effective in treating prostate tumors in mice.

October 13 - 19, 1999 (Volume 28, Number 10)
Copyright 1999, The Regents of the University of California.
Produced and maintained by the Office of Public Affairs at UC Berkeley.
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