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Understanding the response to immunotherapy in humans

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Abstract

Whether the efforts of the last decade aimed at the development of vaccines against tumor-specific antigens encountered success or failure is a matter of expectations. On the bright side, we could optimistically observe that anti-cancer-vaccines stand as an outstanding example of the successful implementation of modern biotechnology tools for the development of biologically sound therapeutics. In particular, vaccines against melanoma (the prototype model of tumor immunology in humans) can reproducibly induce cytotoxic T cell (CTL) responses exquisitely specific for cancer cells. This achievement trespasses the specificity of any other anti-cancer therapy. The skeptics, on the other end, might point out that immunization only rarely leads to cancer regression, labeling, therefore, this approach is ineffective. In our opinion this judgment stems from the naïve expectation that CTL induction is sufficient for an effective immune response. Here we propose that more needs to be understood about the mechanisms required for the induction of a therapeutically relevant immune response in humans. In particular, we will discuss the variables related to cancer heterogeneity, the weight of individual patients’ polymorphism(s), the role of the T cell activation and differentiation and, finally, the complex relationship between immune and cancer cells within the tumor microenvironment.

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References

  1. Appay V, Dunbar PR, Callan M, et al (2002) Memory CD8+ T cells vary in differentiation phenotype in different persistent virus infections. Nat Med 8:379

    Google Scholar 

  2. Appay V, Nixon DF, Donahoe SM, et al (2000) HIV-specific CD8(+) T cells produce antiviral cytokines but are impaired in cytolytic function. J Exp Med 192:63

    Google Scholar 

  3. Belli F, Testori A, Rivoltini L, et al (2002) Vaccination of metastatic melanoma patients with autologous tumor-derived heat shock protein gp96-peptide complexes: clinical and immunologic findings. J Clin Oncol 20:4169

    Google Scholar 

  4. Bettinotti M, Kim CJ, Lee K-H, et al (1998) Stringent allele/epitope requirements for MART-1/Melan A immunodominance: implications for peptide-based immunotherapy. J Immunol 161:877

    Google Scholar 

  5. Boon T, Cerottini J-C, Van den Eynde B, et al (1994) Tumor antigens recognized by T lymphocytes. Annu Rev Immunol 12:337

    Google Scholar 

  6. Boon T, Coulie PG, Van den Eynde B (1997) Tumor antigens recognized by T cells. Immunol Today 18:267

    Google Scholar 

  7. Champagne P, Ogg GS, King A, et al (2001) Skewed maturation of memory HIV-specific CD8 T lymphoctes. Nature 410:106

    Google Scholar 

  8. Colaco CALS (2004) Cancer immunotherapy: simply cell biology?. Trends Mol Med (in press)

  9. Cormier JN, Salgaller ML, Prevette T, et al (1997) Enhancement of cellular immunity in melanoma patients immunized with a peptide from MART-1/Melan A. Cancer J Sci Am 3:37

    Google Scholar 

  10. Cuenca A, Cheng F, Wang H, et al (2003) Extra-lymphatic solid tumor growth is not immunologically ignored and results in early induction of antigen-specific T-cell anergy: dominant role of cross-tolerance to tumor antigens. Cancer Res 63:9007

    Google Scholar 

  11. Curtsinger JM, Johnson CM, Mescher MF (2003) CD8 T cell clonal expansion and development of effector function require prolonged exposure to antigen, costimulation, and signal 3 cytokine. J Immunol 171:5165

    Google Scholar 

  12. Dunn GP, Bruce AT, Ikeda H, et al (2002) Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol 3:991

    Google Scholar 

  13. Fuchs EJ, Matzinger P (1996) Is cancer dangerous to the immune system? Semin Immunol 8:271

    Google Scholar 

  14. Hamann D, Baars PA, Rep MHG, et al (1997) Phenotype and functional separation of memory and effector human CD8+ T cells. J Exp Med 186:1407

    Google Scholar 

  15. Horig H, Kaufman HL (2003) Local delivery of poxvirus vaccines for melanoma. Semin Cancer Biol 13:417

    Google Scholar 

  16. Howell WM, Bateman AC, Turner SJ, et al (2002) Influence of vascular endothelial growth factor single nucleotide polymorphisms on tumour development in cutaneous malignant melanoma. Genes Immun 3:229

    Google Scholar 

  17. Howell WM, Calder PC, Grimble RF (2002) Gene polymorphisms, inflammatory diseases and cancer. Proc Nutr Soc 61:447

    Google Scholar 

  18. Hsueh EC, Morton DL (2003) Antigen-based immunotherapy of melanoma: Canvaxin therapeutic polyvalent cancer vaccine. Semin Cancer Biol 13:401

    Google Scholar 

  19. Jin P, Wang E (2003) Polymorphism in clinical immunology. From HLA typing to immunogenetic profiling. J Transl Med 1:8

    Google Scholar 

  20. Kaech SM, Hemby S, Kersh E, Ahmed R (2002) Molecular and functional profiling of memory CD8 T cell differentiation. Cell 111:837

    Google Scholar 

  21. Kammula US, Lee K-H, Riker A, et al (1999) Functional analysis of antigen-specific T lymphocytes by serial measurement of gene expression in peripheral blood mononuclear cells and tumor specimens. J Immunol 163:6867

    Google Scholar 

  22. Kast WM, Levitsky H, Marincola FM (2004) Synopsis of the 6th Walker’s Cay Colloquium on Cancer Vaccines and Immunotherapy. J Transl Med 2:20

    Google Scholar 

  23. Khong HT, Restifo NP (2002) Natural selection of tumor variants in the generation of “tumor escape” phenotypes. Nat Immunol 3:999

    Google Scholar 

  24. Kim CJ, Parkinson DR, Marincola FM (1997) Immunodominance across the HLA polymorphism: implications for cancer immunotherapy. J Immunother 21:1

    Google Scholar 

  25. Leach DR, Krummel MF, Allison JP (1996) Enhancement of antitumor immunity by CTLA-4 blockade. Science 2716:1734

    Google Scholar 

  26. Lee JE, Reveille JD, Ross MI, et al (1994) HLA-DQB1*0301 association with increased cutaneous melanoma risk. Int J Cancer 59:510

    Google Scholar 

  27. Lee K-H, Wang E, Nielsen M-B, et al (1999) Increased vaccine-specific T cell frequency after peptide-based vaccination correlates with increased susceptibility to in vitro stimulation but does not lead to tumor regression. J Immunol 163:6292

    Google Scholar 

  28. Lee PP, Yee C, Savage PA, et al (1999) Characterization of circulating T cells specific for tumor-associated antigens in melanoma patients. Nat Med 5:677

    Google Scholar 

  29. Lengauer C, Kinzler KW, Vogelstein B (1998) Genetic instabilities in human cancers. Nature 3962:643

    Google Scholar 

  30. Malyguine A, Strobl S, Shafer-Weaver K, et al (2004) A modified human ELISPOT assay to detect specific responses to primary tumor cell targets. J Transl Med 2:9

    Google Scholar 

  31. Mankoff SP, Brander C, Ferrone S, et al (2004) Lost in translation: obstacles to translational medicine. J Transl Med 2:14

    Google Scholar 

  32. Marincola FM (1994) Interleukin-2. Biol Ther Cancer Updates 4:1

  33. Marincola FM (2003) Translational medicine: a two way road. J Transl Med 1:1

    Google Scholar 

  34. Marincola FM. Ferrone S (2003) Immunotherapy of melanoma: the good news, the bad news and what to do next. Semin Cancer Biol 13:387

    Google Scholar 

  35. Marincola FM, Jaffe EM, Hicklin DJ, et al (2000) Escape of human solid tumors from T cell recognition: molecular mechanisms and functional significance. Adv Immunol 74:181

    Google Scholar 

  36. Marincola FM, Shamamian P, Rivoltini L, et al (1996) HLA associations in the anti-tumor response against malignant melanoma. J Immunother 18:242

    Google Scholar 

  37. Marincola FM, Wang E, Herlyn M, et al (2003) Tumors as elusive targets of T cell-directed immunotherapy. Trends Immunol 24:334

    Google Scholar 

  38. Matzinger P (2001) Danger model of immunity. Scand J Immunol 54:2

    Google Scholar 

  39. Migueles SA, Laborico AC, Shupert WL, et al (2002) HIV-specific CD8+ T cell proliferation is coupled to perforing expression and is maintained in nonprogressors. Nat Immunol 3:1061

    Google Scholar 

  40. Minev BR (2002) Melanoma vaccines. Semin Oncol 29:479

    Google Scholar 

  41. Mocellin S, Panelli MC, Wang E, et al (2002) The dual role of IL-10. Trends Immunol 24:36

    Google Scholar 

  42. Monsurrò V, Nagorsen D, Wang E, et al (2002) Functional heterogeneity of vaccine-induced CD8+ T cells. J Immunol 168:5933

    Google Scholar 

  43. Monsurrò V, Nielsen M-B, Perez-Diez A, et al (2001) Kinetics of TCR use in response to repeated epitope-specific immunization. J Immunol 166:5817

    Google Scholar 

  44. Monsurrò V, Wang E, Panelli MC, et al (2003) Active-specific immunization against cancer: is the problem at the receiving end? Semin Cancer Biol 13:473

    Google Scholar 

  45. Monsurrò V, Wang E, Yamano Y, et al (2004) Quiescent phenotype of tumor-specific CD8+ T cells following immunization. Blood (in press)

  46. Nagorsen D, Panelli M, Dudley ME, et al (2003) Biased epitope selection by recombinant vaccina-virus (rVV)-infected mature or immature dendritic cells. Gene Ther 10:1754

    Google Scholar 

  47. Neidhardt-Berard EM, Berard F, Banchereau J, et al (2004) Dendritic cells loaded with killed breast cancer cells induce differentiation of tumor-specific cytotoxic T lymphocytes. Breast Cancer Res 6:R322

    Google Scholar 

  48. Nemunaitis J, Sterman D, Jablons D, et al (2004) Granulocyte-macrophage colony-stimulating factor gene-modified autologous tumor vaccines in non-small-cell lung cancer. J Natl Cancer Inst 96:326

    Google Scholar 

  49. Nielsen M-B, Monsurrò V, Miguelse S, et al (2000) Status of activation of circulating vaccine-elicited CD8+ T cells. J Immunol 165:2287

    Google Scholar 

  50. Ochsenbein AF, Klenerman P, Karrer U, et al (1999) Immune surveillance against a solid tumor fails because of immunological ignorance. Proc Natl Acad Sci USA 96:2233

    Google Scholar 

  51. Ohnmacht GA, Wang E, Mocellin S, et al (2001) Short term kinetics of tumor antigen expression in response to vaccination. J Immunol 167:1809

    Google Scholar 

  52. Old LJ, Chen YT (1998) New paths in human cancer serology. J Exp.Med 187:1163

    Google Scholar 

  53. Paczesny S, Banchereau J, Wittkowski KM, et al (2004) Expansion of melanoma-specific cytolytic CD8+ T cell precursors in patients with metastatic melanoma vaccinated with CD34+ progenitor-derived dendritic cells. J Exp Med 199:1503

    Google Scholar 

  54. Paczesny S, Ueno H, Fay J, et al (2003) Dendritic cells as vectors for immunotherapy of cancer. Semin Cancer Biol 13:439

    Google Scholar 

  55. Panelli MC, Martin B, Nagorsen D, et al (2004) A genomic and proteomic-based hypothesis on the eclectic effects of systemic interleukin-2 admnistration in the context of melanoma-specific immunization. Cells Tissues Organs 177:124

    Google Scholar 

  56. Panelli MC, Riker A, Kammula US, et al (2000) Expansion of tumor/T cell pairs from fine needle aspirates (FNA) of melanoma metastases. J Immunol 164:495

    Google Scholar 

  57. Panelli MC, Wang E, Phan G, et al (2002) Genetic profiling of peripharal mononuclear cells and melanoma metastases in response to systemic interleukin-2 administration. Genome Biol 3:RESEARCH0035

    Google Scholar 

  58. Panelli MC, Wang E, Monsurro V, et al (2004) Overview of melanoma vaccines and promising approaches. Curr Oncol Rep 6:414

    Google Scholar 

  59. Panelli MC, White RL Jr, Foster M, et al (2004) Forecasting the cytokine storm following systemic interleukin-2 administration. J Transl Med 2:17

    Google Scholar 

  60. Parmiani G, Castelli C, Dalerba P, et al (2002) Cancer immunotherapy with peptide-based vaccines: what have we achieved? Where are we going?. J Natl Cancer Inst 94:805

    Google Scholar 

  61. Parmiani G, Castelli C, Rivoltini L, et al (2003) Immunotherapy of melanoma. Semin Cancer Biol 13:391

    Google Scholar 

  62. Perez-Diez A, Spiess PJ, Restifo NP, et al (2002) Intensity of the vaccine-elicited immune response determines tumor clearence. J Immunol 168:338

    Google Scholar 

  63. Phan GQ, Touloukian CE, Yang JC, et al (2003) Immunization of patients with metastatic melanoma using both class I- and class II-restricted peptides from melanoma-associated antigens. J Immunother 26:349

    Google Scholar 

  64. Pittet MJ, Speiser DE, Lienard D, et al (2001) Expansion and functional maturation of human tumor antigen-specific CD8+ T cells after vaccination with antigenic peptide. Clin Cancer Res 7:796s

    Google Scholar 

  65. Pittet MJ, Speiser DE, Valmori D, et al (2001) Ex vivo analysis of tumor antigen specific CD8+ T cell responses using MHC/peptide tetramers in cancer patients. Int Immunopharmacol 1:1235

    Google Scholar 

  66. Pittet MJ, Zippelius A, Speiser DE, et al (2001) Ex vivo IFN-γ secretion by circulating CD8 T lymphocytes: implications of a novel approach for T cell monitoring in infectious and malignant diseases. J Immunol 166:7634

    Google Scholar 

  67. Pockaj BA, Sherry RM, Wei JP, et al (1994) Localization of111indium-labeled tumor infiltrating lymphocytes to tumor in patients receiving adoptive immunotherapy. Augmentation with cyclophosphamide and correlation with response. Cancer 73:1731

    Google Scholar 

  68. Rivoltini L, Castelli C, Carrabba M, et al (2003) Human tumor-derived heat shock protein 96 mediates in vitro activation and in vivo expansion of melanoma- and colon carcinoma-specific T cells. J Immunol 171:3467

    Google Scholar 

  69. Rosenberg SA (1997) Cancer vaccines based on the identification of genes encoding cancer regression antigens. Immunol Today 18:175

    Google Scholar 

  70. Rosenberg SA, Lotze MT, Yang JC, et al (1989) Experience with the use of high-dose interleukin-2 in the treatment of 652 cancer patients. Ann Surg 210:474

    Google Scholar 

  71. Rosenberg SA, Yang JC, Schwartzentruber D, et al (1998) Immunologic and therapeutic evaluation of a synthetic tumor associated peptide vaccine for the treatment of patients with metastatic melanoma. Nat Med 4:321

    Google Scholar 

  72. Rubin JT, Adams SD, Simonis T, et al (1991) HLA polymorphism and response to IL-2 bases therapy in patients with melanoma. Abstracts of the Society for Biological Therapy 1991 Annual Meeting 1:18

    Google Scholar 

  73. Rubio V, Stuge TB, Singh N, et al (2003) Ex vivo identification, isolation and analysis of tumor-cytolytic T cells. Nat Med 9:1377

    Google Scholar 

  74. Salgia R, Lynch T, Skarin A, et al (2003) Vaccination with irradiated autologous tumor cells engineered to secrete granulocyte-macrophage colony-stimulating factor augments antitumor immunity in some patients with metastatic non-small-cell lung carcinoma. J Clin Oncol 21:624

    Google Scholar 

  75. Sallusto F, Lenig D, Forster R, et al (1999) Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature 4014:659

    Google Scholar 

  76. Scheibenbogen C, Letsch A, Schmittel A, et al (2003) Rational peptide-based tumor vaccine development and T cell monitoring. Semin Cancer Biol 13:423

    Google Scholar 

  77. Scheibenbogen C, Schmittel A, Keilholz U, et al (2000) Phase 2 trial of vaccination with tyrosinase peptides and granulocyte-macrophage colony-stimulating factor in patients with metastatic melanoma. J Immunother 23:275

    Google Scholar 

  78. Shafer-Weaver K, Sayers T, Strobl S, et al (2003) The Granzyme B ELISPOT assay: an alternative to the51Cr-release assay for monitoring cell-mediated cytotoxicity. J Transl Med 1:14

    Google Scholar 

  79. Sondak VK, Sosman J (2003) Results of clinical trials with an allogeneic melanoma tumor cell lysate vaccine: Melacine. Semin Cancer Biol 13:409

    Google Scholar 

  80. Speiser DE, Colonna M, Ayyoub M, et al (2001) The activatory receptor 2B4 is expressed in vivo by human CD8+ effector alpha beta T cells. J Immunol 167:6165

    Google Scholar 

  81. Speiser DE, Lienard D, Pittet MJ, et al (2002) In vivo activation of melanoma-specific CD8(+) T cells by endogenous tumor antigen and peptide vaccines. A comparison to virus-specific T cells. Eur J Immunol 32:731

    Google Scholar 

  82. Speiser DE, Pittet MJ, Rimoldi D, et al (2003) Evaluation of melanoma vaccines with molecularly defined antigens by ex vivo monitoring of tumor specific T cells. Semin Cancer Biol 13:461

    Google Scholar 

  83. Speiser DE, Pittet MJ, Rimoldi D, et al (2003) Evaluation of melanoma vaccines with molecularly defined antigens by ex vivo monitoring of tumor-specific T cells. Semin Cancer Biol 13:461

    Google Scholar 

  84. Talebi T, Weber JS (2003) Peptide vaccine trials for melanoma: preclinical background and clinical results. Sem Cancer Biol 13:431

    Google Scholar 

  85. Thor Straten P, Schrama DD, Andersen MH, et al (2004) T cell clonotypes in cancer. J Transl Med (in press)

  86. Thurner B, Haendle I, Roder C, et al (1999) Vaccination with MAGE-3A1 peptide-pulsed mature, monocyte-derived dendritic cells expands specific cytotoxic T cells and induces regression of some metastases in advanced stage IV melanoma. J Exp Med 190:1669

    Google Scholar 

  87. Tomaru U, Yamano Y, Nagai M, et al (2003) Detection of virus-specific T cells and CD8+ T-cell epitopes by acquisition of peptide-HLA-GFP complexes: analysis of T-cell phenotype and function in chronic viral infections. Nat Med 9:469

    Google Scholar 

  88. Van Baarle D, Kostense S, Oers MHJ van, et al (2002) Failing immune control as a result of impaired CD8+ T-cell maturation: CD27 might provide a clue. Trends Immunol 23:586

    Google Scholar 

  89. Vanderlugt CL, Miller SD (2002) Epitope spreading in immune-mediated diseases: implications for immunotherapy. Nat Rev Immunol 2:85

    Google Scholar 

  90. Wang E, Miller LD, Ohnmacht GA, et al (2002) Prospective molecular profiling of subcutaneous melanoma metastases suggests classifiers of immune responsiveness. Cancer Res 62:3581

    Google Scholar 

  91. Wang E, Adams S, Zhao Y, et al (2003) A strategy for detection of known and unknown SNP using a minimum number of oligonucleotides. J Transl Med 1:4

    Google Scholar 

  92. Wang E, Marincola FM (2000) A natural history of melanoma: serial gene expression analysis. Immunol Today 21:619

    Google Scholar 

  93. Wang E, Marincola FM, Stroncek D (2003) Human leukocyte antigen (HLA) and human neutrophil antigen (HNA) systems. In: Hoffman R, et al (eds) Hematology: Basic principles and practice, 4th edn. Elsevier Science, Philadelphia

  94. Wang E, Panelli MC, Monsurro V, et al (2004) Gene expression profiling of anticancer immune responses. Curr Opin Mol Ther 6:288

    Google Scholar 

  95. Wherry EJ, Teichgraber V, Becker TC, et al (2003) Lineage relationship and protective immunity of memory CD8 T cell subsets. Nat Immunol 4:225

    Google Scholar 

  96. Wolfel T, Klehmann E, Muller C, et al (1989) Lysis of human melanoma cells by autologous cytolytic T cell clones. Identification of human histocompatibility leukocyte antigen A2 as a restriction element for three different antigens. J Exp Med 170:797

    Google Scholar 

  97. Zea AH, Curti BD, Longo DL, et al (1995) Alterations in T cell receptor and signal transduction molecules in melanoma patients. Clin Cancer Res 1:1327

    Google Scholar 

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  1. Immunogenetics Section, Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, MD, 20892-1184, USA

    Ena Wang, Monica C. Panelli & Francesco M. Marincola

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  1. Ena Wang
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  2. Monica C. Panelli
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  3. Francesco M. Marincola
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Correspondence to Francesco M. Marincola.

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Wang, E., Panelli, M.C. & Marincola, F.M. Understanding the response to immunotherapy in humans. Springer Semin Immun 27, 105–117 (2005). https://doi.org/10.1007/s00281-004-0198-7

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