Emerging Vaccines Take Aim at Preventing Recurrent Breast Cancer
By Joe Munch
|Kaplan-Meier plots depict disease-free survival for patients in the phase I and II trials of the E75 vaccine. Following standard treatment for breast cancer, patients were vaccinated with E75 and granulocyte-macrophage colony-stimulating factor or remained unvaccinated (controls).
advances have been made in the treatment of breast cancer, and cures
are achieved in many patients. However, there are still patients whose
cancer recurs, and most of these patients will die of their disease.
This indicates a need for other therapies that can be used to prevent
recurrent disease. One potential option is breast cancer vaccines.
“Breast tumors are made up of so many different types of cells that we
have to use many different drugs and therapies to treat them,” said
Jennifer Litton, M.D., an assistant professor in the Department of
Breast Medical Oncology at The University of Texas MD Anderson Cancer
Center. “Vaccines come at the cancer in a totally different way than
our current systemic therapies do.” Vaccines thus may augment the
effects of adjuvant treatments currently used to forestall recurrence.
Potential clinical role
Several types of adjuvant therapy are used to prevent breast cancer
from returning; the therapy or combination of therapies used depends on
the individual patients and their disease. For example, radiation
therapy is used for patients who have undergone breast-conserving
surgery, and chemotherapy may benefit patients at high risk of
recurrence. Hormonal therapy with tamoxifen or an aromatase inhibitor
is used in patients with estrogen receptor–positive disease, and
immunotherapy with trastuzumab is used in those with tumors that highly
express human epidermal growth factor receptor 2 (HER2).
Today, several clinical trials are evaluating the use of breast cancer
vaccines—not as an alternative to currently available preventive
therapies for recurrent disease but as an additional adjuvant therapy.
“This is a novel approach specifically for people who want another form
of therapy to decrease the chance of the cancer coming back,” Dr.
Litton said. “People are looking for something extra that may improve
their outcome but doesn’t expose them to a lot of extra toxicity.”
Cancer vaccines stimulate patients’ immune systems to recognize and
kill tumor cells. The vaccines consist of a tumor-associated antigen
that, once introduced into a patient’s body, elicits an immune
response. Several systems have been devised to deliver tumor-associated
antigens into the body, including whole-cell vaccines, viral vector
vaccines, and dendritic cell vaccines, which are custom made from the
patient’s own white blood cells. The only therapeutic cancer vaccine
currently approved by the U.S. Food and Drug Administration is
sipuleucel-T (Provenge), a dendritic cell vaccine used in men with
metastatic hormone-refractory prostate cancer.
The breast cancer vaccines being investigated at MD Anderson are of a
fourth type, peptide vaccines. Peptide vaccines are made by taking a
small amino acid sequence (peptide) from a tumor-associated antigen.
The tumor-associated antigen most frequently used in breast cancer
vaccines is the HER2 oncoprotein, which promotes tumor growth.
Once taken from the antigen, the peptide is mixed with an
immunoadjuvant to help stimulate an immune response. The immunoadjuvant
used in the trials being conducted at MD Anderson is
granulocyte-macrophage colony-stimulating factor (GM-CSF), which has
been used primarily to treat neutropenia in transplant recipients.
When the peptide–GM-CSF combination is injected, GM-CSF stimulates the
dendritic cells in the area of injection to take up and process the
peptide so that it can be better presented to the immune system. The
length of the peptide dictates the type of immune cell it stimulates.
Current clinical studies
Several HER2-derived peptide vaccines are being studied in clinical
trials at MD Anderson. Although the vaccines are based on a HER2
peptide, they have the most benefit in the 60% of breast cancer
patients with low HER2 expression (1+ or 2+ by immunohistochemistry).
Phase III trial of E75
The E75 vaccine (NeuVax) is the most studied of the HER2-derived
peptide vaccines. The 9-amino-acid peptide E75 binds with major
histocompatibility complex (MHC) class I molecules to stimulate
CD8-positive T cells; when these T cells recognize a target as foreign,
they attack it and release cytotoxic enzymes to kill it. Because E75 is
an MHC class I peptide, the vaccine works only in patients whose cells
are positive for human leukocyte antigen (HLA)-A2 or HLA-A3; only cells
with those HLA types will present the peptide on the cell surface to
activate T cells.
In May 2012, Elizabeth Mittendorf, M.D., Ph.D., an assistant professor
in the Department of Surgical Oncology, and her colleagues published
the 24-month landmark analysis of their phase I and II trials of E75.
The group’s findings opened the door to the phase III PRESENT
(Prevention of Recurrence in Early-Stage, Node-Positive Breast Cancer
with Low to Intermediate HER2 Expression with NeuVax Treatment) study,
currently the only phase III trial of a breast cancer vaccine. Dr.
Mittendorf is the overall principal investigator of the multinational
This randomized, double-blind, placebo-controlled trial will enroll
approximately 700 breast cancer patients who were rendered disease free
following standard treatment. Patients must be positive for HLA-A2 or
HLA-A3 and have had cancers that were scored as HER2 1+ or 2+ by
immunohistochemistry. The vaccine will be given once a month for 6
months and then given as a booster inoculation every 6 months
thereafter through 3 years. Because GM-CSF causes inflammation at the
injection site, it will be given to patients in each study group,
serving as the immunoadjuvant for the vaccine group and as an active
placebo for the control group. The primary endpoint of the study is
3-year disease-free survival.
Positive results from this trial, researchers hope, would eventually
lead to indications for the E75 vaccine in the routine care of breast
cancer patients. “We are all cautiously optimistic—and excited—as we
wait for the results. If they do show that E75 has significant benefit,
it could be an amazing opportunity for our cancer patients,” Dr. Litton
Phase II trial of GP2 and AE37
The GP2 vaccine works in much the same way as the E75 vaccine. Like
E75, the GP2 peptide is 9 amino acids long and binds to MHC class I
molecules to stimulate CD8-positive T cells; thus, the vaccine works
only in patients who are positive for HLA-A2 or HLA-A3. In contrast, the
AE37 peptide, which is longer than the E75 and GP2 peptides, binds to
MHC class II molecules and stimulates CD4-positive T cells, thereby
eliciting a more robust immune response. Although MHC class II peptides
can be HLA-restricted, AE37 is a promiscuous peptide, meaning that
blood cells of almost any HLA type can present it. In addition, the
AE37 peptide is paired with the Ii-Key protein, which enhances the
presentation of the peptide to the immune system.
Both the GP2 and AE37 vaccines are being investigated in an ongoing
phase II trial to determine whether the individual vaccines can prevent
the recurrence of node-positive or high-risk node-negative breast
cancer. Patients are sorted into groups depending on their HLA status
and then randomly assigned to receive the appropriate vaccine plus
GM-CSF or GM-CSF alone (as the control).
The AE37 trial’s planned interim analysis revealed that at a median of
22 months, the recurrence rate in the vaccinated patients was 10.3%,
whereas the recurrence rate in the control group receiving only GM-CSF
was 18.0%. The difference represents a 43% reduction in recurrence
“These data are encouraging,” Dr. Mittendorf said. “Obviously, we need
longer follow-up, and we need to finish accrual in the trial, but the
data suggest that it is reasonable to look forward to investigating the
AE37 vaccine in a phase III setting.”
The interim results for the GP2 vaccine are not yet available.
One of the benefits of peptide vaccines such as those being
investigated at MD Anderson is that they can be given “off the shelf.”
This makes them more convenient and less expensive than the custom-made
dendritic cell vaccines.
Dr. Litton, who has referred a number of patients to the breast cancer
vaccine trials, said that patients’ enthusiasm about participating in a
vaccine trial has been overwhelmingly positive. “Some patients tell me
that they feel empowered by using their own bodies, their own immune
systems, to fight the cancer,” she said.
But the main reason the trials are so popular with patients is that the
vaccines offer a potential anticancer benefit with very little risk of
toxicity. Most patients have a grade 1 or 2 local toxic response, which
means redness at the injection site; and some patients experience grade
1 or 2 systemic symptoms, mostly in the form of minor flu-like symptoms
for 4–6 hours after receiving the vaccine.
“These are people who have gone through chemotherapy, lost their hair,
and had terrible gastrointestinal side effects, toxicity in their
nails, and all those other things,” Dr. Mittendorf said. “So a
treatment that is basically not toxic is very attractive.”
Dr. Litton echoed Dr. Mittendorf’s sentiments. “It has not been a hard
trial for people to become interested in. In fact, I’ve had several
people come from different parts of the country just to be part of the
trial,” Dr. Litton said. “And we really appreciate all the patients who
have stepped forward to participate. It’s always important to encourage
people to participate in clinical trials; otherwise we could never move
forward with therapies such as this.”
These vaccines are not for everyone, however. Earlier clinical trials
revealed that the peptide vaccines had limited efficacy in patients
with late-stage, metastatic breast cancer.
“There’s a long list of reasons why these vaccines are not set up to be
administered to patients who have diffusely metastatic disease,” Dr.
Mittendorf said. “It would be difficult, with a peptide vaccine, to
mount enough of an immune response to eradicate bulky disease. The
microenvironment and immune environment around tumors change as tumors
progress, so bulky metastatic tumors also have a less favorable
environment for the immune system to function in. And a lot of patients
with diffusely metastatic disease have received multiple lines of
chemotherapy, which we suspect has a detrimental effect on the immune
The future of breast cancer vaccines holds many possibilities. Antigens
such as cyclin E and folate-binding protein may be targeted for
vaccination. Novel immunoadjuvants are being developed that may elicit
an immune response more potent than that elicited by GM-CSF. And new
approaches using vaccines and harnessing other aspects of the body’s
immune system against recurrent breast cancer may be forthcoming.
“I would like to see some of these vaccines combined with other
exciting immunotherapies that are coming on board,” Dr. Mittendorf
said. For instance, a vaccine could be paired with a drug that inhibits
CTLA-4, a protein that downregulates T cells. “Ipilimumab, an antibody
that targets CTLA-4, could be used to take the brakes off the immune
system. A vaccine would stimulate the T cells, and the anti–CTLA-4
treatment would allow them to proliferate,” she said.
Eventually, such vaccines could be used to treat patients much earlier
in the course of their disease. “I think it would be an exciting route
to look forward to in the frontline setting as well,” Dr. Litton said.
“We could potentially cure more people up front at the time of
EA, Alatrash G, Xiao H, et al. Breast cancer vaccines: ongoing National
Cancer Institute–registered clinical trials. Expert Rev Vaccines
information, call Dr. Elizabeth Mittendorf at 713-792-2362 or Dr. Jennifer Litton at 713-792-2817.
articles in OncoLog, January 2013 issue:
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