Cancer is a major cause of morbidity and mortality worldwide. Over 10 million new cancer diagnoses and 7 million cancer-related deaths occurred in the year 2000 [1
]. Moreover, the global incidence of cancer is expected to increase, with up to 15 million new cases and 12 million deaths expected in the year 2020 [2
]. Factors impacting cancer incidence and prevalence include the demographic shift in the population toward older ages, improvements in screening and diagnosis, the use of tobacco and other substances, infectious agents, and the adoption of the Western lifestyle by developing nations [3
]. Concerted efforts to optimize the use of surgery, radiation, chemotherapy, and endocrine manipulation have resulted in substantial improvements in the morbidity and mortality associated with cancer in Western societies, but developing countries have more limited access to optimized cancer therapies. Furthermore, additional improvements in clinical outcomes with these therapies are unlikely due to mechanisms of therapeutic resistance that are fundamental to the transformed tumor cell. The limited access to healthcare endemic to developing countries, together with the barrier of drug resistance limiting progress in Westernized societies, argues for a radically different approach to cancer therapy and prevention.
Using cancer vaccines to harness the power of the cancer patient's own immune system is a highly attractive and innovative approach to cancer management. The use of immunization to prevent acute infectious diseases is one of the great achievements of modern medicine. Prophylactic vaccines have essentially eradicated smallpox and polio, and have dramatically decreased the morbidity and mortality associated with multiple other infectious diseases. Notably, a number of malignancies are associated with infectious diseases (), with infections accounting for the development of almost 25% of cancers in developing countries and up to 10% of cancers in developed countries [4
]. Notably, tumors involving the cervix, stomach, and liver account for the highest incidence and mortality of cancers with infectious etiologies [6
Infections associated with cancer development
Although vaccines have been quite successful for preventing infectious disease, therapeutic immunization in the setting of established, chronic disease, including both chronic infections and cancer, has been much less successful. This difference is related to multiple factors. First, the immune response to acute and chronic disease is quite different. Humoral immunity (the antibody response) is essential for controlling and eradicating acute infections, whereas cellular immunity (the T-cell response) is responsible for eradicating established cancers and chronically infected host cells. Second, the immune system recognizes acute infections as foreign in an environment with limited immunoregulatory pathways to limit the response. In contrast, it recognizes chronically infected or transformed cells in the context of established immunoregulatory pathways that maintain a parasitic relationship between the affected cell and the host. Third, the burden of infected or transformed host cells frequently exceeds the extent of the immune response, thereby limiting the clinical impact of immunization for significant burdens of established, chronic disease. A final challenge for the development of both prophylactic and therapeutic cancer vaccines is that, in contrast to infectious disease, the pivotal antigens that serve as targets for the immune response to neoplasms remain largely unknown.
Attempts to manipulate the immune system for cancer therapy date back to 1893, when William Coley reported the regression of soft-tissue sarcomas in patients with acute bacterial infections. Based on this observation, he tested the intravenous administration of bacterial extracts to stimulate tumor-specific immune responses [7
]. Although there was evidence of tumor regression, this nonspecific activation of the immune response was associated with serious side effects. Recent progress in our understanding of the molecular and cellular basis of immunity has greatly facilitated the growth of immunotherapy. The mechanisms by which the immune response is initiated and controlled are known in substantial detail. As a result, the field is poised to become a major modality of cancer care.
It is now clear that, in the presence of a pro-inflammatory or danger signal, activated professional antigen-presenting cells (APC) initiate CD4+
T-cell responses by capturing, endocytosing, and processing tumor antigens released by tumor cells. These antigens are processed by the endosome into MHC Class II-binding peptides of 12 – 20 amino acids, and by the proteosome into MHC Class I-binding peptides of 8 – 10 amino acids [8
]. The transporter of antigen processing (TAP) transfers the MHC Class I peptide epitopes to the endoplasmic reticulum, where they associate with MHC Class I molecules and are translocated to the cell surface. Professional APC simultaneously present tumor antigens to both CD4+
T cells in the context of MHC Class II and MHC Class I, respectively, effectively cross-priming the antigen-specific immune response [9
]. Activated CD4+
T cells initiate and amplify the CD8+
T-cell response directly by providing co-stimulatory cytokines, and indirectly by upregulating a number of co-stimulatory molecules on the APC that provide accessory signals for T-cell activation. Activated CD8+
T cells then acquire the potential to migrate to tumor sites and lyse tumor cells [10
]. Alternatively, transformed tumor cells may present tumor antigens directly to CD8+
T cells, resulting in tumor-specific immunity. Notably, in a quiescent environment devoid of an inflammatory or danger signal, critical co-stimulatory molecules are not upregulated on either the APC or the tumor cell, resulting in downregulation of the tumor-specific T-cell response [11
]. The context in which a tumor antigen is detected by the immune system at the time of immune priming and activation thus has profound implications for nature of the ensuing response, and thus the clinical development of vaccine-based strategies for cancer treatment and prevention.
The success of immunization in infectious diseases suggests that the identification of pivotal antigens for immune-mediated tumor rejection will facilitate the development of highly targeted and effective tumor vaccines for cancer management. The suitability of a candidate antigenic target for cancer immunotherapy is determined by multiple factors: its tissue expression profile; the diversity, scope, and avidity of the antigen-specific T cell repertoire; the presence or absence of pre-existing immune tolerance; and the commonality of the tumor antigen between patients and diverse tumor types [12
]. Given the clear importance of T cells in the antitumor immune response, tumor antigen identification efforts have historically focused on T cell targets. However, increasing evidence suggests that B cell-mediated immunity (in addition to other components of the immune system) may be important for tumor rejection [13
]. Thus, antigen discovery efforts have shifted toward the identification of antigens that elicit both B cell and T cell immunity. The distinct types of tumor antigens are summarized in .
Distinct vaccine platforms incorporate tumor antigens in different ways to activate tumor immunity. Vaccines can be highly targeted, such as peptide-based vaccines, or less well-defined, such as whole tumor cells or tumor cell lysates. In general, vaccine platforms are designed to specifically manipulate B cells, T cells, or professional APC [15
]. Humoral immunity can be activated by vaccinating with carbohydrate antigens delivered by whole tumor cells or as conjugates with proteins such as keyhole limpet hemocyanin (KLH). T-cell immunity can be induced directly by the vaccine, either by genetically modifying tumor cells themselves to express co-stimulatory molecules for direct antigen presentation, or by modifying professional APC to express tumor antigens by gene transfer or direct antigen loading. T cells can also be activated indirectly by the sustained local delivery of cytokines to recruit professional APC to the site of antigen deposition in vivo
. The systematic screen of a panel of cytokines in murine models identified the cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) as the most potent in inducing antitumor immunity [16
]. GM-CSF-secreting tumor vaccines have been tested in numerous Phase I and II clinical trials in patients with melanoma, renal cell carcinoma, prostate cancer, pancreatic cancer, and breast cancer. These trials have demonstrated the safety and bioactivity of this approach, and have suggested the potential for clinical benefit. Phase III clinical trials of this vaccination strategy are currently underway in prostate cancer.