Gastrointestinal (GI) malignancies, which
include colorectal, pancreatic, gastric, esophageal, hepatocellular,
gallbladder, and small bowel cancers, are the leading cause of cancer
in the United States, accounting for approximately 18.5% of all new
cases, with an estimated incidence of 226,000 cases in 1999. As a
group, GI malignancies also are the number two cause of cancer death,
estimated to be responsible for approximately 131,000 deaths in 1999.
Despite recent advances in the understanding of GI cancer at the
molecular level, as well as improvements in adjuvant chemotherapy
and/or radiation therapy, disease stage remains the best predictor of
survival (Table 1). The highest
cure rate occurs when the tumor is locally confined and complete
surgical resection is possible. Unfortunately, only a minority of
cases are diagnosed early.[2-4]
Although adjuvant management of each GI malignancy is specific to
that tumor, adjuvant therapy for colon cancer serves as a useful
paradigm for GI malignancies as a group.[5,6] Colon cancer not only
represents the most common GI malignancy, as well as an extensively
characterized model of multistep carcinogenesis, but also shares
similar biology and gene mutations that could potentially be
exploited by improvements in both chemotherapy and radiation therapy,
as well as by emerging immunomodulating methods.
Approximately 50% to 70% of patients with colorectal carcinoma have
tumors that are potentially resectable at the time of diagnosis.
However, the overall survival rate of patients who undergo resection
(all stages) is on the order of 50%. For patients who present with
Dukes A or B1 disease, adjuvant chemotherapy is not
recommended, as the cure rate with surgery alone ranges from 85% to
90%. Adjuvant chemotherapy has had the most significant impact in
patients with Dukes C colon cancer (stage III disease), as has
been chronicled in a recent review. Despite this reason for
optimism, the opportunity exists to improve outcomes for patients
with all stages of colon cancer.
The immune system comprises a number of cell types, which, when
activated, are extremely efficient in recognizing and killing their
target. In particular, B and T cells each possess vast arrays of
clonally distributed antigen receptors that enable them to recognize
foreign antigens and to discriminate self from nonself. In fact, it
has been estimated that both B and T cells express receptors (through
recombination of the genes encoding for their receptors at the time
of maturation in the bone marrow and thymus, respectively) that
recognize more than 1 million different antigens. Therefore, the
immune system should be able to recognize the product of any new
genetic alteration within a developing tumor cell.
The B-cell receptor, which is a surface immunoglobulin that can bind
antigens on soluble molecules, recognizes free antigenic determinants (Figure
1). Therefore, special antigen processing is not required for
the binding of the B-cell receptor to its antigen.
In contrast, the T-cell receptor recognizes fragments of the
antigenic protein bound to major histocompatibility (MHC) class I and
II molecules on another cell. This peptideMHC protein complex
is formed as a result of fragmentation of intracellular proteins
within the cytoplasm of a cell and subsequent association with a
binding site on the MHC molecule (Figure
T-Cell Antigen Processing
Two forms of T-cell antigen processing exist. Professional
antigen-presenting cells (eg, macrophages, B cells, and dendritic
cells) have the ability to internalize extracellular proteins via
endocytosis and process them through the exogenous pathway. These
proteins are taken up into low-pH vesicles (lysosomal compartment),
where they undergo fragmentation. Peptide fragments (10 to 25 amino
acids in length) then bind to the MHC class II protein, prior to
expression of the complex on the cell surface. This complex is
recognized exclusively by CD4+ helper T-cells.
Most tumor cells cannot process and present antigen through the
exogenous pathway, as they usually do not derive from professional
antigen-presenting cells. However, all cells, including tumor cells,
can process and present antigens that derive from cellular proteins
through the endogenous pathway (Figure 2).
The cellular protein is degraded within the cytoplasm of the cell by
specialized machinery (the proteasome), and the peptide fragment is
subsequently transported into the endoplasmic reticulum via
transporter associated with antigen processing (TAP). Once in the
endoplasmic reticulum, the peptide fragment binds to the MHC class I
molecule before the complex reaches the cell surface. CD8+ T cells
exclusively recognize antigens in this way.
In general, CD4+ T-cells function in helper or regulatory capacities
in immune responses, while CD8+ cells function as cytotoxic T cells
and have the capacity to lyse their targets. Categories of candidate
antigens that are recognized by B and T cells are listed in Table
Immunotherapy is a novel therapeutic approach that can either: (1)
recruit and activate tumor-specific T cells, which, in turn, can
directly lyse a tumor cell; or (2) employ monoclonal antibodies that
target tumor-specific antigens. Monoclonal antibodies lyse the tumor
either directly or indirectly, via delivery of a cytotoxic agent.
Both approaches are attractive for several reasons[9,10]:
Immunotherapy, via either activation of tumor-specific T cells or use
of monoclonal antibodies, acts via a mechanism that is distinct from
the mechanisms of chemotherapy or radiation therapy. Thus,
immunotherapy represents a noncross-resistant treatment with an
entirely different spectrum of toxicities.
The immune system can recognize a broad diversity of potential
antigens while orchestrating selective, as well as specific,
cytotoxic responses. This feature may be essential in recognizing and
eliminating a heterogeneous tumor population while avoiding normal
Preclinical animal models using both forms of immunotherapy have been
able to eliminate small burdens of established tumorsa
situation that corresponds to the state of minimal residual disease
commonly found after resection of human tumors.[9-11]
Several clinical trials have already tested various monoclonal
antibodies for their ability to treat GI cancers.[11-15] However,
clinical testing of vaccines that induce T-cellmediated immune
responses has trailed behind. The results of preclinical studies
clearly show that T-cellmediated vaccine therapy can induce
antitumor immune responses that are potent enough to eradicate
colorectal tumors. Clinical studies are currently underway to
test these vaccines in patients with pancreatic and colorectal
carcinomas (see Figure 3).
Taken together, these studies provide evidence that specific immune
responses can be activated against GI cancers if the immune system is
sufficiently primed or if specific antibodies unique to tumor
antigens are identified.
Two Basic Approaches
Immunotherapy can be broadly divided into passive and active
therapeutic approaches (Table 3).
Passive immunotherapy mainly involves the use of unlabeled or labeled
monoclonal antibodies that are specifically raised against tumor
antigens. To date, antibodies have been the most successful form of
immunotherapy clinically. They are being used as diagnostic tools,
prognostic indicators, and for the treatment of cancer.
As shown in Figure 4, there are
three ways in which monoclonal antibodies can induce an antitumor
response. Advantages of monoclonal antibody therapy include specific
targeting of tumor cells while sparing normal tissue, relative ease
of administration, and low toxicity profile. The major disadvantages
include the absence of T-cell activation, which, therefore precludes, T-cellmediated
cytotoxic killing or the generation of memory immune responses.
Another potentially limiting factor relates to tumor heterogeneity.
Specifically, all tumor cells within a proliferating mass may not
express the antigen being targeted by the antibody.
Despite some disadvantages, it is encouraging to note that passively
administered monoclonal antibodies have already been shown to induce
significant clinical responses in several diseases, including
lymphoma and breast cancer. These studies and detailed discussions on
this topic have been published elsewhere. However, the results
provide an additional rationale for developing vaccine approaches
that can induce natural tumor-specific antibody responses in the patient.
Active immunotherapy is typically divided into nonspecific and
specific processes. Nonspecific therapy attempts to augment an immune
response without actually targeting a specific tumor antigen.
Examples include the use of bacillus Calmette-Guérin (BCG),
interleukin-2 (IL-2 [Proleukin], and levamisole (Ergamisol).
In contrast, specific therapy, which is also called vaccine therapy,
targets specific tumor antigens that can generate a specific B- or
T-cellmediated immune responses. Active specific therapy can
also generate a specific memory T-cell population to mount a response
to future tumor challenge. Furthermore, the induction of cellular
immune responses has the added benefit of allowing natural access to
the microenvironment of the tumor. Examples include vaccines that
target the different cellular proteins listed in
Table 2. This review will focus on current concepts in vaccine therapy.
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