Scientists have found that vaccination with a heat-killed, non-toxic yeast that is genetically engineered to manufacture a common tumour protein can induce specific and repeated anti-tumour immune responses in mice. Vaccination extends overall survival and reduces tumour size in mice that have been injected with cancer cells displaying the same protein that was engineered into the yeast.
Results of this research by scientists at the National Cancer Institute (NCI), part of the National Institutes of Health, can be found in the July 1, 2008 issue of "Clinical Cancer Research,"
"These results provide a rationale for evaluating yeast vaccines in cancer immunotherapy studies in humans," said study author James W. Hodge, Ph.D., in NCI's Center for Cancer Research.
The type of yeast used in this study, Saccharomyces cerevisiae, does not cause disease in humans and has been used as a delivery vehicle for antigens, which are proteins usually on the surface of cells or organisms that stimulate immune responses. The tumour-associated antigen made by the genetically engineered yeast in this study is carcinoembryonic antigen (CEA). CEA is commonly found on cancers of the colon, rectum, stomach, breast, and lung.
The current research was designed to determine the effects of this yeast-based vaccine on tumour growth and overall survival using colon and pancreatic cancer models. These studies demonstrated that the vaccine can elicit both CD4+ and CD8+ T-lymphocyte responses, which recruit help from other immune cells and then attack and destroy cells that bear foreign or tumour-associated antigens. Additional study findings showed that successive administrations of the vaccine resulted in increasing antigen-specific T-cell responses. Vaccination with the yeast-CEA vaccine at multiple sites induced greater T-cell responses than when the same dose of vaccine was given at a single site. Furthermore, tumour-bearing mice vaccinated with yeast-CEA had reduced tumour volumes and increased overall survival compared to control mice.
One of the reasons for interest in Saccharomyces cerevisiae as a vaccine vehicle is its lack of toxicity. Besides being relatively non-toxic, Saccharomyces cerevisiae is heat-killed before administration. It can also be easily engineered to express one or more antigens in large quantities, can be grown and purified rapidly, and is very stable. In addition, its safety in humans has already been established in several clinical trials.
In this study, the researchers performed 24 tests on mice that received either no treatment or the yeast-CEA vaccine. They found that body-weight measurements, blood cell counts, serum enzyme levels, and autoimmune assays were all within the normal range for the vaccinated mice and were similar to those of control mice, indicating no toxicity or autoimmunity associated with the yeast-CEA vaccine.
Since therapeutic control of cancers with vaccines is likely to require repeated vaccine administrations to effectively activate tumour-specific immune responses -- especially when trying to stimulate the body's defenses against one of its own proteins -- the researchers explored whether host immune responses to the first yeast-CEA vaccination would decrease or neutralize the effectiveness of booster shots of the vaccine. On the contrary, they found that repeated administration induced greater immune responses.
These data have implications for use of the yeast-CEA vaccine in humans. A potential future application of these findings to humans would be to vaccinate patients who have CEA-positive tumours with yeast-CEA and measure CEA-specific immune responses. In view of the findings described here, patients could be vaccinated at multiple sites, targeting different lymph nodes, to maximize immune responses against CEA. "These results thus form the rationale for the use of yeast-CEA in immunotherapy protocols for carcinoma patients with CEA-positive tumours," said study author Jeffrey Schlom, Ph.D., of NCI's Center for Cancer Research.
These studies were conducted as part of a Collaborative Research and Development Agreement with GlobeImmune, Inc., Louisville, Colo. GlobeImmune is a biopharmaceutical company pioneering the discovery, development and manufacturing of targeted molecular immunotherapies.