Sniffing Out The Promise Of Anti-Angiogenesis Therapy

Gill's data on the anti-angiogenesis peptide IM862 in the treatment of Kaposi's Sarcoma (KS)-the most common cancer associated with HIV-will be presented at the annual meeting of the American Society of Clinical Oncology, and will be featured in a press conference on novel cancer therapies on Sunday, May 16, at 11 a.m.

In Phase II of the clinical trial of IM862-from which the data presented were taken-Gill, a professor of medicine and pathology at the University of Southern California School of Medicine, along with Peter Brooks, Ph.D., Jeffrey Weber, M.D., Ph.D., and Anil Tulpule, M.D., all from USC, treated 35 patients with an intranasal solution administered as a nose drop of IM862. They found that 37 percent of the patients showed a major response-either complete resolution of the KS lesions (4 patients) or partial reduction in tumor size (9 patients)-within six weeks of beginning treatment. In another 17 patients, the disease has not progressed for six months or longer.

"All this occurred with very few side effects," says Gill, "which were limited mostly to mild headaches."

IM862-now well into Phase III clinical trials-is among the first anti-angiogenesis drugs to get to this phase all on its own, says Gill. "Most of the other anti-angiogenic drugs are combined with chemotherapy," he notes. "This may end up being the way this family of drugs will be developed." (The chemicals which started the anti-angiogenesis debate-angiostatin and endostatin-have not yet reached Phase I trials.)

IM862, a thymic dipeptide, a small protein, was developed by Cytran, Inc., a private held company located in Kirkland, Wash. It does not go after tumor cells directly-in fact, says Gill, "it is not cytotoxic to any tumor cells." It inhibits blood vessel formation and/or modulates the immune system.

KS is treatable (though not curable) with conventional chemotherapy, but, notes Gill, "chemotherapy comes along with so much toxicity that people will only stay on it for a period of time before they literally get sick of it." IM862, on the other hand, may be taken for a prolonged period of time if the tumors' response remains positive.

In addition to being safe, IM862 is a small molecule that makes synthesis and production of the peptide fairly simple. It also makes nasal administration possible. "It can get over the nasal membrane intact," says Gill, so that more than 70 percent of the given dose winds up in the bloodstream. Because the peptide is destroyed by the stomach, it can't be put into pill form, says Gill. "And, obviously, administering the drug through a more convenient route is preferable," he adds.

"Unlike many other cancer drugs that must be given by injection, this peptide can be self administered by the patient as a nose drop," says Gill.

Perhaps an intriguing thing about anti-angiogenesis drugs like IM862 is that it works indirectly by altering the function of other cells. IM862, for instance, seems to interact with a number of different immune system cells once it has made its way into the body. The peptide appears to stimulate natural killer (NK) cells by enhancing production of the cytokine interleukin-12.

This immune stimulation, potent on its own, also has an anti-angiogenic effect, says Gill, "NK cells produce factors which are toxic to endothelial cells," he explains. Endothelial cells are the cells out of which blood vessels are made-and from which KS develops.

But IM862's effect on blood vessel formation reaches even further. Gill and his colleagues found that when chicken allantoic membrane was exposed to IM862 (the vessel-rich embryonic membrane is a standard tool for testing anti-angiogenic activity), blood vessel formation was blocked. Later they found that the blood vessel count in tumors implanted in mice was reduced when the tumor was treated with IM862.

Its main effect, says Gill, appears to be in reducing production of vascular endothelial growth factors, or VEGFs, and blocking the function of BFGF which Gill says are "major mediators of angiogenesis, tumor growth and spread. These growth factors are produced by tumors and the stroma around tumors."

And it does all this despite a half-life in the body of all of five minutes. "Obviously, that's too short a timespan for it to do anything directly," says Gill. "That's why we need to consider the secondary effects it causes: the decrease in VEGF production, the increase in IL12 production, the stimulation of natural killer cells and their products."

One of its secondary effects is on monocytes-white blood cells which are the precursors of macrophages. IM862 on its own isn't able to make a dent on the proliferation of endothelial cells. Add monocytes into the mix, however, and the peptide begins to make itself heard. Monocytes-immune cells that eventually develop into macrophages-secrete a number of growth factors, explains Gill, and hence have a significant role in blood vessel formation. When you treat a monocyte's chemical secretions-or supernatants-with IM862, the potency of the growth factors is reduced. "IM862 treated supernatants reduce endothelial cell proliferation by two-thirds," says Gill. "For patients with KS-and potentially a host of other cancers-that's all you need to reduce or even obliterate the disease."

Studies looking at IM862's efficacy in treating ovarian carcinoma and melanoma are also ongoing and studies of other cancers are planned.

"The initial idea of anti-angiogenesis therapy was to stop tumor growth and spread," says Gill. "But in the lab, we and others have seen that newly-formed vessels are susceptible to actual cell death if we deprive them of certain factors. That leads us to think that if we can destroy newly formed vessels, the cells dependent on them for their supply of nutrients will also die. And that is certainly what seems to be happening here."