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(Drug information on trastuzumab) (Herceptin), the aromatase inhibitors anastrozole(Drug information on anastrozole) (Arimidex) and letrozole(Drug information on 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]