Hot new immune therapy from UC Berkeley is being readied for clinical trials against prostate cancer and melanoma

By Robert Sanders, Public Affairs


A promising new cancer therapy developed at the University of California, 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, New Jersey, 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, Calif., which has an exclusive license to the patent covering the technology from UC 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 at UC Berkeley and the 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."

Allison is director of the Cancer Research Laboratory and an investigator in the Howard Hughes Medical Institute at UC Berkeley.

Medarex has used its patented technique for creating antibodies to make fully human, high-affinity antibodies that inhibit the CTLA-4 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 CTLA-4 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 CTLA-4 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 the journal 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."

Recently, 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 GM-CSF (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.

"The combination therapy seems very, very powerful, and I think it has a bright future," Small said. "But we first have to complete Phase I clinical trials to show the safety and effectiveness of CTLA-4 blockade alone in humans."

According to Allison, tumors by themselves don't incite a T-cell attack because T cells respond to the push and pull of two different receptors - what he terms "yin and yang" receptor molecules. One, a receptor called CD28, triggers an attack while the other, CTLA-4, suppresses it. Both are activated by key-like molecules called B7-1 and B7-2 when presented along with a tumor antigen by so-called antigen presenting cells. Antigens are molecules sported by tumor cells that advertise they are abnormal.

Apparently, when both B7-1 and B7-2 are present, the negative effect of CTLA-4 is stronger than the positive effect of CD28, and the T-cells basically ignore tumor cells, allowing them to grow unchallenged.

Blocking the CTLA-4 receptor thus removes the brake on the T cell and allows it to attack the tumor.

Because CTLA-4 blockade apparently unleashes an autoimmune attack against the tumor, the treatment sometimes may cause the immune system to attack normal tissue as well. In the mice they treated for melanoma, for example, Allison and his colleagues observed that the immune system sometimes attacked and eliminated melanin containing skin cells, turning the mice white. This condition, called depigmentation, occurs in many patients treated for melanoma, and correlates with an improvement in the patient's condition.

Because of possible autoimmune reactions, Allison said, the first clinical trials likely will involve treatment of cancers of organs that are not vital: pigmented skin cells, the source of melanomas; the prostate; the breast and ovaries.

"We don't really think this will be a problem, because we only treat mice for a week," Allison said. "That's the beauty of this - we are activating the immune system, basically trying to get T cells to go on the attack for a while and ambush the tumor, and then we let the immune system go back to normal. Hopefully, that will be enough for lasting immunity to the cancer."

Medarex, a biopharmaceutical company developing monoclonal antibody-based therapeutics, is enthusiastic about the therapy.

"Dr. Allison's groundbreaking work in immunology has laid the foundation for a new approach to cancer immunotherapy," said Donald L. Drakeman, president and CEO of Medarex, in a statement issued Aug. 31.

"We are excited about the potential application of this technology to many disease states including cancer, infectious diseases and autoimmune conditions," he said.

Clinicians like Small are equally excited.

"Generally, immune therapies for prostate cancer have been underexplored," Small said. "Our work suggests that immune modulation is an important means of attacking prostate cancer, and this antibody may prove to be the most significant addition to our armamentarium."

The work of Allison and his colleagues has been supported by the National Cancer Institute of the National Institutes of Health, the Howard Hughes Medical Institute and by CaP CURE, The Association for the Cure of Cancer of the Prostate.


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