Yeast-Based Vaccine Induces Immune Responses
and Reduces Tumor Size in Mice
Scientists have found that vaccination with a heat-killed, non-toxic
yeast that is genetically engineered to manufacture a common tumor
protein can induce specific and repeated anti-tumor immune responses
in mice. Vaccination extends overall survival and reduces tumor
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 NCIís 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 tumor-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 tumor 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 tumor-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, tumor-bearing mice vaccinated with yeast-CEA
had reduced tumor 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
Since therapeutic control of cancers with vaccines is likely to
require repeated vaccine administrations to effectively activate
tumor-specific immune responses — especially when trying
to stimulate the bodyís 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 tumors
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 tumors," said study author Jeffrey
Schlom, Ph.D., of NCIís 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.
For more information on Dr. Hodgeís laboratory, please go to http://ccr.cancer.gov/staff/staff.asp?profileid=5666.
For more information about cancer, please visit the NCI website
at http://www.cancer.gov, or
call NCIís Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).
The National Institutes of Health (NIH) — The Nation's
Medical Research Agency — includes 27 Institutes and Centers
and is a component of the U.S. Department of Health and Human Services.
It is the primary federal agency for conducting and supporting basic,
clinical and translational medical research, and it investigates
the causes, treatments, and cures for both common and rare diseases.
For more information about NIH and its programs, visit www.nih.gov.
Reference: Wansley EK, Chakraborty M, Hance KW,
Bernstein MB, Boehm AL, Guo Z, Quick D, Franzusoff A, Greiner J,
Schlom J, and Hodge JW. Vaccination with a recombinant Saccharomyces
cerevisiae expressing a tumor antigen breaks immune tolerance and
elicits therapeutic antitumor responses. Clinical Cancer Research,
July 1, 2008. Volume 14, Issue 13.