By Dean A. Haycock

Special To BioWorld Today

Cells of the immune system keep asking, "Who goes there?" And, unfortunately, cancer cells keep answering, "Nobody." And they get away with it.

One reason the immune system often fails to recognize and destroy cancer cells may be because they don't look enough like foreign invaders. Specifically, they do not fly the molecular flags that mark them as targets to be destroyed by prowling immune cells.

This deception may not go on forever, however. A report in the July 22 issue of the Proceedings of the National Academy of Sciences (PNAS), titled "Manipulation of T cell costimulatory and inhibitory signals for immunotherapy of prostate cancer," shows how close researchers are coming to correcting this unhealthy situation.

The paper describes a novel method for testing potential immunotherapies for prostate cancer. With the help of genetically engineered mice, the scientists show that by activating T cells and preventing their inactivation, they can produce a clear anti-prostate cancer immune response in mice. The work builds on recent discoveries of how T cells are regulated.

Two Signals Needed To Trigger T Cells

Immunologists have determined that complete T cell activation requires two distinct signals. The first is provided by interaction between the T cell receptor and an antigen-major histocompatibility complex. The complex could be presented on an antigen-presenting cell or on a cancer cell.

The second necessary signal is provided by interaction of a different molecule on the surface of T cells, called CD28, with molecules referred to as the costimulatory B7 family of ligands. The B7 ligands are expressed on antigen-presenting cells.

"In order to have costimulation, they both have to be present on one cell. They either both have to be present on the cancer cell or both have to be present on an antigen-presenting cell. Nature relies on them being on an antigen-presenting cell, which can be a macrophage or other immune cell. But Nature typically does not put both signals on cancer cells," Eugene Kwon told BioWorld Today.

Kwon, the first author of the report, is a urologist and a researcher in the laboratory of kidney and electrolyte metabolism in the National Heart, Lung and Blood Institutes (NHLBI) at the National Institutes of Health, in Bethesda, Md. The work was done in collaboration with Targeted Genetics Inc., of Seattle.

Kwon's co-authors include James Allison, Cancer Research Laboratory director, and immunologist Arthur Hurwitz, both of the University of California, Berkeley; Maurice Burg, chief of NHLBI's kidney and electrolyte metabolism laboratory; and Norman Greenberg, assistant professor at the Baylor College of Medicine, in Houston.

If researchers can get cancer cells to send out the right signals by expressing the appropriate molecules, the immune system could take over the job modern medicine now tries to accomplish with chemotherapy, surgery and radiation.

Applying new information about T cell function to a new animal model of prostate cancer, the authors of the PNAS article show that mice with healthy immune systems reject prostate cancer cells that have been modified to express one of the B7 costimulatory signals. Mice that lack T cells, by contrast, fail to reject the cancer cells and develop prostate tumors.

"B7 primes, or jump-starts, T cells," Kwon explained.

To Kwon this represents an improvement over the current gene therapy strategies, which are contingent on fairly high transduction rates in vivo.

"That is a real problem because it is difficult to get that situation where you can say 'Well, if only 10 percent of the cells are affected, this would be therapeutic.' In this situation, we have demonstrated that if you activate the T cells, they can come back and kick the tumor pretty hard once all the proper signals are given," Kwon said.

The PNAS paper also presents data showing that blocking the inhibitory action of a molecule on the surface of T cells can boost the immune response to prostate cancer cells. This T cell "on-off switch" is known as CTLA-4.

"By blocking that, you pretty much keep the T cells from becoming inactive. You get a much more potent and durable response," Kwon said.

The downside of that, some people theorize, might be the development of an autoimmune disease.

"But actually we would like to know how far we could push it. Ideally, we would like to mount a push against the prostate because it is a fairly expendable organ and it has other pathology, such as benign prostatic hyperplasia, which theoretically could be immunologically targeted," Kwon noted.

Overall, the data offer encouraging prospects for the use of immune-based therapies for prostate cancer. The work also introduces a valuable animal model of the disease for evaluating immunotherapies.

The researchers are now concentrating on trying to elucidate the exact mechanisms that might be involved in the anticancer response they observed.

"We have an idea that some of it follows the classical conditions of T cells being activated and killing cancer cells, but there are also indications that part of it just happens and we don't know why. We would like to know why," Kwon said.

This method, described in the PNAS article, is a good screening model, but the researchers are looking forward to their next major project. They are preparing an important in vivo experiment involving the transgenic mouse that has been engineered to develop prostate cancer.

"It will be a huge transgenic experiment using state-of-the-art immunotherapy strategies to treat advanced-stage disease," Kwon said. *