BETHESDA, Md. -- Research has suggested that the immunesystem's poor response to tumor-specific antigens couldaccount for its inability to kill cancer tumors. Researchers atthe 88th Meeting of the National Cancer Advisory Boardreported last week on methods to boost immune response.
Elizabeth Jaffee, a professor of oncology at Johns HopkinsOncology Center, strengthened immune response to tumors byremoving tumor cells from mice that had tiny cancers,irradiating the cells and inserting a cytokine gene. She thenreinjected the tumor cells into the animals. Granulocytemacrophage colony stimulating factor (GM-CSF) was the mostpotent of the cytokines that she tested.
Although Jaffee has received permission from the RecombinantDNA Advisory Committee for Phase I trials, transfecting andreinjecting tumor cells would be cumbersome in the clinic, shesaid. As an alternative, Jaffee has been using massspectrometry to search for antigens -- with some success.
Olivera Finn, associate professor of immunology at thedepartment of molecular genetics and biochemistry at theUniversity of Pittsburgh School of Medicine, has discovered apowerful antigen that is present in cancers of the breast,prostate, pancreas, colon, and some renal cell carcinomas.
The antigen is located on the filamentous strands that projectoutward from cancerous cells like elongated cilia. "Thismolecule, the protein backbone of human mucin muc-1, isencoded by a gene the likes of which we have never seen," saidFinn. Most of the gene is composed of 20-200 repeats of asequence that codes for 20 amino acids. The first five aminoacids of each repeat bind cytotoxic T cells.
That determined the design of a synthetic antigen. It contains105 amino acids -- five repeats plus the first five amino acidsof a sixth, or six T cell binding sites.
Therapy would involve injecting the antigen directly intopatients, which in theory will stimulate mucin-specific T cellsto proliferate and kill tumors. In animal studies, T cellsproliferated, but no animal model contains the mucin gene.Finn anticipates receiving investigational new drug approval(IND) for a cancer vaccine by the end of the year.
Finn has been developing several related vaccines in whichnon-tumor cells, which are more immunogenic than tumorcells, would be transfected with muc-1 cDNA plus IL-2 and IL-4. The vaccines are being tested in laboratory and in primatestudies, but human trials are at least several years away.
The molecular details of an old epidemiological observation,which are now becoming clear, lend credence to Finn'sapproach: The rate of breast cancer is lower in women whohave been pregnant and have lactated than in women whohave done neither.
Finn recounted an anecdote about a woman who had breastcancer at 21 and was alive and well seven years later despite avery poor prognosis. "The tumor was very positive for theepitope we are studying," said Finn.
Two years after a mastectomy, the woman became pregnantand had tremendous mastitis, evidence of a powerful immunereaction. There was no tumor, but Finn's slides showed that thebreast ducts were packed with T cells, some of which wereclinging to a fragment of mucin. This is highly unusual.
"Our hypothesis is that the tumor provided the first immunity,which was strongly boosted by pregnancy and lactation, andthat mucin muc-1 had attracted the T cells," said Finn.
-- David C. Holzman Washington Editor
(c) 1997 American Health Consultants. All rights reserved.