NEWS RELEASE, 3/19/96
Antibodies stimulate tumor rejection and confer subsequent immunity, UC Berkeley scientists report
Berkeley -- University of California at Berkeley scientists have found a way to overcome the body's general reluctance to attack cancer cells, in essence freeing the immune system to launch a coordinated attack against a tumor and destroy it.
The UC Berkeley immunologists injected mice with antibodies that block the immune system's own suppressors, and in nearly every case the mice fought off and rejected their tumors. The treatment also immunized them against tumors injected later.
"We are enhancing the activity of T-cells to go after tumors," says James P. Allison, professor of immunology at UC Berkeley. T-cells are the white blood cells of the immune system that specialize in attacking and killing invading viruses and cancer cells.
"Because the technique involves blocking negative aspects of the immune pathway, this technique could work against all types of tumors," Allison adds. "The most important application may be to clean up metastases, to get that last tumor cell out there."
The technique also could be used in combination with current therapies that attempt to boost the immune system.
Allison and his UC Berkeley colleagues report their findings in this week's issue of Science.
Of the mice injected with antibodies, nearly all rejected the tumors, and the majority remain tumor-free to date. Some were later injected with fresh tumor cells, and most of these successfully fought them off as well.
What makes this more than a laboratory curiosity is that the technique works with real tumors, not just genetically engineered tumors, Allison says. Most experimental immunotherapies for cancer today involve manipulating the tumor to make it more susceptible to immune system attack.
"The remarkable thing is that it works with wild-type tumors, so you don't have to genetically engineer the tumor cells," Allison says. "You just go in and treat the tumor."
He predicts the technique will be most useful in treating metastases, the secondary tumors that break off from the major tumor and spread throughout the body. These are nearly impossible to eliminate surgically or with radiation, and are usually attacked through chemotherapy.
Allison's research has centered around the various molecules that stimulate T-cells to mount an immune system attack against viruses or cancer cells. Three years ago he and his UC Berkeley colleagues succeeded in halting tumor growth in mice by inserting genes for T-cell "costimulators" into tumor cells. Further research, however, indicated that a component of the immune system was inhibiting a T-cell attack, even when costimulators were present. Allison had a hunch that a poorly-understood molecule called CTLA-4 might be that inhibitor.
He and his group confirmed that CTLA-4 is a receptor that suppresses the action of T-cells when it is activated. He decided to try to block CTLA-4 by injecting antibodies to it, which he hoped would bind to the receptor and render it ineffective.
When he and postdoctoral researchers Dana R. Leach and Matthew F. Krummel did this, the mice's T-cells suddenly seemed to notice the tumors and mounted an attack that destroyed them in nearly all mice treated. To date the researchers have included in their trials about 50 mice, half of them controls that received no antibodies and which in all cases developed full-blown tumors. The mice were injected with two kinds of wild-type tumor cells, one a colon cancer and the other a fibrosarcoma.
Allison says that the reason tumors don't generate a T-cell attack by themselves is that T-cells are responding to the push and pull of two different receptors -- what he terms "yin and yang" receptor molecules -- one of which triggers a T-cell attack and one of which suppresses it.
Tumor cells normally sport molecules called antigens on their surfaces that tell the body's T-cells they are abnormal. But T-cells need more than this to attack. The two "yin-yang" receptors -- analagous to locks -- must also be activated by key-like molecules called B7-1 and B7-2. These costimulators are produced by a specialized immune system cell called an antigen-presenting cell.
T-cells respond only when these two small molecules interact with the yin-yang receptors at the same time that the antigen stimulates the T-cell.
The response is contradictory, however, because one receptor, CD28, stimulates an attack while the other, CTLA-4, suppresses an attack. 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.
Allison's group and another at Bristol-Myers Squibb Pharmaceutical Research Institute in Seattle simultaneously reported three years ago that putting the gene for the B7 molecules into tumor cells makes them produce these costimulatory signals on their own, just as the antigen-presenting cells do. The tumor cells then have all they need to trigger a T-cell attack, and experiments in mice showed that in many cases the mice rejected preexisting tumors after transfection with the genes for B7-1 and B7-2.
Allison was disappointed with the power of this technique, however, and looked for other tricks to stimulate a full-bore immune system attack.
What he discovered and reports in this week's Science is that by blocking the CTLA-4 receptor with antibodies, B7-1 and B7-2 can no longer reach and activate CTLA-4. Its suppressive effect thus disappears, allowing the CD28 receptor to initiate a coodinated attack on the tumor.
One question that remains is whether blocking CTLA-4 triggers a T-cell response or whether it prevents an ongoing T-cell response from damping out. If the former is the case, there may be some danger of generating an autoimmune response, Allison says.
He continues to work on CTLA-4 blockers combined with other anticancer agents, such as lympokines, and is looking at their effect on other types of mouse tumors.
His work was supported by a grant from the National Institutes of Health.
Jim Allison can be reached at (510) 643-6012 or via email at email@example.com. He will be in Bethesda, Md., Wednesday and Thursday, March 20 and 21, at the Hyatt Regency Hotel, 800-233-1234.
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