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The concept of anti-tumor immunity is over a century old while our general understanding of MHC class I- and class II-restricted antigen processing and presentation is much younger. As the new principles have been applied to the old problem, a measure of progress can be appreciated. However, many important details of processing and presentation remain unknown, and the technologies for identifying and exploiting viable T cell targets on an individualized basis are truly in their infancies and limited by the lack of basic knowledge. Therefore, we are far from having enough information to determine whether or not immunotherapy will be a standard approach to cancer. Based upon the rate of recent progress, the upcoming years should provide many opportunities for applying new concepts in antigen processing and presentation to experimental models and, ultimately, patients.

Despite the wealth of information that has been acquired regarding the way T cells recognize their targets, we are left with far more questions than answers regarding how to manipulate the immune response to better treat cancer patients. Clearly, most patients have a broad repertoire of T cells capable of recognizing their tumor cells. Despite the presence of these tumor reactive T cells and our ability to increase their frequency though vaccination or adoptive transfer, patients still progress. From the T cell side, defects in T cell signaling may account for much of our failure to achieve significant numbers of objective clinical responses. In spite of these negatives, the horizon does remain bright for T cell based immune therapy of cancer. The periodic objective clinical response tells us that immune therapy can work. Now that we know that cancer patients have the capacity to mount immune responses against their tumors, current and future investigations with agents which alter T cell function combined with vaccination or adoptive T cell transfer may help tip the balance towards effective immune therapies.

The results from in vitro immunological experiments, murine tumor models and patients with cancer clearly demonstrate that tumors have multiple mechanisms to evade the immune response. During the early stages of tumor development malignant cells can be poor stimulators, present poor targets or become resistant to the innate immune response, while at later stages, progressively growing tumors impair the adaptive immune response by blocking the maturation and function of antigen presenting cells and causing alterations in T cell signal transduction and function. Preliminary results also suggest a correlation between some of these changes and an increased metastatic potential of the tumor cells, a diminished response to immunotherapy, and poor prognosis. Carefully coordinated basic research studies and clinical immunotherapy trials will be required to fully determine the impact on the outcome of the disease and the response to treatment. However, understanding the mechanisms used by tumor cells to evade the immune system could result in new therapeutic approaches for preventing and/or reversing these immune alterations and have the potential of improving the current results of immunotherapy trials.

Much recent progress has been made in the identification of new tumor antigens and their epitopes that may serve as potential cancer vaccines. Many of these have been studied as synthetic peptide vaccines corresponding to epitopes identified as presented by particular common human class I HLA molecules, especially HLAA2.1, the most common human class I molecule. Although a number of strategies for immunization against cancer have been investigated, no strategy targeting a specific antigen has yet proven consistently more clinically effective than synthetic peptides. Peptides have the advantage that they can be easily modified by epitope enhancement to improve binding to the MHC molecule or the T cell receptor, and they can be combined with cytokines, chemokines, and costimulatory molecules to increase vaccine potency and steer the responses toward a desired phenotype, such as CTL or Th1 cells. Peptides can also be coated onto dendritic cells, the ultimate professional antigen presenting cell, to bypass any defect in antigen-presenting cell function or maturation related to the presence of the cancer. Thus, as both research tools and as potential clinical vaccines, synthetic peptides remain at the forefront of research in the vaccine immunotherapy of cancer.

Our knowledge of the immune system and how it interacts with tumor cells continues to grow. With each advance in basic science comes a new opportunity to develop an effective treatment strategy. Many such opportunities have arisen in the past few decades and this chapter has attempted to describe how these new advances have been combined with a variety of undefined cellular antigen preparations in an attempt to develop effective cancer vaccines. None of the strategies described in this chapter have been sufficiently effective to become part of standard therapy. However, the approaches tested have generally been well-tolerated by patients with advanced cancer and the evidence of immunologic activity and examples of impressive clinical activity in a wide variety of malignancies, suggests that these strategies can be the building blocks upon which new advances are added and effective treatments developed.

Improvements in our understanding of tumor immunology have facilitated significant progress in the development of cancer vaccines. Early clinical trials have generated evidence for the safety of tumor vaccines, and have provided a suggestion of clinically significant bioactivity. They have also highlighted the challenges of cancer vaccine development. These include developing strategies for overcoming immune tolerance, and approaches for identifying the most active tumor rejection antigens for cancer vaccine formulation. Furthermore, these early studies highlight the importance of identifying important pharmacodynamic interactions between standard cancer treatment modalities and tumor vaccines. Surgical debulking is one approach for minimizing the impact of tumor burden, and patients with minimal residual disease are likely to be the most ideal candidates for vaccine therapy. The impact of chemotherapy on vaccine activity is a developing area of clinical research, with regard to both its positive and negative impact on the development of antigenspecific immunity. The impact of ionizing radiation on the immune response to cancer vaccines is an underdeveloped area that also warrants further investigation. Finally, the advent of biologically targeted therapies such as the monoclonal antibodies Trastuzumab and Rituximab offer new opportunities for combining cancer vaccines with novel drugs in combinatorial treatment strategies with the potential for significant synergism. It is clear that the careful preclinical and clinical investigation of these issues will guide the most effective clinical testing of cancer vaccines, and facilitate their ultimate incorporation into standard clinical practice.