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 2).
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 2.
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 tissue toxicity.
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(Drug information on 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.