By Vicki Brower

Special To BioWorld Today

Chimeric Therapies Inc., a Costa Mesa, Calif., start-up, has received the go-ahead from the FDA to begin Phase I/II trials for solid organ transplants in mismatched donor-recipients using the company's facilitating cell technology.

Chimeric cofounder Suzanne Ildstad said the investigator-sponsored trials will include about 15 heart patients and 15 kidney patients. She discussed the experimental studies at the recent American Association for the Advancement of Science meeting, in Philadelphia.

"If this works, universal organ transplants may be possible, which may alleviate the chronic shortage of organs," she observed.

A transplant surgeon who formerly worked with pioneer Thomas Starzl at the University of Pittsburgh, Ildstad joined Philadelphia's Allegheny University of the Health Sciences in early 1996, where she established an interdisciplinary research institute for transplantation immunology, the Institute for Cellular Therapeutics, and a cell processing laboratory.

Two years ago, Ildstad isolated a rare type of immune cell that facilitates engraftment of bone marrow transplantation, which she dubbed the "facilitating cell."

Shortly afterward she founded Chimeric Therapies to commercialize the discovery in bone marrow and solid organ transplantation with Olav Bergheim, who serves as CEO. Bergheim spent 18 years at Baxter Healthcare Corp., of Deerfield Ill., working in the area of immunotherapy.

Chimeric also has an ongoing Phase I/II trial in bone marrow transplantation from mismatched donor-recipients for leukemia patients. That study began in 1997 and is currently accruing patients.

The company's core technology consists of removing T, B and natural killer cells from bone marrow while preserving the facilitating cells to help stem cells engraft and down-regulate graft-vs.-host disease (GVHD). The technology may reduce, or eliminate, the need for immunosuppressive therapy in solid organ transplants, Ildstad said. Moreover, she added, thereafter, anyone who is a candidate for a bone marrow transplant for leukemia would have a donor.

Discovery Based On Hunch

The discovery of facilitating cells came from a hunch Ildstad had. "Ten years ago, we knew that stem cells were good for engrafting, and also thought that T cells were necessary, too," Bergheim said. "When T cells were removed from the bone marrow, it eliminated GVHD but there was also impaired engraftment."

However, Ildstad hypothesized there was another type of cell responsible for engraftment, but eliminated from bone marrow with T cells during the purification process. It didn't make sense to her that T cells, which attack foreign bodies, would also be responsible for helping foreign marrow engraft. So she continued studying the bone marrow of mice and looked for another type of cell.

She found the facilitating cells — although they comprise less than 1 percent of bone marrow — and discovered they helped stem cells engraft, but did not promote an immune reaction like T cells.

The use of facilitating cells to promote engraftment of bone marrow actually creates in the recipient a chimeric, or hybrid, immune system, explained Bergheim, in which cells of the donor and recipient coexist without the usual immune reaction.

Both types of cells undergo a deletional tolerance process in the recipient's thymus, in which only those cells tolerized, or chimerized, leave the thymus. Dendritic cells in the thymus are thought to sort out those that would hurt the body; the remaining cells receive a mixed, or chimeric, genetic coding of both the donor and recipient, Bergheim said.

Ildstad and her coresearchers reported on the leukemia trial at the American Society of Hematology meeting last year. Of 11 patients who lacked matched bone marrow donors, all had 100 percent engraftment from mismatched donors using the facilitating cells — in contrast to the 30 percent historically in matched donor-recipients.

Seven of the 11 patients still survive, and while they have had varying degrees of GVHD, the cases have been mild, with all responding to steroid therapy. Since then, the process of purification of bone marrow has been refined. It is expected to dramatically lower instances of GVHD in the new solid organ transplantation trial.

Autoimmune Disease Treatment Also Possible

Unexpected results with preclinical experiments point to another use of facilitating cells in bone marrow transplantation (BMT).

Ildstad found when she performed a BMT in mice with a variety of autoimmune conditions, the severity of those ailments seemed to diminish. Chimeric is targeting use of BMTs with facilitating cells as therapy for rheumatoid arthritis, Type I diabetes and ulcerative colitis. The company expects to conduct clinical trials in aplastic anemia and Type I diabetes.

Chimeric is a "bioservice company," Bergheim said, and as such, is marketing its technology through a small number of cell processing centers that supply engineered stem cell grafts to a large number of clinics.

Its revenues are derived primarily from cell processing and graft engineering services on a per-patient basis, rather than from selling specific drugs or devices.

Venture capital funding from Domain Associates, Biotechnology Investments Ltd., Asset Management Co., and Sofinnova Investments enabled Chimeric to set up administrative offices in Costa Mesa and construct an additional laboratory in Philadelphia, which recently opened to perform graft processing operations.

Chimeric also has established contracts with two multinational pharmaceutical companies covering the exclusive use of monoclonal antibodies for its immunoselection process. Its has 20 employees involved in cell processing, process development, quality systems and clinical and regulatory affairs.

The company formed a German subsidiary in Munich and began clinical trials in June 1997 at the University of Tubingen in leukemia. Negotiations also are under way in Paris at the St. Louis Hospital, a large transplantation center, for clinical trials later this year. *