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Identification of Human Tumor Antigens Recognized by T-Cells and Their Use for Immunotherapy

  • Progress in Hematology
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Abstract

Identification of human tumor antigens led to development of new immunotherapies for patients with cancer. Identification of T-cell epitopes allowed us to monitor antitumor T-cell responses quantitatively and qualitatively during immunotherapy as well as to develop more efficient immunotherapies with sufficient amounts of antigens in more immunogenic forms. Various immunotherapies, passive immunotherapies, including adoptive transfer of tumor reactive T-cells or allo-geneic antigen-specific donor T-cells, and active immunization with identified tumor antigens or dendritic cells pulsed with tumor antigens are being evaluated in clinical trials. Although tumor regression has been observed in some patients, further improvement is required.

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References

  1. Wang R, Wang X, Johnston S, Zeng G, Robbins P, Rosenberg S. Development of a retrovirus-based complementary DNA expression system for the cloning of tumor antigens.Cancer Res. 1998;58: 3519–3525.

    PubMed  CAS  Google Scholar 

  2. Wang RF, Wang X, Atwood AC, Topalian SL, Rosenberg SA. Cloning genes encoding MHC class II-restricted antigens: mutated CDC27 as a tumor antigen.Science. 1999;284:1351–1354.

    Article  PubMed  CAS  Google Scholar 

  3. denHaan JMM, Meadows LM, Wang W, et al. The minor histo- compatibility antigen HA-1: a diallelic gene with a single amino acid polymorphism.Science. 1998;279:1054–1057.

    Article  CAS  Google Scholar 

  4. Touloukian CE, Leitner WW, Topalian SL, et al. Identification of a MHC class II-restricted human gp100 epitope using DR4-IE transgenic mice.J Immunol. 2000;164:3535–3542.

    Article  PubMed  CAS  Google Scholar 

  5. Jager E, Nagata Y, Gnjatic S, et al. Monitoring CD8 T cell responses to NY-ESO-1: correlation of humoral and cellular immune responses.Proc Natl Acad Sci USA. 2000;97:4760–4765.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  6. Kawakami Y, Suzuki Y, Shofuda T, et al. T cell immune responses against melanoma and melanocytes in cancer and autoimmunity.Pigment Cell Res. 2000;13:163–169.

    Article  PubMed  Google Scholar 

  7. Brinkmann U, Vasmatzis G, Lee B, Pastan I. Novel genes in the PAGE and GAGE family of tumor antigens found by homology walking in the dbEST database.Cancer Res. 1999;59:1445–1448.

    PubMed  CAS  Google Scholar 

  8. Romero, Cerottini JC, Waanders GA. Novel methods to monitor antigen-specific cytotoxic T-cell responses in cancer immunother- apy.Mol Med Today. 1998;4:305–312.

    Article  PubMed  CAS  Google Scholar 

  9. Lee PP, Yee C, Savage PA, et al. Characterization of circulating T cells specific for tumor-associated antigens in melanoma patients.Nat Med. 1999;5:677–685.

    Article  PubMed  CAS  Google Scholar 

  10. Rosenberg S, Yang J, Schwartzentruber D, et al. Impact of cytokine administration on the generation of antitumor reactivity in patients with metastatic melanoma receiving a peptide vaccine.J Immunol. 1999;163:1690–1695.

    PubMed  CAS  Google Scholar 

  11. Panelli MC, Riker A, Kammula U, et al. Expansion of tumor-T cell pairs from fine needle aspirates of melanoma metastases.J Immunol. 2000;164:495–504.

    Article  PubMed  CAS  Google Scholar 

  12. Parkhurst MR, Salgaller M, Southwood S, et al. Improved induction of melanoma reactive CTL with peptides from the melanoma antigen gp100 modified at HLA-A0201 binding residues.J Immunol. 1996;157:2539–2548.

    PubMed  CAS  Google Scholar 

  13. Tsuboi A, Oka Y, Udaka K, et al. Enhanced induction of human WT1-specific cytotoxic T lymphocytes with a 9-mer WT1 peptide modified at HLA-A*2402-binding residues.Cancer Immunol Immunother. 2002;51:614–620.

    Article  PubMed  CAS  Google Scholar 

  14. Fong L, Hou Y, Rivas A, et al. Altered peptide ligand vaccination with Flt3 ligand expanded dendritic cells for tumor immunotherapy.Proc Natl Acad Sci USA. 2001;98:8809–8814.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  15. Robbins PF, El-Gamil M, Li YF, et al. A mutated ß-catenin gene encodes a melanoma-specific antigen recognized by tumor infiltrating lymphocytes.J Exp Med. 1996;183:1185–1192.

    Article  PubMed  CAS  Google Scholar 

  16. Rubinfeld B, Robbins P, El-Gamil M, Albert I, Prfiri E, PolakisP. Stabilization of beta-catenin by genetic defects in melanoma cell lines.Science. 1997;275:1790–1792.

    Article  PubMed  CAS  Google Scholar 

  17. Wolfel T, Hauer M, Schneider J, et al. A p16INK4a-insensitive CDK4 mutant targeted by cytolytic T lymphocytes in a human melanoma.Science. 1995;269:1281–1284.

    Article  PubMed  CAS  Google Scholar 

  18. Baurain JF, Colau D, vanBaren N, et al. High frequency of auto-logous anti-melanoma CTL directed against an antigen generated by a point mutation in a new helicase gene.J Immunol. 2000;164: 6057–6066.

    Article  PubMed  CAS  Google Scholar 

  19. Yotnda P, Firat H, Garcia-Pons F, et al. Cytotoxic T cell response against the chimeric p210 BCR-ABL protein in patients with chronic myelogenous leukemia.J Clin Invest. 1998;101:2290–2296.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Yotnda P, Garcia F, Peuchmaur M, et al. Cytotoxic T cell response against the chimeric ETV6-AML1 protein in childhood acute lymphoblastic leukemia.J Clin Invest. 1998;102:455–462.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Yun C, Senju S, Fujita H, et al. Augmentation of immune response by altered peptide ligands of the antigenic peptide in a human CD4+ T-cell clone reacting to TEL/AML1 fusion protein.Tissue Antigens. 1999;54:153–161.

    Article  PubMed  CAS  Google Scholar 

  22. Yasukawa M, Ohminami H, Kaneko S, et al. CD4(+) cytotoxic T-cell clones specific for bcr-abl b3a2 fusion peptide augment colony formation by chronic myelogenous leukemia cells in a b3a2-specific and HLA-DR-restricted manner.Blood. 1998;92:3355–3361.

    PubMed  CAS  Google Scholar 

  23. D’Souza S, Rimoldi D, Lienard D, Lejeune F, Cerottini J, Romero P. Circulating melan-A/MART-1 specific cytolytic T lymphocyte precursors in HLA-A2(+)melanoma patients have a memory phenotype.Int J Cancer. 1998;78:699–706.

    Article  PubMed  Google Scholar 

  24. Dunbar PR, Smith CL, Chao D, et al. A shift in the phenotype of melan-A-specific CTL identifies melanoma patients with an active tumor-specific immune response.J Immunol. 2000;165:6644–6652.

    Article  PubMed  CAS  Google Scholar 

  25. Kawakami Y, Eliyahu S, Jennings C, et al. Recognition of multiple epitopes in the human melanoma antigen gp100 associated with in vivo tumor regression.J Immunol. 1995;154:3961–3968.

    PubMed  CAS  Google Scholar 

  26. Jager E, Ringhoffer M, Karbach J, Arand M, Oesch F, Knuth A. Inverse relationship of melanocyte differentiation antigen expression in melanoma tissues and CD8+ cytotoxic-T-cell responses: evidence for immunoselection of antigen-loss variants in vivo.Int J Cancer. 1996;66:470–476.

    Article  PubMed  CAS  Google Scholar 

  27. Rosenberg S, Yang J, Schwartzentruber D, et al. Immunologic and therapeutic evaluation of a synthetic peptide vaccine for the treatment of patients with metastatic melanoma.Nat Med. 1998;4: 321–327.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Dudley ME, Wunderlich JR, Robbins PF, et al. Cancer regression and autoimmunity in patients after clonal repopulation with anti-tumor lymphocytes.Science. 2002;298:850–854.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Yee C, Thompson JA, Roche P, et al. Melanocyte destruction after antigen-specific immunotherapy of melanoma: direct evidence of T cell-mediated vitiligo.J Exp Med. 2000;192:1637–1644.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Lally KM, Mocellin S, Ohnmacht GA, et al. Unmasking cryptic epitopes after loss of immunodominant tumor antigen expression through epitope spreading.IntJ Cancer. 2001;93:841–847.

    Article  CAS  Google Scholar 

  31. Murphy GP, Tjoa BA, Simmons SJ, et al. Phase II prostate cancer vaccine trial: report of a study involving 37 patients with disease recurrence following primary treatment.Prostate. 1999;39:54–59.

    Article  PubMed  CAS  Google Scholar 

  32. Murphy GP,Tjoa BA, Simmons SJ, et al. Infusion of dendritic cells pulsed with HLA-A2-specific prostate-specific membrane antigen peptides: a phase II prostate cancer vaccine trial involving patients with hormone-refractory metastatic disease.Prostate. 1999;38: 73–78.

    Article  PubMed  CAS  Google Scholar 

  33. Molldrem JJ, Clave E, Jiang YZ, et al. Cytotoxic T lymphocytes specific for a nonpolymorphic proteinase 3 peptide preferentially inhibit chronic myeloid leukemia colony-forming units.Blood. 1997;90:2529–2534.

    PubMed  CAS  Google Scholar 

  34. Molldrem JJ, Lee PP, Wang C, et al. Evidence that specific T lymphocytes may participate in the elimination of chronic myelogenous leukemia.Nat Med. 2000;6:1018–1023.

    Article  PubMed  CAS  Google Scholar 

  35. Cormier J, Hijazi Y, Abati A, et al. Heterogeneous expression of melanoma-associated antigens and HLA-A2 in metastatic melanoma in vivo.Int J Cancer. 1998;75:517–524.

    Article  PubMed  CAS  Google Scholar 

  36. Marchand M, Baren N, Weynants P,et al. Tumor regressions observed in patients with metastatic melanoma treated with an antigenic peptide encoded by MAGE-3 and presented by HLA-A1.IntJ Cancer. 1999;80:219–230.

    Article  CAS  Google Scholar 

  37. Thurner B, Haendle I, Roder C, et al. 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. 1999;190:1669–1678.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Matsushita M, Ikeda H, Kizaki M, et al. Quantitative monitoring of the PRAME gene for the detection of minimal residual disease in leukaemia.Br J Haematol. 2001;112:916–926.

    Article  PubMed  CAS  Google Scholar 

  39. Vogt MH, van den Muijsenberg JW, Goulmy E, et al. The DBY gene codes for an HLA-DQ5-restricted human male-specific minor histocompatibility antigen involved in graft-versus-host disease.Blood. 2002;99:3027–3032.

    Article  PubMed  CAS  Google Scholar 

  40. Dickinson AM, Wang XN, Sviland L, et al. In situ dissection of the graft-versus-host activities of cytotoxic T cells specific for minor histocompatibility antigens.Nat Med. 2002;8:410–414.

    Article  PubMed  CAS  Google Scholar 

  41. Mutis T, Gillespie G, Schrama E, Falkenburg JHF, Moss P, Goulmy E. Tetrameric HLA class I-minor histocompatability antigen peptide complexes demonstrate minor histocompatibility antigen-specific cytotoxic T lymphocytes in patients with graft-versus-host disease.Nat Med. 1999;5:839–842.

    Article  PubMed  CAS  Google Scholar 

  42. Mutis T, Verdijk R, Schrama E, Esendam B, Brand A, Goulmy E. Feasibility of immunotherapy of relapsed leukemia with ex vivo-generated cytotoxic T lymphocytes specific for hematopoietic system-restricted minor histocompatibility antigens.Blood. 1999;93: 2336–2341.

    PubMed  CAS  Google Scholar 

  43. Maruya E, Saji H, Seki S, et al. Evidence that CD31, CD49b, and CD62L are immunodominant minor histocompatibility antigens in HLA identical sibling bone marrow transplants.Blood. 1998;92: 2169–2176.

    PubMed  CAS  Google Scholar 

  44. Oka Y, Elisseeva OA, Tsuboi A, et al. Human cytotoxic T-lymphocyte responses specific for peptides of the wild-type Wilms’ tumor gene (WT1) product.Immunogenetics. 2000;51:99–107.

    Article  PubMed  CAS  Google Scholar 

  45. Andersen MH, Pedersen LO, Capeller B, Brocker EB, Becker JC, thor Straten P. Spontaneous cytotoxic T-cell responses against survivin-derived MHC class I-restricted T-cell epitopes in situ as well as ex vivo in cancer patients.Cancer Res. 2001;61:5964–5968.

    PubMed  CAS  Google Scholar 

  46. Arai J, Yasukawa M, Ohminami H, Kakimoto M, Hasegawa A, Fujita S. Identification of human telomerase reverse transcriptase- derived peptides that induce HLA-A24-restricted antileukemia cytotoxic T lymphocytes.Blood. 2001;97:2903–2907.

    Article  PubMed  CAS  Google Scholar 

  47. Schroers R, Huang XF, Hammer J, Zhang J, Chen SY. Identification of HLA DR7-restricted epitopes from human telomerase reverse transcriptase recognized by CD4+ T-helper cells.Cancer Res. 2002; 62:2600–2605.

    PubMed  CAS  Google Scholar 

  48. Paludan C, Bickham K, Nikiforow S, et al. Epstein-Barr nuclear antigen 1-specific CD4(+) Th1 cells kill Burkitt’s lymphoma cells.J Immunol. 2002;169:1593–1603.

    Article  PubMed  CAS  Google Scholar 

  49. Rooney CM, Smith CA, Ng CYC, et al. Infusion of cytotoxic T cells for the prevention and treatment of Epstein-Barr virus-induced lymphoma in allogeneic transplant recipients.Blood. 1998;92: 1549–1555.

    PubMed  CAS  Google Scholar 

  50. Roskrow MA, Suzuki N, Gan Y, et al. Epstein-Barr virus (EBV)- specific cytotoxic T lymphocytes for the treatment of patients with EBV-positive relapsed Hodgkin’s disease.Blood. 1998;91: 2925–2934.

    PubMed  CAS  Google Scholar 

  51. Hsu FJ, Caspar CB, Czerwinski D, et al. Tumor-specific idiotype vaccines in the treatment of patients with B-cell lymphoma-longterm results of a clinical trial.Blood. 1997;89:3129–3135.

    PubMed  CAS  Google Scholar 

  52. Timmerman JM, Czerwinski DK, Davis TA, et al. Idiotype-pulsed dendritic cell vaccination for B-cell lymphoma: clinical and immune responses in 35 patients.Blood. 2002;99:1517–1526.

    Article  PubMed  CAS  Google Scholar 

  53. Clay TM, Custer MC, McKee MD, et al. Changes in the fine specificity of gp100(209-217)-reactive T cells in patients following vaccination with a peptide modified at an HLA-A2.1 anchor residue.J Immunol. 1999;162:1749–1755.

    PubMed  CAS  Google Scholar 

  54. Rivoltini L, Squarcina P, Loftus D, et al. A superagonist variant of peptide MART1/Melan A27-35 elicits anti-melanoma CD8+ T cells with enhanced functional characteristics: implication for more effective immunotherapy.Cancer Res. 1999;59:301–306.

    PubMed  CAS  Google Scholar 

  55. Nestle F, Alijagic S, Gilliet M, et al. Vaccination of melanoma patients with peptide- or tumor lysate-pulsed dendritic cells.Nat Med. 1998;4:328–332.

    Article  PubMed  CAS  Google Scholar 

  56. Murphy G, Tjoa B, Ragde H, Kenny G, Boynton A. Phase I clinical trial: T-cell therapy for prostate cancer using autologous dendritic cells pulsed with HLA-A0201-specific peptides from prostate-specific membrane antigen.Prostate. 1996;29:371–380.

    Article  PubMed  CAS  Google Scholar 

  57. Small EJ, Fratesi P, Reese DM, et al. Immunotherapy of hormone- refractory prostate cancer with antigen-loaded dendritic cells.J Clin Oncol. 2000;18:3894–3903.

    Article  PubMed  CAS  Google Scholar 

  58. Reichardt VL, Okada CY, Liso A, et al. Idiotype vaccination using dendritic cells after autologous peripheral blood stem cell transplantation for multiple myeloma: a feasibility study.Blood. 1999; 93:2411–2419.

    PubMed  CAS  Google Scholar 

  59. Banchereau J, Palucka AK, Dhodapkar M, et al. Immune and clinical responses in patients with metastatic melanoma to cd34(+) progenitor-derived dendritic cell vaccine.Cancer Res. 2001;61: 6451–6458.

    PubMed  CAS  Google Scholar 

  60. Heiser A, Coleman D, Dannull J, et al. Autologous dendritic cells transfected with prostate-specific antigen RNA stimulate CTL responses against metastatic prostate tumors.J Clin Invest. 2002; 109:409–417.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. Wang RF, Wang HY. Enhancement of antitumor immunity by prolonging antigen presentation on dendritic cells.Nat Biotechnol. 2002;20:149–154.

    Article  PubMed  CAS  Google Scholar 

  62. Schuler-Thurner B, Schultz ES, Berger TG, et al. Rapid induction of tumor-specific type 1T helper cells in metastatic melanoma patients by vaccination with mature, cryopreserved, peptide-loaded mono-cyte-derived dendritic cells.J Exp Med. 2002;195:1279–1288.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  63. Panelli MC, Wunderlich J, Jeffries J, et al. Phase 1 study in patients with metastatic melanoma of immunization with dendritic cells presenting epitopes derived from the melanoma-associated antigens MART-1 and gp100.J Immunother. 2000;23:487–498.

    Article  PubMed  CAS  Google Scholar 

  64. Fong L, Brockstedt D, Benike C, et al. Dendritic cell-based xenoantigen vaccination for prostate cancer immunotherapy.J Immunol. 2001;167:7150–7156.

    Article  PubMed  CAS  Google Scholar 

  65. Kugler A, Stuhler G, Walden P, et al. Regression of human metastatic renal cell carcinoma after vaccination with tumor cell-dendritic cell hybrids.Nat Med. 2000;6:332–336.

    Article  PubMed  CAS  Google Scholar 

  66. Choudhury BA, Liang JC, Thomas EK, et al. Dendritic cells derived in vitro from acute myelogenous leukemia cells stimulate autologous, antileukemic T-cell responses.Blood. 1999;93:780–786.

    PubMed  CAS  Google Scholar 

  67. Fujii S, Shimizu K, Fujimoto K, et al. Analysis of a chronic myelogenous leukemia patient vaccinated with leukemic dendritic cells following autologous peripheral blood stem cell transplantation.Jpn J Cancer Res. 1999;90:1117–1129.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  68. Morse MA, Coleman E, Akabani G, Niehaus N, Coleman D, Lyerly HK. Migration of human dendritic cells after injection in patients with metastatic malignancies.Cancer Res. 1999;59:56–58.

    PubMed  CAS  Google Scholar 

  69. Rosenberg S, Zhai Y, Yang J, et al. Immunizing patients with metastatic melanoma using recombinant adenoviruses encoding MART-1 or gp100 melanoma antigens.J Natl Cancer Inst. 1998;90: 1894–1900.

    Article  PubMed  CAS  Google Scholar 

  70. Rosenberg SA, Yannelli JR, Yang JC, et al. Treatment of patients with metastatic melanoma with autologous tumor-infiltrating lymphocytes and interleukin 2.J Natl Cancer Inst. 1995;86:1159–1166.

    Article  Google Scholar 

  71. Salgaller M, Marincola F, Cormier J, Rosenberg S. Immunization against epitopes in the human melanoma antigen gp100 following patient immunization with synthetic peptides.Cancer Res. 1996;56: 4749–4757.

    PubMed  CAS  Google Scholar 

  72. Molldrem JJ, Lee PP, Wang C, Champlin RE, Davis MM. A PR1- human leukocyte antigen-A2 tetramer can be used to isolate low- frequency cytotoxic T lymphocytes from healthy donors that selectively lyse chronic myelogenous leukemia.Cancer Res. 1999;59: 2675–2681.

    PubMed  CAS  Google Scholar 

  73. Mutis T, Blokland E, Kester M, Schrama E, Goulmy E. Generation of minor histocompatibility antigen HA-1-specific cytotoxic T cells restricted by nonself HLA molecules: a potential strategy to treat relapsed leukemia after HLA-mismatched stem cell transplantation.Blood. 2002;100:547–552.

    Article  PubMed  CAS  Google Scholar 

  74. Ruggeri L, Capanni M, Urbani E, et al. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants.Science. 2002;295:2097–2100.

    Article  PubMed  CAS  Google Scholar 

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  1. Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University, School of Medicine, 160-8582, Tokyo, Japan

    Yutaka Kawakami

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Correspondence to Yutaka Kawakami.

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Kawakami, Y. Identification of Human Tumor Antigens Recognized by T-Cells and Their Use for Immunotherapy. Int J Hematol 77, 427–434 (2003). https://doi.org/10.1007/BF02986609

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