By David N. Leff

A novel anticancer drug, Beta-alethine by name, made its clinical bow Monday afternoon in Toronto, at the 28th annual congress of the International Society of Hematology.

Attendees at the event's Immunological Therapy Session heard pathologist Floyd Taub, Chairman and Chief Medical Officer of LifeTime Pharmaceuticals Inc. in College Park, Md., report on "Beta-alethine: TNF alpha, antitumor effects and delayed type hypersensitivity in follicular B-cell lymphoma."

In all, eight lymphoma patients and six with myeloma received the drug treatment at Jewish General Hospital in Montreal, which is affiliated with McGill University. Their open-label, non-randomized Phase I/II trials were sponsored by LifeTime, developer of the proprietary drug, which strongly stimulates the immune system.

Prior to his 15-minute presentation at 4:45 p.m. Monday, Taub told BioWorld Today: "Beta-alethine [BT] seems to have excellent bioactivity - first in mice, chickens, cats and dogs, now in humans. It's extremely potent - the human dose is a couple of micrograms in total - and very nontoxic. One of the things we'll be presenting is the fact that it was administered at roughly 1 million times lower than the predicted toxic dose, and there were no significant side effects."

Of the eight lymphoma patients evaluated, after fortnightly BT therapy for 85 days or longer, he reported, "Maximal response in bi-dimensional tumor measurements included one patient with 53 percent decrease, one with 25 to 50 percent decrease, one with zero to 25 percent, and five with increasing disease (7 percent to 156 percent)."

Taub also presented preclinical results of BT given to a dozen animal models carrying tumors from several types of human malignancy, including breast cancer and melanoma.

"In immunocompetent mice," he recalled, "there was an elimination of pre-existing tumors. And in immune-deficient, nude mice - partially immunosuppressed by lacking T cells - BT treatment produced a significant decrease in the growth rate of the breast cancer, although it wasn't eliminated.

"Interestingly," he continued, "in the human studies we found that same thing happening in patients who started the trial with a delayed-type hypersensitivity standard skin test - in which the T-cell system recognizes common antigens that everyone is exposed to. Of patients who started the study with immune systems able to recognize the antigens enough, with some functional capacity left, three out of four ended the trial with smaller cancers than they began with.

"In contrast, if their T-cell arm was lacking functionally, and they could not mount skin-test reactions before the study, BT increased their ability to mount these immune reactions, but not enough so they went on to have an anticancer effect."

BT Sends In Immune Team's Top Player

The drug's ability to unleash immune system cytokines with anticancer potential relies largely on one cytokine in particular - tumor necrosis factor alpha (TNF). One of the two types of T lymphocyte helper cells, T_H1, puts out TNF in quantity.

"TNF," Taub observed, "is probably the molecule that has the most potent and most dramatic anticancer effect of any of the biological molecules, in the setting of coordinated cytokine production. It is synthesized internally and transported to the membrane, or free in solution. When TNF remains on the T cell or monocyte membrane surface, those cells become armed with it." As he told the conference, "Compared to their pre-trial status, the majority of patients receiving BT showed increased TNF expression on the surface of their lymphocytes."

Taub made the point that "immunotherapy was originally focused on treating 'minimal residual disease' - after surgery, radiation and cytotoxic chemotherapy. While it is regrowth and metastasis of these small tumors that leads to approximately one death per minute in the U.S., the Canadian trial's computer-assisted tomography scanned documented shrinkage in cancers 100,000 times that size, following single-agent, subcutaneous injections of Beta-alethine."

In light of the Canadian experience, LifeTime is now sponsoring trials of myeloma and lymphoma patients at four cancer centers in the U.S. - at Emory University in Atlanta, the University of Maryland in Baltimore, and two community medical facilities, the private Helios Clinic, in Boulder, Colo., and Victory Over Cancer - a not-for-profit clinic in Rockville, Md. The four centers aim to enroll a combined total of 54 patients.

"Also," Taub pointed out, "we will be treating early-stage myeloma and lymphoma patients, including 'indolent' - slowly progressive myeloma and lymphoma. And what is somewhat unusual," he added, "is that in these new Phase I/II trials we are also treating people with progressive premalignant disease to prevent the conversion to malignancy. There aren't that many drugs," he commented, "that are approved for preventing cancer."

The trial includes an entity Taub calls progressive "MGUS." He explained:

"MGUS stands for 'Monoclonal gammopathy of uncertain significance.' It's a precursor to multiple myeloma. One clone of cells has already gone wild, and is producing a monoclonal protein spike - an antibody. But it hasn't yet begun to erode the bone, and people can remain with MGUS for long periods of time. Up to 25 percent of the elderly population has an abnormal monoclonal protein, but most of those are stable. In some of them, the protein is increasing, and progressing toward becoming a malignant myeloma."

From Tumors To Infections To Vaccines

For now, his company is looking at cancer indications. "And the theory of immunotherapeutics," Taub pointed out, "has been for a long time that it will not have any effect on late-stage cancers. They'll be good for minimal residual disease, or for early disease - as where we're preventing early myelomas by using BT. But once there's a big tumor, it's believed, the immune system will not be powerful enough to have any significant effect."

The clinical trial data challenge that dogma: "We saw in the first trial in Canada," Taub pointed out, "that even 10 centimeter- [4-inch] diameter lesions could shrink dramatically. So there are potential applications, not only in various stages of cancer, but in infectious diseases as well - such as hepatitis C or AIDS, where the pathogen is in more of a state of equilibrium than in cancer. It also enhances the activity of vaccines. In the future we anticipate partnerships with vaccine companies. So, given the minimal side effects profile we see now, and the evidence of biological activity," Taub concluded, "I think you will see this drug on the market for one indication or another."