Two studies presented at the Era of Hope Department of
Defense Breast Cancer Research Program meeting exemplify different
but equally promising approaches to the development of cancer
vaccines. Both approaches capitalize on recent advances in the
understanding of the bodys natural disease-fighting mechanisms.
Researchers from the University of Washington, Seattle, developed an
experimental cancer vaccine that for the first time generated an
immune response against a protein overexpressed in some patients with
breast and other cancers by stimulating a response to helper T-cells.
Previous vaccine studies have concentrated on stimulating killer T-cells.
This is one of the first trials to show that its possible
to generate an immune response to a cancer protein by immunizing
patients with fragments of the protein, said Mary L. Disis, MD,
associate professor of medicine. It is also the first step
toward the long-term goal of developing an affordable and hopefully
practical vaccine to prevent cancer recurrence.
The vaccine is made from fragments of HER2/neu. Dr. Disis and
her colleagues chose to test HER2/neu as a vaccine after
preliminary studies found that some patients had preexisting low
levels of immunity to the protein. They hypothesized that a vaccine
that boosted this preexisting immunity might induce an antitumor effect.
Production of Helper T-Cells Stimulated
The study, designed to evaluate the vaccines safety and ability
to generate an immune response, included 64 patientsall of whom
had completed treatment for stage III or IV breast, ovarian, and lung
cancer and showed either no evidence of disease or were stable on
hormonal therapy. The course of 6-monthly vaccinations was completed
by 38 patients. The rest did not complete the study due to disease
progression, which required a return to standard treatment.
Of patients who received all six vaccinations, 90% developed an
immune response to the protein fragments, and 75% developed an immune
response to the protein itself. The vaccine stimulated the production
of helper T-cells and was totally nontoxic, said Dr. Disis.
After the course of vaccinations was completed, the researchers
continued to monitor a subset of patientswho volunteered for
long-term follow-upto see how long their immunity to HER2/neu
persisted. Immune responses occurred in some patients who had not
shown a response after receiving all six vaccinations; others
experienced an increased immune response during the long-term
follow-up period. Four patients retained immunity for 2 years or
longer after they were vaccinated.
Immune System Remembers
These follow-up data suggest that the immune system may be able
to remember and respond to the protein long after
vaccination has taken placethe hallmark of a successful
vaccine, said Dr. Disis. However, she acknowledged that it will
take a larger and longer clinical study to determine whether this
vaccine can indeed create long-term immunologic memory
and stop cancer from recurring.
The eventual goal of Dr. Disis and her colleagues is to develop a
vaccine that could be used routinely to prevent cancer recurrence. In
the process, the researchers are currently testing other formulations
of the vaccine, using different adjuvants agents, to see which one
generates the most effective immune response against the HER2/neu
protein. The most promising formulation will be tested for
effectiveness in preventing cancer recurrence in patients with stage
III breast cancer who are at high risk for relapse.
Novel Delivery of Dendritic Cells
In data presented at the meeting by another research group,
significant regression of breast tumors occurred in mice treated with
an experimental cancer vaccine. For the first time, researchers
injected dendritic cells directly into breast tumors.
The next step is to find the best way of translating these
findings into a human clinical trial, said Christopher J. Kirk,
phd, a research fellow in the Tumor Immunology Program, University of
Michigan Medical Center, Ann Arbor. If this strategy proves
effective in humans, the ultimate hope is that immunotherapy with
dendritic cells could be used in conjunction with chemotherapy,
potentially lowering the chemotherapy doses and thereby reducing side
effects while improving efficacy.
In this study, the researchers gave four intratumoral injections of
dendritic cells to 25 mice. In 5 of the 25 treated mice, tumors
regressed completely for more than 3 months, and new tumors
grafted into the same animals did not grow. In the remaining mice,
tumor growth was reduced by two-thirds, compared with control mice.
The researchers then gave two injections of dendritic cells combined
with tumor necrosis factor (TNF)-alpha directly into breast tumors in
another 10 mice. This time, tumors were eliminated in half of the
treated mice, and overall tumor growth was reduced by approximately
80%, compared with control mice.
Preliminary Human Studies
In a preliminary study to test the feasibility of this approach in
humans, six patients with advanced breast cancer are receiving
intratumoral injections of dendritic cells once a week for 3 weeks.
(TNF-alpha cannot be given to humans because it produces severe side
effects. The researchers are exploring other potential agents that
can safely be given to patients to boost the antitumor effect of
dendritic cells by causing tumor apoptosis.)
In other studies of cancer vaccines using dendritic cells, the cells
have been injected into patients skin, blood, or lymph nodes.
This approach requires performing a biopsy first to remove tumor
cells from the patient. Then the tumor cells are killed and
fed to the dendritic cells in the laboratory.
Intratumoral injection of the dendritic cells makes these preliminary
steps unnecessary, said Dr. Kirk.
Using dendritic cells to make a cancer vaccine for humans is a
labor-intensive process. The cells must be derived from the
patients own white blood cells. The white blood cells are grown
in the laboratory with proteins that promote the growth of dendritic cells.