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Toward a Breast Cancer Vaccine:Work in Progress

Toward a Breast Cancer Vaccine:Work in Progress

ABSTRACT: Advances in biotechnology and basic immunology have converged to create an unprecedented opportunity to use vaccines to harness the power of the immune system in the fight against breast cancer. Cancer vaccines have several therapeutic advantages over more traditional breast cancer treatment modalities. First, targeting the antitumor immune response to critical tumor-specific antigens defines a therapy with exquisite specificity and minimal toxicity. Second, immune-mediated tumor destruction occurs by mechanisms distinct from those underlying the efficacy of chemotherapy and hormone therapy. Thus, immunotherapy offers an approach to circumventing the intrinsic drug resistance that currently underlies therapeutic failure. Third, the phenomenon of immunologic memory endows immunotherapy with the potential for creating a durable therapeutic effect that is reactivated at the onset of disease relapse. Moreover, immunologic memory also underlies the potential future use of vaccines for the prevention of breast cancer. Early clinical trials have highlighted the promise of breast cancer vaccines, and have further defined the challenges facing translational scientists and clinical investigators. The judicious application of laboratory advances to clinical trial design should facilitate the development of immunotherapy as an additional major therapeutic modality for breast cancer, with the potential for breast cancer prevention as well as treatment.

Concerted efforts over the past
2 decades to optimize the management
of early breast cancer
have decreased the morbidity of breast
cancer treatment and resulted in a decline
in breast cancer mortality.[1]
Newer, less toxic therapeutic agents
such as trastuzumab (Herceptin), the
aromatase inhibitors anastrozole
(Arimidex) and letrozole (Femara),
and the selective estrogen downregulator
fulvestrant (Faslodex) have been
incorporated into the management of
advanced breast cancer. The success
of these drugs in prolonging the survival
of women with advanced disease
has prompted an evaluation of
their use in early breast cancer, and
they are likely to be incorporated into
adjuvant therapy as well.

In spite of these improvements in
therapy, the limitations of currently
available therapeutic approaches are
highlighted by the most recent 15-
year breast cancer survival rate of only
60%.[1] These data argue for the development
of innovative treatment
approaches that can circumvent the
intrinsic drug resistance that underlies
treatment failure.

Immunotherapy for
Cancer Treatment

Passive or active manipulation of
the immune system to effectively seek
out and destroy tumor cells offers one
approach for surmounting the therapeutic
obstacles of both inherent and
acquired drug resistance.[2] Passive
immunotherapies include both the
adoptive transfer of tumor-specific
cytotoxic T lymphocytes and the administration
of monoclonal antibodies
specific for a given tumor antigen.
These monoclonal antibodies can be
unmodified, or modified to deliver a
radioactive ligand or cellular toxin
specifically to tumor cells.

Active immunotherapies are characterized
either by the use of nonspecific
immunologic adjuvants such as
systemic cytokines or bacterial adjuvants
to alter the context in which
tumor cells are detected by the immune
system, or by specific immunization
with vaccines that direct
immune activation specific for the
delivered tumor antigen(s). Cancer
vaccines thus represent a novel therapeutic
modality that offers multiple
advantages over traditional chemotherapy,
hormone therapy, and passive
immunotherapy. These include
exquisite tumor specificity, minimal
toxicity, and a durable therapeutic effect
due to the phenomenon of immunologic
memory.

In this article, we present the rationale
and current data supporting the
use of immunotherapy in the management
of breast cancer. First, we
will review the immunologic mechanisms
that underlie the efficacy of
passive and active immunotherapies
for breast cancer treatment. Second,
we will summarize what is currently
known about breast tumor antigens.
Third, we will review the use of trastuzumab
as proof of principle for the
application of immunotherapy to
breast cancer treatment. Fourth, we
will review the breast cancer vaccine
platforms that are under active clinical
investigation, as well as the early
clinical trials that have been completed.
Finally, we will discuss the barriers
to breast cancer vaccine development
and describe various strategies for addressing
them.

Immunologic Priming
and Mechanisms of
Tumor Cell Destruction

The immune system comprises a
complex network of interacting cell
types that mediate adaptive, antigenspecific
immunity and innate, nonspecific
immunity. The hallmark of
the adaptive immune response is antigen-
specificity. This underlies both
the humoral immunity mediated by
B cells and the cellular immunity mediated
by CD4+ helper T cells and
CD8+ cytotoxic T cells. Both B and
T cells express a repertoire of specific
antigen receptors that is compre

hensive in scope, with the capacity
for recognizing over 1 million distinct
antigens.

B-Cell Immunity
The B-cell antigen receptor consists
of a surface-bound immunoglobulin
molecule that binds directly to
antigenic determinants on soluble proteins,
carbohydrates, or nucleic acids.
No specialized antigenic processing
is required prior to binding to the Bcell
receptor. After activation, B cells
differentiate into plasma cells, which
then secrete antigen-specific immunoglobulin
(Figure 1A).[3]

T-Cell Immunity
In contrast, antigen-specific T-cell
immunity is controlled by the recognition
of fragments of intact antigen
bound to major histocompatibility
complex (MHC) molecules. Antigen
processing for subsequent T-cell recognition
can occur through two distinct
pathways.[4] All nucleated cells
are able to present endogenous antigens
in the context of MHC class I.
Intracellular proteins undergo proteasome-
mediated degradation, and 8 to
12 amino acid peptide fragments are
transported into the endoplasmic reticulum
by the transporter associated with antigen processing. In the endoplasmic
reticulum, the peptide fragment
associates with MHC class I
molecules, and the complex is transported
to the cell surface.

Professional
Antigen-Presenting Cells

Professional antigen-presenting
cells (macrophages, B cells, and dendritic
cells) can present antigen in the
context of both MHC class I and
class II. In addition to being active in
the endogenous antigen-processing
pathway, they have the ability to take
up and process extracellular proteins

through the exogenous pathway. Exogenous
proteins are taken up by endocytosis
into acidic lysosomes, where
they are fragmented into peptides 10
to 25 amino acids long. These peptide
fragments then bind to MHC class II
and are transported to the cell surface.

Professional antigen-presenting
cells induce more potent immune responses
than other nucleated cells
largely by virtue of their ability to
activate CD4+ T cells to provide the
requisite help for the development
of potent, durable antigen-specific
CD8+ cytotoxic T-cell immunity
(Figure 2).[5] Thus, although CD8+
T cells ultimately are directly responsible
for tumor lysis,[6] the CD8+
T-cell response is attenuated at multiple
levels without the support of
CD4+ helper T cells.

Innate Immunity
The innate arm of the immune system
plays an important role in antitumor
immunity in several ways. First,
emerging data suggest that innate immunity
has evolved to provide a
unique mechanism for marking the
transformed cell as a danger to the
host. The expression of stress-induced,
MHC class I-like molecules (MICA,
MICB, and proteins of the ULBP family)
on the surface of tumor cells
"marks" them for recognition by natural
killer (NK) cells, gamma-delta-
T cells, and CD8+ T cells expressing
the NKG2D receptor (Figure 3). The
interaction of the NKG2D receptor
with these stress-induced ligands provides
critical accessory signals for restoring
the potency of cell-mediated
cytotoxicity.[7]

In addition, dendritic cells function
as a critical link between innate
and adaptive immunity. Immature
dendritic cells in the periphery function
as immunologic sentinels, detecting
pathogens by virtue of toll-like
receptors (TLR) that bind pathogenassociated
molecular patterns (PAMP)
not typically present in the host.[8]
The TLR-PAMP interaction induces
the maturation of dendritic cells, priming
them to activate antigen-specific
adaptive immunity.

Innate and adaptive immunity are
further linked by the recruitment of
innate immune effectors by the adaptive
immune response. Human antibodies
of the immunoglobulin (Ig)G1
and IgG3 isotypes direct the elimination
of tumor cells by antibodydependent
cellular cytotoxicity or
complement-mediated cytotoxicity
(Figures 1B and 1C).[9] Antibodydependent
cellular cytotoxicity occurs
when immune effector cells engage
an antibody-bound tumor cell via the
Fc-gamma receptor (particularly subtypes
I and III). The tumor cell is then
killed by phagocytosis or lysis, depending
on whether the effector cell
is a neutrophil, a macrophage, or an
NK cell.

The activation of complement by
antibody-bound tumor cells similarly
leads to tumor cell death by engaging
complement receptors (C1qR, CR1
[CD35], or CR3 [CD11b/CD18]) on
neutrophils, macrophages, or NK
cells. Alternatively, direct complement
activation leads to the ultimate
formation of the membrane attack
complex, and thus destruction of the
tumor cell membrane. Although efforts
to date have primarily focused
on manipulating adaptive immunity,
increasing evidence suggests that orchestrating
the efforts of innate and
adaptive immune effectors is likely to
result in the most potent immunemediated
tumor destruction.

Relevant Breast
Tumor Antigens

The development of either passive
immunotherapy or active vaccination
strategies for breast cancer treatment
will be greatly facilitated by identifying
relevant breast tumor antigens.
Numerous breast tumor antigens have
been identified based on the biology
of breast cancer, the identification of
proteins to which breast cancer
patients develop antibody or T-cell
responses, or the identification of immunologically
relevant antigens in
other diseases that are also expressed
in breast cancer. These include carcinoembryonic
antigen (CEA)[10];
Mucin-1 (MUC-1)[11]; p53[12]; sialyl-
Tn[13]; the melanoma associated
antigens MAGE,[14] BAGE,[15]
GAGE,[16] and XAGE[17]; and
HER2/neu.[18]

Of these antigens, HER2/neu has
emerged as an important therapeutic
target for biologic and immune-based
therapies. Interestingly, patients with
both early- and late-stage breast cancers
have low levels of preexisting
humoral and cellular responses to
HER2/neu.[18,19] These observations
suggest that, although patients can
mount a HER2/neu-specific immune
response to their tumor, the response
is inadequate to control or eradicate
the disease. Trastuzumab, a humanized
monoclonal antibody specific for
HER2/neu, can result in remissions in
breast cancer patients with disseminated
disease that is resistant to
other therapies.[20] Accordingly,
HER2/neu represents perhaps the first
validated target for the immunemediated
rejection of breast cancer.
Breast tumor antigens that have been
explored to date are summarized in
Table 1.[10-18,21-32]

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