Parts Of The Book

Part I of the book introduces principles of cancer immunobiology. In Chapter 2, the central concept of immunoediting is introduced. This fundamental process has three parts, termed immunosurveillance, immune equilibrium, and immune escape, which lead to control, stasis, or outgrowth of a malignancy. Immunoediting starts with the immune recognition and destruction of cells that have acquired genetic and epigenetic alterations characteristic of tumor cells, but at the same time, the selective pressure produced by immunoediting drives tumor evolution and progression. In this process, the cell-intrinsic traits of cancer (immortalization, growth deregulation, apoptotic resistance, and tumor suppressor inactivation) lead to the development of subclinical or occult lesions that are not clinically important until cell-extrinsic traits (invasion, angiogenesis, metastasis, and immune escape) have been achieved. The complex roles for inflammatory cells and altered immunity in the development of cell-extrinsic traits represent an increasingly important area for investigation. Chapter 3 discusses key aspects of immunosurveillance, including the generation of innate and adaptive immune responses to tumor cells. Chapter 4 examines cytokines that promote immune tolerance to tumors. Chapter 5 explains immune "sculpting" processes that occur in the tumor from the evolution of the battle between immune cells and tumor cells; this discussion focuses key roles played in the inflammatory tumor microenvironment by natural killer cells (NK cells). Chapter 6 discusses the emergence of the diverse immunosuppressive networks ultimately evolved by tumors that successfully escape immune control.

Part II provides an overview of accepted and experimental classes of cancer therapeutics that clinics use. Chapter 7 introduces standard cytotoxic chemotherapeutics, which along with radiotherapy continue to represent the major part of the armentar-ium used by clinical oncologists. Chapter 8 introduces the new classes of small molecule drugs termed molecular targeted therapeutics, many of which are still in clinical trials, that take advantage of the latest understanding in modern cancer genetics and cell biology. Chapter 9 offers an overview of cancer pharmacology and safety assessment for both "classical" types of cytotoxic drugs as well as modern molecular-targeted therapeutics, where the central goal is learning whether "hitting the target" in the tumor cell can be achieved in a relatively safe and effective manner. In Chapters 10-11, various active immuno-therapeutic approaches that are being tested clinically are summarized, and Chapter 11 also includes a special focus on various types of cancer vaccines.

Part III introduces a set of molecular targets and tactics that are hypothesized to improve cancer treatment by defeating immune suppression. In Chapters 12-13, a discussion of the rationale for interest in combining immunotherapy and cytotoxic chemotherapy is presented. Evidence that cytotoxic chemotherapy acts in part by stimulating immune activity has existed for some time, but this evidence is not widely known. Furthermore, while cancer pharmacology and cancer immunology are each very well-developed fields, there have been few efforts to investigate combinatorial regimens at either the preclinical or clinical level. These chapters highlight reasons why such investigations should be of interest to pursue. Chapters 14-17 provide an overview of several important cell-based mechanisms of immune suppression that appear to arise almost universally in cancer, including the production of inhibitory dendritic cells and coinhibitory molecules, T regulatory cells, tumor-associated macrophages, and suppressor myeloid cells. The importance of these mechanisms to tumor outgrowth is underscored by the fact that many tumors are actually composed of a large proportion if not a majority of these cell types, as compared to other tumor stromal cells or tumor cells themselves. Chapters 18-20 introduce three important molecular mechanisms of immune suppression in tumors, including those mediated by the cell surface molecules galectin-1 and programmed death ligand-1 (PDL-1), the cata-bolic enzymes indoleamine 2,3-dioxygenase (IDO) and arginase, and the vascular regulator inducible nitric oxide synthase (iNOS). Strategies for therapeutic inactivation of these mechanisms, which have been justified in preclinical models, are moving forward for evaluation in clinical trials.

Acknowledgments

Work in the authors' laboratories is supported by National Cancer Institute grants CA82222, CA100123, and CA109542 and the Lankenau Hospital Foundation (G.C.P.); by National Cancer Institute grants of the Specialized Program of Research Excellence in Gastrointestinal Cancer (CA62924) and Breast Cancer (CA88843); by the Avon Foundation for Breast Cancer Research and the National Cooperative Drug

Discovery Group (U19CA72108); and by generous donations from the Goodwin Family and The Sol Goldman Pancreatic Research Center (E.M.J.). Dr. Jaffee is the Dana and Albert "Cubby" Broccoli Professor of Oncology. G.C.P. would like to acknowledge contributions from long-term collaborator A.J. Muller toward development of the perspectives offered in this chapter. G.C.P. declares competing financial interests as a significant stockholder and scientific advisory member at New Link Genetics Corporation, a biotechnology company that has licensed intellectual property to develop inhibitors of the immune sup-pressive enzyme IDO for combinatorial cancer treatment, as described in patents WO 2004 093871 "Novel methods for the treatment of cancer" (pending) and WO 2004 094409 "Novel IDO inhibitors and methods of use" (pending).

References

Dunn, G. P., Old, L. J., and Schreiber, R. D. (2004). The three Es of cancer immunoediting. Ann. Rev. Immunol. 22, 329-360. Folberg, R., Hendrix, M. J., and Maniotis, A. J. (2000). Vasculogenic mimicry and tumor angiogenesis. Am. J. Pathol. 156, 361-381. Hanahan, D., and Weinberg, R. A. (2000). The hallmarks of cancer. Cell 100, 57-70.

Further Reading

Emens, L. A., and Jaffee, E. M. (2005). Leveraging the activity of tumor vaccines with cytotoxic chemotherapy. Cancer Res. 65, 8059-8064.

Muller, A. J., and Scherle, P. A. (2006). Targeting the mechanisms of tumoral immune tolerance with small-molecule inhibitors. Nature Rev. Cancer 6, 613-625.

Prendergast, G. C. (ed.) (2004). Molecular Cancer Therapeutics: Strategies for Drug Discovery and Development. Wiley-Liss: New York.

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