As outlined in the review by Drs. Emens and Jaffee entitled "Toward a Breast Cancer Vaccine: Work in Progress," the development of anticancer vaccines has closely paralleled advances in the field of immunology. Basic immunology has provided and will continue to provide important insights into human immunity that directly relate to the design and study of immunotherapeutics. To date, the most important scientific observations applicable to immunotherapy include the following:
- Increased understanding of peptide presentation, major histocompatibility complex (MHC) binding, and recognition.
- The important role of CD4+ cells-not just CD8+ cytotoxic T cells-in generating effective immune responses.
- The vital functions of antigenpresenting cells and costimulatory molecules in the process of inducing immunity.
- The realization that tumor antigens nearly always represent selfantigens, and that many patients generate a detectable endogenous antitumor immune response.
Since most tumor-associated antigens represent aberrantly expressed or overexpressed self-antigens, induction of an effective antitumor immune response requires overcoming the normal mechanisms by which the body avoids autoimmunity. Tolerance can be broken when these self-antigens are processed, presented, and recognized as foreign, leading to the induction of antitumor effector elements. But the mere presence of antitumor T and B cells does not necessarily lead to tumor destruction-antitumor immunity needs to achieve sufficient magnitude and duration to result in cancer regression. The biologic activity of antigenspecific immune effectors can be detected and quantified using a number of analytic tools, including the enzyme-linked immunospot assay (ELISpot), intracellular cytokine staining, peptide:MHC tetramer analysis, cytotoxic T-lymphocyte (CTL) function and CTL precursor (CTLp) frequency studies. These powerful assays measure defined biomarkers that allow investigators to quantify immune responses to vaccine interventions. Data gathered from the measurement of immune biomarkers can be used to optimize antitumor immunotherapy. The best vaccine approaches, the most relevant antigenic targets for the immune system, and the optimal delivery system can thus be identified. Immune assays represent the most powerful method of systematically ascertaining the essential elements of protective immunity, and subsequently directing the development of more potent vaccines with which to target cancer. New Capabilities
With the availability of immunologic assays capable of measuring antitumor activity, investigators can now study the size, quality, and durability of immune responses capable of trafficking through the protective milieu of a cancer. In addition, characteristics of antitumor immunity can be compared to the vigorous protective responses that arise against immunogenic pathogens such as cytomegalovirus or Epstein-Barr virus. Since it is presumed that vaccine strategies will find their greatest efficacy in the treatment of patients with minimal tumor burden, immune assays can help to provide important biologic milestones before cancer vaccines are tested in large comparative clinical trials. This is particularly important for the development of vaccine immunotherapy for breast cancer. Because breast cancer often demonstrates prolonged onset and can exhibit an indolent course, evaluation of survival benefit after vaccination for minimal disease will require large numbers of patients and prolonged follow-up. Immunologic monitoring can permit investigators to quickly validate induced responses and allow scientists to prioritize their resources and research in the quest to achieve significant clinical outcomes. Remaining Barriers
Despite the conceptual promise that the development of immunotherapies will be hastened by assaying the biologic activity of vaccines, significant barriers still exist to the identification of a reliable surrogate biomarker for a clinically beneficial response. Immune monitoring assays clearly document the intrinsic variability of both endogenous and induced antigen-specific immune responses. As a result, the mere detection of an immune re- sponse at any given time may be understandably viewed with some skepticism, given the variations observed at time points before and after vaccination. The ability to induce and then sustain an antigen-specific response over time may represent a more important two-dimensional measure of immune recognition. Furthermore, correlation between immunologic end points and clinical responses-including the most important outcome of survival-remains elusive to date. Currently available immunologic monitoring techniques have provided an opportunity to improve our understanding of antitumor immunity. Nonetheless, the biologic inconsistencies observed in these assays, and perhaps in the body's own functional response to self-antigens, remain challenges for the use of immunotherapy to treat cancer. Future Directions
The development of vaccines with clinical efficacy against breast cancer and other malignancies will remain closely linked to the search for reliable biomarkers of antitumor immunity. Reliable standardized methods of assaying the biologic activity of vaccines can help to identify the optimal strategies that are ultimately tested in phase III clinical trials. The introduction of molecular and genetic screening techniques into the scientific armamentarium will likely lead to advancements in developing assays capable of defining significant biologic end points for cancer vaccines; genotypic and molecular profiling may also help to better define the subsets of heterogeneous cancer patients who would derive the most benefit from immune therapies. The ongoing progress seen in understanding, measuring, and manipulating the human immune system makes the development of a clinically effective cancer vaccine a realistic and exciting goal for the future.