By David N. Leff

Phase I clinical trials are not supposed to measure efficacy, just toxicity and mode of administration, period.

But now and then that period looks more like an exclamation point. That is, the study's results include clinical benefit from the drug under study, which by rights was intended to show up only in Phase II or Phase III protocols.

Such is the case of eight Chinese brain tumor patients treated with an experimental monoclonal antibody conjugated to a cell-killing radioactive isotope. Techniclone Corp., of Tustin, Calif., which developed the therapeutic together with the University of Southern California (USC) in Los Angeles, calls it TNT * tumor necrosis therapy. (Not to be confused with TNF * tumor necrosis factor.)

On May 9, 1997, nuclear medicine specialist Changying Jiang, of Shanghai Medical University, reported her eight-patient Phase I study to the Fifth Annual Meeting of the Chinese Association of Nuclear Medicine. The clinical trial was part of a collaboration between the Shanghai Neurological Institute and pathologists at USC.

The eight patients in the trial had advanced recurrent malignant gliomas. They received injections of the TNT monoclonal either intravenously, to the cerebrospinal fluid, or directly into their brain lesions. "Seven patients," Jiang reported, "achieved complete remissions with disease-free periods ranging from 12 to 15 months. The eighth patient died five months post-therapy of non-treatment-related causes."

Cell biologist and immunologist Clive Taylor chairs pathology and laboratory medicine at USC. "Considering that almost all patients with this type of aggressive tumor relapse in less than six months," he observed, "the ability to achieve a 12- to 15-month disease-free period is quite significant."

USC immunologist and cell biologist Alan Epstein is a co-author of the Chinese paper, a co-inventor with Taylor of the TNT technology and a scientific advisor to Techniclone.

"We put the antibody into China about 18 months ago," Epstein told BioWorld Today, and they of their own choosing brought it to the Neurological Institute. China has 55,000 cases a year of brain cancer, among ten million annually diagnosed with cancer, and one million dying of the disease."

These grim statistics, he recounted, explain how "this fairly unique experimental situation of U.S. cooperation with the People's Republic of China came about:

"In Shanghai some three and one-half years ago, we met a very powerful businessman, Yang Rong, CEO of Brilliance Holdings Inc. [BHI], the first Chinese company to go public on the New York Stock Exchange. Initially involved in the automotive industry," Epstein continued, "Rong wanted to set up a pharmaceutical branch of BHI.

"He laid the way for us to do the clinical trial in Shanghai, basically because of China's cancer mortality figures. Rong felt that this was something he wanted to do to help his populace."

The outcome was that BHI set up a research collaboration with USC, and is funding it with $500,000 a year.

Epstein and Taylor began commuting to Shanghai to help set up the clinical studies of TNT. "We helped them buy all their equipment," Epstein recalled, "get the lab set up, quality control and so on, and trained people."

"Particularly at the outset," Taylor told BioWorld Today, "we helped them establish a protocol based on our limited experience with TNT in the U.S.

"TNT," Taylor continued, "has been given here to seven advanced, metastatic prostate cancer patients in a Phase I toxicology study. We achieved subjective clinical remissions in five of the seven, two of whom went out to two and one-half years, and did very well."

Besides their eight brain cancer patients, Epstein said, "the Chinese have given TNT to one renal, one gastric, two or three hepatomas, three colon cancer cases, and four prostate cancers. They've also very successfully treated three lung cancers, with major remissions that lasted 14 months in one patient. The other two got very good uptakes in their tumors, but were lost to follow-up That's one of the problems in China. Once treated, they go home to their villages."

A 100-percent human monoclonal, developed by Cambridge Antibody Ltd., of the U.K., should be ready for clinical trials this year.

So far, the TNT being tried in China consists of chimeric recombinant monoclonal antibodies, Epstein said, "about 70 percent human, 30 percent murine. This mouse part contains the active site that binds the tumor's dead and dying cells."

Taylor explained: "It's been known for 50 years or more that malignant tumors have very high proliferation rates compared to normal cells. Also, that tumor cells show a lot of necrosis, degeneration. When we pathologists look at tumors microscopically to diagnose them, one feature that helps us recognize malignancy is the presence of dead and dying cells, necrosing at their core."

He went on: "One reason they die is that their chromosomes are so full of mutations they don't have a full cell machinery. Second, they outgrow their own blood and oxygen supply, and kill themselves off. Very malignant tumors, like Burkitt's lymphoma, for example, have a 95 percent proliferation rate and a 90 percent death rate.

"The central parts of any tumor," Taylor went on, "have these necrotic target tissues — mainly we think, DNA histones, which coil the DNA in the cell's nucleus.

"If we try to get at these histone antigens with a drug," Taylor pointed out, "this isn't going to help us. We'll just be attacking cells that are already dead. We need to get to them with something that will attack the living cells next door to the dead ones."

So he and Epstein evolved their TNT strategy to hit those moribund epitopes with a histone-specific antibody packing a cytotoxic isotope. "That isotope labels the dead cells, but kills the 10 live ones that sit around the dead cells," he pointed out.

At this stage in the technology transfer, Epstein's lab at USC, he said, "makes the TNT as a raw product, ships it to China for radiolabeling with iodine-131, and then it goes right into the patient within 24 hours. But eventually," he added, "the agreement between Techniclone and BHI is that if the product goes well, the Chinese company will do the production aspects as well. They have already designed a $70 million biotechnology center to handle all production and labeling facilities."

The Chinese scientists are now applying for permission to expand their still-ongoing trial of TNT in brain cancer to a 300-patient multicenter study. *