By Randall Osborne

Editor

"Autologous." The word, to those unfamiliar with it, sounds vaguely like part of a computer procedure, such as "autologous sorting," or maybe the genus name of some rare, deadly (but non-existent) microscopic parasite, like "Autologous maleficias."

In fact, the word means "from the same organism." Most often in biotechnology, it's heard in connection with bone marrow transplants, stem cell transplants, and cancer vaccines such as those developed by AVAX Technologies Inc., of Kansas City, Mo.

There has been much ballyhoo over pharmacogenomics' promise of personalized medicine, and autologous cancer vaccines may have touched that base already. Using each individual's tumor cells to make the vaccine, firms such as AVAX aim to spur the patient's own immune system to fight the patient's own disease.

Often, a problem such as cancer must be attacked on many fronts at once, so autologous vaccines despite difficulties in their manufacture, and despite regulatory complexities must be taken seriously.

Investors, no doubt, took seriously last month's news from AVAX, which said the FDA put its M-Vax (for melanoma) and O-Vax (for ovarian cancer) autologous cancer vaccines on "clinical hold" pending further review. AVAX put its stock on hold the day of the news, too.

The company's shares (NASDAQ:AVXT) were trading at $1.312, up 3.12 cents, on March 23 when put on hold. They were priced in the same range late last week. AVAX has about 16 million shares outstanding and a market cap of about $24 million.

AVAX said the FDA's move has nothing to do with the handling of tumor cells, preparation of vaccines, or manufacturing, but relates to "evolving requirements for cell-derived products," such as those applied to what AVAX calls its AC Vaccine technology.

The company added that it wasn't sure what the agency wants, but "the sterility issue" cited by the FDA involves "an extremely limited number of tumors received by the company to date." The firm characterized the delay as likely "short term" and "temporary."

More than 400 patients have been treated by the autologous vaccines. Under way is a multicenter pivotal registration trial of M-Vax in stage III melanoma, as well as a Phase II trial in stage IV melanoma.

The FDA has given M-Vax orphan drug status in the U.S., and it's already available in Australia. The AC Vaccine approach is being tested in a Phase II trial in ovarian cancer, and in Japan for use in the treatment of breast cancer.

AVAX is allowed to keep dosing patients already undergoing treatment with vaccine already proven sterile, and the agency has 30 days to spell out what it requires of AVAX in order for the trials to continue at their planned rate.

The company is the first to meet a snag with the FDA over rules related to cell-derived products in the area of autologous cancer vaccines rules that would be hard to establish, maintain and enforce in any case, since the drug batch is always changing, because the patient is always new.

"We're moving into new frontiers," said Rich Rainey, AVAX's vice president of finance and administration.

The FDA said regulation of tissues and cells is always evolving, but there's nothing new in the works targeting cancer vaccines specifically.

Richard Steffen, therapeutics oncology chief in the clinical trial design and analysis division of the agency's Center for Biologics Evaluation and Research, said cancer vaccines are "probably a third of the products we deal with."

He told BioWorld Financial Watch that "certainly, the whole area of cell and gene therapy, which we lump together in the same administrative area, the techniques of cell isolation, culture and cell expansion are changing," because of advances in science.

None of this is specific to cancer vaccines, although it may affect them, he said.

AVAX noted that its Philadelphia manufacturing facility meets the agency's Good Manufacturing Practices guidelines, and the company's delivery system can meet the demand for vaccines from a single, centrally located facility.

"Only recently has the approach been noticed by the big players [in the industry]," Rainey told BioWorld Financial Watch. "It's a very capital-intensive business, not unlike a service business."

Cost and precision in manufacturing become key issues together, and AVAX's procedure requires careful control, Rainey noted. The central facility has made the grade, but other links in the procedural chain must be looked after, he added.

"The first line of treatment is always surgery," Rainey said. "The patient goes in and gets the tumor excised," after which it's placed on dry ice and shipped to AVAX.

"We break it down into cancer cells and process it," he said. "There's about a one-month delay, basically to see if the patient will cure from the surgery." Patients who are treated get seven weekly doses, and one booster dose."

The vaccine is created by a process called haptenization.

"It's the introduction of a foreign substance onto the outer membrane [of the tumor cells], so the immune system doesn't recognize the membrane," said Gary Knappenberger, director of regulatory affairs for AVAX. As the hapten, the small molecule dinitro phenyl is used along with an agent that boosts immune response (cyclophosphamide, commonly used in chemotherapy).

Altering the cell this way "offers enough stimulation that the body starts reacting to the tumor cells themselves," Knappenberger said.

This strategy works in 75 percent to 80 percent of cases, he told BioWorld Financial Watch. The big, hard-to-control risk comes much earlier in the process at the hospital.

Sterile handling of tumor samples "isn't something surgeons are used to doing," Rainey said. "They're used to taking the tumor, cutting a piece for [the pathology lab], and discarding it. We know that once it's in the container, sterile, it's fine and we control it from then on."

There hasn't been a distinct set of rules about handling the tumor after its removal and before shipping to AVAX, he added.

"Not up to this point, let's put it that way," he said. "Each hospital has slightly different practices, and each surgeon has slightly different practices, even at state hospitals. We're putting additional safeguards into place."

Steffen said he could not speak of AVAX's case specifically, but "the more handling, period, whether it's on site or off site, the more chance of contamination."

Location of the cancer matters, too.

"Colorectal cancer is a very common cancer, so it's an area of great interest, and the colon is not a clean area," he said. "Lung cancer would be another one. There are bacteria in the breathing passages."

M-Vax, the product being tested by AVAX, takes aim at melanoma.

"If it's from the skin, it will probably be contaminated somewhat, but you try to remove as much infection as possible, and you probably would be able to sterilize it relatively well," he said.

Hospital handling is another matter, Steffen added.

"That's always a problem, and not just with tumor vaccines," he said. "When you do surgery, you can always introduce a few bacteria. It's a problem they have with organ transplants. There have to be definite procedures to take a healthy kidney out of one operating room across the hall to another operating room."

Others exploring autologous cancer vaccines include Antigenics LLC, of New York; Cell Genesys Inc., of Foster City, Calif.; Dendreon Corp., of Seattle; and Intracel Corp., of Rockville, Md.

Although any firm working in the space will have to deal with FDA rules, AVAX is finding just as critical and maybe almost as complicated the matter of keeping the process clean, a problem that has bedeviled medicine for a long time.

"What we've said is that our process is an aseptic process," Knappenberger said. "But if you get a nonsterile sample, you come out with a nonsterile product."