Cancer Immune Therapy Edited by G. Stuhler and P. Walden ...

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4.6 Concluding Remarks 4.6 Concluding Remarks Important progress in the systematic analysis of T cell-mediated immunity against human tumors has finally led to the identification of the targets involved. To date, well over 50 different tumor antigens have been defined at the molecular level. These include both MHC class I- and II-restricted epitopes that can be effectively mimicked by well-defined synthetic peptides. Although some of the antigenic peptides identified thus far represent mutated sequences that uniquely occur in individual tumors, the majority of antigenic peptides are in fact non-mutated self-antigens. Thus tumor immunity can be regarded more as a special case of autoimmune reaction. This fact has important implications. On one hand, interesting observations in some paraneoplastic syndromes would suggest that damage of normal tissue is mediated, at least in part, by T cells directed against antigens whose expression is shared by certain normal cell types and the target tumor cells [94]. It is also possible that the observed increased incidence of vitiligo in melanoma patients treated with high-dose IL-2 [95] reflects the destruction of melanocytes mediated by immunity triggered by the transformed melanocytes. On the other hand, effective antitumor immunity may be limited to variable extents by the processes of central and peripheral tolerance that are essential to avoid the potentially devastating effects of autoimmunity. The search for new tumor antigens continues. The initial studies which focused on CD8 T cell responses to melanoma have now been extended to many other types of tumors, and to the analysis of specific antibody and CD4 T cells responses. New technologies are constantly applied to this endeavor. Improved reverse immunology approaches for the accurate forecast of new T cell epitopes will be of special value to mine the human genome, soon to be completed and freely available in public databases. The main objective of these efforts is to identify good candidates for the design of cancer vaccines. The ideal candidates should be expressed in a wide variety of tumors and yet absent in normal tissues. They should be efficiently processed by both tumor and professional antigen presenting cells. They should also be strong immunogens, a quality that may critically depend on both their ability to stably bind to MHC molecules and the existence of minimal specific immune tolerance. It is likely that only few in a large palette of tumor antigens may meet these qualities. The molecular identification of Tcell-defined tumor antigens has ushered a new era in tumor immunology. It has provided targets for the design of specific cancer vaccines. Numerous phase I clinical trials of immunization have been completed recently with encouraging results and many more are underway. New adjuvants and antigen delivery systems are being developed. One of the most important advances is the ability to monitor antigen-specific T cells in cancer patients. Direct flow cytometry based assays such as tetramers and cytokine release assays allow the enumeration and functional characterization of single antigen-specific T cells directly ex vivo. Results from analyses based on these new tools provide convincing evidence for the existence of frequent natural immune responses against tumors in cancer patients. It is now clear that patients often mount immune responses against their tumors. These can be mediated by both CD8 and CD4 T cells, and target multiple antigens, 51
52 4 T Cells In Tumor Immunity restricted by several MHC alleles. In spite of these responses tumors progress and multiple mechanisms of escape from immune pressure have been identified. These are explained in another chapter of this book. Thus, the major challenge ahead for specific immunotherapy to achieve clinical benefit is to design intervention procedures allowing us to induce potent as well as sustained immune responses directed against multiple targets on the tumor. The hope is that these types of responses should cope with tumors and minimize the possibilities of escape. To accomplish these colossal tasks, a better understanding of the interplay of tumors and effector lymphocytes in the tumor environment is urgently needed. References 1 V. Shankaran, H. Ikeda, A. T. Bruce, J. M. White, P. E. Swanson, L. J. Old, R.D. Schreiber, Nature 2001; 410:1107. 2 N. J. London, S. M. Farmery, E. J. Will, A. M. Davison, J. P. Lodge, Lancet 1995; 346: 403. 3 M. Burnet, Prog Exp. Tumor Res 1970; 13:1. 4 S. Mukai, J. Kjaergaard, S. Shu, G. E. Plautz, Cancer Res 1999; 59: 5245. 5 G. Willimsky,T. Blankenstein, Cancer Res 2000; 60: 685. 6 A. K. House, A. G. Watt, Gut 1979; 20: 868. 7 C. M. Balch, L. B. Riley,Y. J. Bae, M. A. Salmeron, C. D. Platsoucas, A. von Eschenbach, K. Itoh, Arch Surg 1990; 125: 200. 8 K. M. Ropponen, M. J. Eskelinen, P. K. Lipponen, E. Alhava,V. M. Kosma, J Pathol 1997; 182: 318. 9 Y. Naito, K. Saito, K. Shiiba, A. Ohuchi, K. Saigenji, H. Nagura, H. Ohtani, Cancer Res 1998; 58: 3491. 10 C. G. Clemente, M. C. Mihm, Jr., R. Bufalino, S. Zurrida, P. Collini, N. Cascinelli, Cancer 1996; 77: 1303. 11 Y. Saiki, H. Ohtani,Y. Naito, M. Miyazawa, H. Nagura, Lab Invest 1996; 75: 67. 12 M. Ikeguchi, H. Saito, K. Katano, S. Tsujitani, M. Maeta, N. Kaibara, Oncology 1997; 54: 311. 13 Y. Ma, M. Xian, J. Li,T. Kawabata, S. Okada, Apmis 1999; 107: 514. 14 Y.Ohashi,S.Ishibashi,T.Suzuki, R. Shineha,T. Moriya, S. Satomi, H. Sasano, Anticancer Res 2000; 20: 3025. 15 S. B. Hosch, J. R. Izbicki, U. Pichlmeier, N. Stoecklein, A. Niendorf, W. T. Knoefel, C. E. Broelsch, K. Pantel, Int J Cancer 1997; 74: 582. 16 K. Schumacher,W. Haensch, C. Roefzaad, P. M. Schlag, Cancer Res 2001; 61: 3932. 17 P. J. Spiess, J. C. Yang, S. A. Rosenberg, J Natl Cancer Inst 1987; 79: 1067. 18 S. A. Rosenberg, P. Aebersold, K. Cornetta, A. Kasid, R. A. Morgan, R. Moen, E. M. Karson, M. T. Lotze, J. C. Yang, S. L. Topalian, et al., N Engl J Med 1990; 323: 570. 19 B. Fisher, B. S. Packard, E. J. Read, J. A. Carrasquillo, C. S. Carter, S. L. Topalian, J. C. Yang, P. Yolles, S. M. Larson, S. A. Rosenberg, J Clin Oncol 1989; 7: 250. 20 A. Knuth, B. Danowski, H. F. Oettgen, L. J. Old, Proc Natl Acad Sci USA 1984; 81: 3511. 21 R. Ueda, H. Shiku, M. Pfreundschuh,T. Takahashi, L. T. Li, W. F. Whitmore, H. F. Oettgen, L. J. Old, J Exp Med 1979; 150: 564. 22 F. Bouet-Toussaint, N. Genetel, N. Rioux-Leclercq, J. Y. Bansard, J. Leveque, F. Guille, J. J. Patard, T. Lesimple,V. Catros-Quemener, Eur Cytokine Netw 2000; 11: 217. 23 R. O. Dillman, L. D. Beutel, A. N. Cornforth, S. K. Nayak, Cancer Biother Radiopharm 2000; 15: 161. 24 J. R. Yannelli, C. Hyatt, S. McConnell, K. Hines, L. Jacknin, L. Parker, M. Sanders, S. A. Rosenberg, Int J Cancer 1996; 65: 413.
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Cancer Immune Therapie: Current and
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Editors: Dr. Gernot Stuhler Univers
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VI Preface Recent years have seen a
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VIII Contents 2.5.3 Antigens Encode
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X Contents 6.4.2 Natural Killer (NK
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XII Contents 9.6 Loading DC with An
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XIV Contents 14.2.2.1 Cancer-specif
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List of Contributors Richard Bucala
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Color Plates Fig. 5.2 The MHC class
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Fig. 5.5 Different immune effector
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Fig. 5.17 Possible pathway for the
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Fig. 6.2 T lymphocytes in the tumor
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Index a acidic and basic fibroblast
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±, see also tumors cationic lipids
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e EBV see Epstein-Barr virus EDR se
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immature Mo-DCs 184 immune cells ±
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MHC class I antigen-processing mach
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±, onco- 209 ±, over-expressed ce
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Page 39 and 40: Part 1 Tumor Antigenicity Cancer Im
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Page 69 and 70: 32 3 Processing and Presentation of
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Page 79 and 80: 42 4 T Cells In Tumor Immunity cult
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Page 85 and 86: 48 4 T Cells In Tumor Immunity Alth
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Page 91 and 92: 54 4 T Cells In Tumor Immunity 53 T
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104 6 Immune Cells in the Tumor Mic
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Tab. 7.1 Effects of tumor-derived m
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122 7 Immunosuppresive Factors in C
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156 8 Interleukin-10 in Cancer Immu
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Part 3 Strategies for Cancer Immuno
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180 9 Dendritic Cells and Cancer: P
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204 Cancer Immune Therapie: Current
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206 10 The Immune System in Cancer:
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232 11 Hybrid Cell Vaccination for
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254 12 Principles and Strategies Em
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270 13 Applications of CpG Motifs f
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288 14 The T-Body Approach: Towards
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300 15 Bone Marrow Transplantation
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312 16 Immunocytokines: Versatile M
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348 17 Immunotoxins and Recombinant
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382 Glossary tion to the variable d
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384 Glossary suppressor gene produc
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386 Glossary press the proper recep
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388 Glossary gp96 See Chaperone. Gr
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390 Glossary cytes and addressing l
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392 Glossary T bodies are being tes
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