A University of Michigan physician has delivered a "wake-upcall" to the immune system of cancerous mice, making theirtumors shrink or disappear completely.

The experiment, written up in Saturday's issue of theProceedings of the National Academy of Sciences, involvedvaccinating the animals with naked DNA representing amolecular ID tag of another mouse strain. Protein based on thismajor histocompatibility complex gene can provoke tissuetransplant rejection.

The "genoculation" induced a cytotoxic T cell response to theMHC tag and, more importantly, to tumor antigens the immunesystem normally does not see, researcher Gary Nabel said.

The mouse experiment provided a conceptual basis for humanclinical trials approved last year. Since June 1992, five patientswith advanced melanoma have been inoculated with anincompatible human MHC gene wrapped inside a fatty liposomeenvelope in a Phase I/II trial conducted in collaboration withVical Inc. of San Diego.

The patients are being followed to establish the safety of usingDNA as a drug, Nabel said, and to track expression of the MHCgene and immune responses.

In BALB/c mice with induced forms of colon adenocarcinoma orfibrosarcoma, pretreating the animals a few days before thetumors were induced doubled survival time and, at best,completely cured one of five animals, Nabel said. Thepresensitization primes the immune system for a more rapidresponse to a second "booster" inoculation.

He suggested that repeat treatment in cancer patients may alsoimprove efficiency, although initially human cancer usuallydoes not divide exponentially the way cancer proliferates inthis animal model.

Nabel speculates that tumors create cytokines that block thebody's immune system from recognizing and destroying themalignant tissue. Although his system is being developed as atherapy to counteract this effect, he said direct transfer of yet-to-be identified tumor antigen genes may one day lead to ashot to prevent cancer from forming in the first place.

"It's a new way of treating disease," he said. "We're bringingthe DNA to the patient as opposed to taking a patient's cancercells to the lab."

-- Nancy Garcia Associate Editor

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