MHC class I antigen presentation and implications for developing a new generation of therapeutic vaccines

Therapeutic Advances in Vaccines

Volumn 2, Issue 3, 2014, Pages 77-89

  Comber, Joseph D ^a   Philip, Ramila ^a  

^a Immunotope Inc   (United States)

Author keywords

Cytotoxic T cells; Epitopes; Immunoproteomics; Mass spectrometry; MHC class I; Motif prediction; Tumor associated antigen; Vaccine

Indexed keywords

EID: 84922571419     PISSN: 20510136     EISSN: None     Source Type: Journal    
DOI: 10.1177/2051013614525375     Document Type: Review

References (95)

1. Admon, A., Barnea, E. and Ziv, T. (2003) Tumor antigens and proteomics from the point of view of the major histocompatibility complex peptides. Mol Cell Proteomics 2: 388–398.
2. Ait-Tahar, K., Cerundolo, V., Banham, A., Hatton, C., Blanchard, T., Kusec, R. et al. (2006) B and CTL responses to the Alk protein in patients with Alkpositive ALCL. Int J Cancer 118: 688–695.
3. Akiyama, Y., Komiyama, M., Nakamura, Y., Iizuka, A., Oshita, C., Kume, A. et al. (2012) Identification of novel MAGE-A6- and MAGE-A12-derived HLAA24- restricted cytotoxic T lymphocyte epitopes using an in silico peptide-docking assay. Cancer Immunol Immunother 61: 2311–2319.
4. Apcher, S., Millot, G., Daskalogianni, C., Scherl, A., Manoury, B. and Fahraeus, R. (2013) Translation of pre-spliced RNAS in the nuclear compartment generates peptides for the MHC class I pathway. Proc Natl Acad Sci U S A 110: 17951–17956.
5. Aruga, A., Takeshita, N., Kotera, Y., Okuyama, R., Matsushita, N., Ohta, T. et al. (2013) Long-term vaccination with multiple peptides derived from cancer-testis antigens can maintain a specific T cell response and achieve disease stability in advanced biliary tract cancer. Clin Cancer Res 19: 2224–2231.
6. Baitsch, L., Fuertes-Marraco, S., Legat, A., Meyer, C. and Speiser, D. (2012) The three main stumbling blocks for anticancer T cells. Trends Immunol 33: 364–372.
7. Berinstein, N., Karkada, M., Morse, M., Nemunaitis, J., Chatta, G., Kaufman, H. et al. (2012) First-inman application of a novel therapeutic cancer vaccine formulation with the capacity to induce multifunctional T cell responses in ovarian, breast and prostate cancer patients. J Transl Med 10: 156.
8. Berntsen, A., Brimnes, M., Thor Straten, P. and Svane, I. (2010) Increase of circulating CD4+CD25HIGHFOXP3+ regulatory T cells in patients with metastatic renal cell carcinoma during treatment with dendritic cell vaccination and low-dose interleukin-2. J Immunother 33: 425–434.
9. Berzofsky, J., Ahlers, J. and Belyakov, I. (2001) Strategies for designing and optimizing new generation vaccines. Nat Rev Immunol 1: 209–219.
10. Block, M., Suman, V., Nevala, W., Kottschade, L., Creagan, E., Kaur, J. et al. (2011) Pilot study of granulocyte-macrophage colony-stimulating factor and interleukin-2 as immune adjuvants for a melanoma peptide vaccine. Melanoma Res 21: 438–445.
11. Blum, J., Wearsch, P. and Cresswell, P. (2013) Pathways of antigen processing. Annu Rev Immunol 31: 443–473.
12. Brichard, V., Van Pel, A., Wolfel, T., Wolfel, C., De Plaen, E., Lethe, B. et al. (1993) The tyrosinase gene codes for an antigen recognized by autologous cytolytic T lymphocytes on HLA-A2 melanomas. J Exp Med 178: 489–495.
13. Brossart, P., Heinrich, K., Stuhler, G., Behnke, L., Reichardt, V., Stevanovic, S. et al. (1999) Identification of HLA-A2-restricted T cell epitopes derived from the MUC1 tumor antigen for broadly applicable vaccine therapies. Blood 93: 4309–4317.
14. Carmichael, M., Benavides, L., Holmes, J., Gates, J., Mittendorf, E., Ponniah, S. et al. (2010) Results of the first phase 1 clinical trial of the Her-2/neu peptide (GP2) vaccine in disease-free breast cancer patients: United States Military Cancer Institute Clinical Trials Group Study I-04. Cancer 116: 292–301.
15. De Jong, A. (1998) Contribution of mass spectrometry to contemporary immunology. Mass Spectrom Rev 17: 311–335.
16. Delamarre, L., Pack, M., Chang, H., Mellman, I. and Trombetta, E. (2005) Differential lysosomal proteolysis in antigen-presenting cells determines antigen fate. Science 307: 1630–1634.
17. Di Marzo Veronese, F., Arnott, D., Barnaba, V., Loftus, D., Sakaguchi, K., Thompson, C. et al. (1996) Autoreactive cytotoxic T lymphocytes in human immunodeficiency virus type 1-infected subjects. J Exp Med 183: 2509–2516.
18. Falk, K., Rotzschke, O., Stevanovic, S., Jung, G. and Rammensee, H. (1991) Allele-specific motifs revealed by sequencing of self-peptides eluted from MHC molecules. Nature 351: 290–296.
19. Feyerabend, S., Stevanovic, S., Gouttefangeas, C., Wernet, D., Hennenlotter, J., Bedke, J. et al. (2009) Novel multi-peptide vaccination in HLA-A2+ hormone sensitive patients with biochemical relapse of prostate cancer. Prostate 69: 917–927.
20. Fisk, B., Blevins, T., Wharton, J. and Ioannides, C. (1995) Identification of an immunodominant peptide of Her-2/neu protooncogene recognized by ovarian tumor-specific cytotoxic T lymphocyte lines. J Exp Med 181: 2109–2117.
21. Fortier, M., Caron, E., Hardy, M., Voisin, G., Lemieux, S., Perreault, C. et al. (2008) The MHC class I peptide repertoire is molded by the transcriptome. J Exp Med 205: 595–610.
22. Haen, S. and Rammensee, H. (2013) The repertoire of human tumor-associated epitopes - identification and selection of antigens and their application in clinical trials. Curr Opin Immunol 25: 277–283.
23. Hanada, K., Yewdell, J. and Yang, J. (2004) Immune recognition of a human renal cancer antigen through post-translational protein splicing. Nature 427: 252–256.
24. Hanahan, D. and Weinberg, R. (2000) The hallmarks of cancer. Cell 100: 57–70.
25. Hawkins, O., Vangundy, R., Eckerd, A., Bardet, W., Buchli, R., Weidanz, J. et al. (2008) Identification of breast cancer peptide epitopes presented by HLAA* 0201. J Proteome Res 7: 1445–1457.
26. Hickman, H., Luis, A., Bardet, W., Buchli, R., Battson, C., Shearer, M. et al. (2003) Cutting edge: class I presentation of host peptides following HIV infection. J Immunol 171: 22–26.
27. Hogan, K., Coppola, M., Gatlin, C., Thompson, L., Shabanowitz, J., Hunt, D. et al. (2003) Identification of a shared epitope recognized by melanoma-specific, HLA-A3-restricted cytotoxic T lymphocytes. Immunol Lett 90: 131–135.
28. Hogan, K., Coppola, M., Gatlin, C., Thompson, L., Shabanowitz, J., Hunt, D. et al. (2004) Identification of novel and widely expressed cancer/ testis gene isoforms that elicit spontaneous cytotoxic T-lymphocyte reactivity to melanoma. Cancer Res 64: 1157–1163.
29. Hu, X., Chakraborty, N., Sporn, J., Kurtzman, S., Ergin, M. and Mukherji, B. (1996) Enhancement of cytolytic T lymphocyte precursor frequency in melanoma patients following immunization with the MAGE-1 peptide loaded antigen presenting cell-based vaccine. Cancer Res 56: 2479–2483.
30. Hunt, D., Henderson, R., Shabanowitz, J., Sakaguchi, K., Michel, H., Sevilir, N. et al. (1992) Characterization of peptides bound to the class I MHC molecule HLA-A2.1 by mass spectrometry. Science 255: 1261–1263.
31. Kameshima, H., Tsuruma, T., Torigoe, T., Takahashi, A., Hirohashi, Y., Tamura, Y. et al. (2011) Immunogenic enhancement and clinical effect by type-I interferon of anti-apoptotic protein, survivinderived peptide vaccine, in advanced colorectal cancer patients. Cancer Sci 102: 1181–1187.
32. Kavanagh, B., Ko, A., Venook, A., Margolin, K., Zeh, H., Lotze, M. et al. (2007) Vaccination of metastatic colorectal cancer patients with matured dendritic cells loaded with multiple major histocompatibility complex class I peptides. J Immunother 30: 762–772.
33. Kawakami, Y., Eliyahu, S., Sakaguchi, K., Robbins, P., Rivoltini, L., Yannelli, J. et al. (1994) Identification of the immunodominant peptides of the MART-1 human melanoma antigen recognized by the majority of HLA-A2-restricted tumor infiltrating lymphocytes. J Exp Med 180: 347–352.
34. Kawashima, I., Tsai, V., Southwood, S., Takesako, K., Sette, A. and Celis, E. (1999) Identification of HLA-A3-restricted cytotoxic T lymphocyte epitopes from carcinoembryonic antigen and Her-2/neu by primary in vitro immunization with peptide-pulsed dendritic cells. Cancer Res 59: 431–435.
35. Keogh, E., Fikes, J., Southwood, S., Celis, E., Chesnut, R. and Sette, A. (2001) Identification of new epitopes from four different tumor-associated antigens: recognition of naturally processed epitopes correlates with HLA-A*0201-binding affinity. J Immunol 167: 787–796.
36. Kirkwood, J., Lee, S., Moschos, S., Albertini, M., Michalak, J., Sander, C. et al. (2009) Immunogenicity and antitumor effects of vaccination with peptide vaccine+/-granulocyte-monocyte colony-stimulating factor and/or IFN-Alpha2b in advanced metastatic melanoma: Eastern Cooperative Oncology Group Phase II Trial E1696. Clin Cancer Res 15: 1443–1451.
37. Koski, G., Koldovsky, U., Xu, S., Mick, R., Sharma, A., Fitzpatrick, E. et al. (2012) A novel dendritic cell-based immunization approach for the induction of durable Th1-polarized anti-Her-2/neu responses in women with early breast cancer. J Immunother 35: 54–65.
38. Lemmel, C., Weik, S., Eberle, U., Dengjel, J., Kratt, T., Becker, H. et al. (2004) Differential quantitative analysis of MHC ligands by mass spectrometry using stable isotope labeling. Nat Biotechnol 22: 450–454.
39. Lemoine, F., Cherai, M., Giverne, C., Dimitri, D., Rosenzwajg, M., Trebeden-Negre, H. et al. (2009) Massive expansion of regulatory T cells following interleukin 2 treatment during a phase I–II dendritic cell-based immunotherapy of metastatic renal cancer. Int J Oncol 35: 569–581.
40. Lesterhuis, W., De Vries, I., Schreibelt, G., Schuurhuis, D., Aarntzen, E., De Boer, A. et al. (2010) Immunogenicity of dendritic cells pulsed with CEA peptide or transfected with CEA MRNA for vaccination of colorectal cancer patients. Anticancer Res 30: 5091–5097.
41. Lesterhuis, W., Schreibelt, G., Scharenborg, N., Brouwer, H., Gerritsen, M., Croockewit, S. et al. (2011) Wild-type and modified Gp100 peptide-pulsed dendritic cell vaccination of advanced melanoma patients can lead to long-term clinical responses independent of the peptide used. Cancer Immunol Immunother 60: 249–260.
42. Li, B., Wang, Y., Chen, J., Wu, H. and Chen, W. (2005) Identification of a new HLA-A*0201-restricted CD8+ T cell epitope from hepatocellular carcinoma-associated antigen HCA587. Clin Exp Immunol 140: 310–319.
43. Mahla, R., Reddy, M., Prasad, D. and Kumar, H. (2013) Sweeten PAMPs: role of sugar complexed PAMPs in innate immunity and vaccine biology. Front Immunol 4: 248.
44. Marincola, F., Rivoltini, L., Salgaller, M., Player, M. and Rosenberg, S. (1996) Differential anti- MART-1/MELANA CTL activity in peripheral blood of HLA-A2 melanoma patients in comparison to healthy donors: evidence of in vivo priming by tumor cells. J Immunother Emphasis Tumor Immunol 19: 266–277.
45. Mittendorf, E., Clifton, G., Holmes, J., Clive, K., Patil, R., Benavides, L. et al. (2012) Clinical trial results of the Her-2/neu (E75) vaccine to prevent breast cancer recurrence in high-risk patients: from US Military Cancer Institute Clinical Trials Group Study I-01 and I-02. Cancer 118: 2594–2602.
46. Morse, M., Secord, A., Blackwell, K., Hobeika, A., Sinnathamby, G., Osada, T. et al. (2011) MHC class I-presented tumor antigens identified in ovarian cancer by immunoproteomic analysis are targets for T cell responses against breast and ovarian cancer. Clin Cancer Res 17: 3408–3419.
47. Mougiakakos, D., Choudhury, A., Lladser, A., Kiessling, R. and Johansson, C. (2010) Regulatory T cells in cancer. Adv Cancer Res 107: 57–117.
48. Nagorsen, D., Keilholz, U., Rivoltini, L., Schmittel, A., Letsch, A., Asemissen, A. et al. (2000) Natural T cell response against MHC class I epitopes of epithelial cell adhesion molecule, Her-2/neu, and carcinoembryonic antigen in patients with colorectal cancer. Cancer Res 60: 4850–4854.
49. Nukaya, I., Yasumoto, M., Iwasaki, T., Ideno, M., Sette, A., Celis, E. et al. (1999) Identification of HLAA24 epitope peptides of carcinoembryonic antigen which induce tumor-reactive cytotoxic T lymphocyte. Int J Cancer 80: 92–97.
50. Nussbaum, A., Kuttler, C., Hadeler, K., Rammensee, H. and Schild, H. (2001) PAPROC: a prediction algorithm for proteasomal cleavages available on the WWW. Immunogenetics 53: 87–94.
51. Oshita, C., Takikawa, M., Kume, A., Miyata, H., Ashizawa, T., Iizuka, A. et al. (2012) Dendritic cellbased vaccination in metastatic melanoma patients: phase II clinical trial. Oncol Rep 28: 1131–1138.
52. Papadopoulos, K., Hesdorffer, C., Suciu-Foca, N., Hibshoosh, H. and Harris, P. (1999) Wild-type P53 epitope naturally processed and presented by an HLA-B haplotype on human breast carcinoma cells. Clin Cancer Res 5: 2089–2093.
53. Parmiani, G., Sensi, M., Castelli, C., Rivoltini, L. and Anichini, A. (2002) T cell response to unique and shared antigens and vaccination of cancer patients. Cancer Immun 2: 6.
54. Purcell, A. and Gorman, J. (2004) Immunoproteomics: mass spectrometry-based methods to study the targets of the immune response. Mol Cell Proteomics 3: 193–208.
55. Ramakrishna, V., Ross, M., Petersson, M., Gatlin, C., Lyons, C., Miller, C. et al. (2003) Naturally occurring peptides associated with HLA-A2 in ovarian cancer cell lines identified by mass spectrometry are targets of HLA-A2-restricted cytotoxic T cells. Int Immunol 15: 751–763.
56. Rotzschke, O., Falk, K., Deres, K., Schild, H., Norda, M., Metzger, J. et al. (1990) Isolation and analysis of naturally processed viral peptides as recognized by cytotoxic T cells. Nature 348: 252–254.
57. Savina, A., Jancic, C., Hugues, S., Guermonprez, P., Vargas, P., Moura, I. et al. (2006) NOX2 controls phagosomal Ph to regulate antigen processing during crosspresentation by dendritic cells. Cell 126: 205–218.
58. Sawada, Y., Yoshikawa, T., Nobuoka, D., Shirakawa, H., Kuronuma, T., Motomura, Y. et al. (2012) Phase I trial of a glypican-3-derived peptide vaccine for advanced hepatocellular carcinoma: immunologic evidence and potential for improving overall survival. Clin Cancer Res 18: 3686–3696.
59. Schrader, A., Varga, Z., Hegele, A., Pfoertner, S., Olbert, P. and Hofmann, R. (2006) Second-line strategies for metastatic renal cell carcinoma: classics and novel approaches. J Cancer Res Clin Oncol 132: 137–149.
60. Schultze, J. and Vonderheide, R. (2001) From cancer genomics to cancer immunotherapy: toward secondgeneration tumor antigens. Trends Immunol 22: 516–523.
61. Seliger, B., Maeurer, M. and Ferrone, S. (2000) Antigen-processing machinery breakdown and tumor growth. Immunol Today 21: 455–464.
62. Sharma, A., Koldovsky, U., Xu, S., Mick, R., Roses, R., Fitzpatrick, E. et al. (2012) Her-2 pulsed dendritic cell vaccine can eliminate Her-2 expression and impact ductal carcinoma in situ. Cancer 118: 4354–4362.
63. Shastri, N., Schwab, S. and Serwold, T. (2002) Producing nature’s gene-chips: the generation of peptides for display by MHC class I molecules. Annu Rev Immunol 20: 463–493.
64. Shen, H., Shao, H., Chen, X., Wu, F., Wang, H., Huang, Z. et al. (2013) Identification of a novel HLAA2- restricted mutated survivin epitope and induction of specific anti-HCC CTLs that could effectively cross-recognize wild-type survivin antigen. Cancer Immunol Immunother 62: 393–403.
65. Shetty, V., Nickens, Z., Testa, J., Hafner, J., Sinnathamby, G. and Philip, R. (2012) Quantitative immunoproteomics analysis reveals novel MHC class I presented peptides in cisplatin-resistant ovarian cancer cells. J Proteomics 75: 3270–3290.
66. Shetty, V., Sinnathamby, G., Nickens, Z., Shah, P., Hafner, J., Mariello, L. et al. (2011) MHC class I-presented lung cancer-associated tumor antigens identified by immunoproteomics analysis are targets for cancer-specific T cell response. J Proteomics 74: 728–743.
67. Sidney, J., Peters, B., Frahm, N., Brander, C. and Sette, A. (2008) HLA class I supertypes: a revised and updated classification. BMC Immunol 9: 1.
68. Skipper, J., Gulden, P., Hendrickson, R., Harthun, N., Caldwell, J., Shabanowitz, J. et al. (1999) Massspectrometric evaluation of HLA-A*0201-associated peptides identifies dominant naturally processed forms of CTL epitopes from MART-1 and Gp100. Int J Cancer 82: 669–677.
69. Skipper, J., Hendrickson, R., Gulden, P., Brichard, V., Van Pel, A., Chen, Y. et al. (1996) An HLA-A2- restricted tyrosinase antigen on melanoma cells results from posttranslational modification and suggests a novel pathway for processing of membrane proteins. J Exp Med 183: 527–534.
70. Slingluff, C., Jr (2011) The present and future of peptide vaccines for cancer: single or multiple, long or short, alone or in combination? Cancer J 17: 343–350.
71. Slingluff, C., Jr, Lee, S., Zhao, F., Chianese-Bullock, K., Olson, W., Butterfield, L. et al. (2013) A randomized phase II trial of multiepitope vaccination with melanoma peptides for cytotoxic T cells and helper T cells for patients with metastatic melanoma (E1602). Clin Cancer Res 19: 4228–4238.
72. Slingluff, C., Jr, Petroni, G., Chianese-Bullock, K., Smolkin, M., Hibbitts, S., Murphy, C. et al. (2007) Immunologic and clinical outcomes of a randomized phase II trial of two multipeptide vaccines for melanoma in the adjuvant setting. Clin Cancer Res 13: 6386–6395.
73. Slingluff, C., Jr, Petroni, G., Olson, W., Smolkin, M., Ross, M., Haas, N. et al. (2009) Effect of granulocyte/ macrophage colony-stimulating factor on circulating CD8+ and CD4+ T cell responses to a multipeptide melanoma vaccine: outcome of a multicenter randomized trial. Clin Cancer Res 15: 7036–7044.
74. Sliwkowski, M. and Mellman, I. (2013) Antibody therapeutics in cancer. Science 341: 1192–1198.
75. Speetjens, F., Kuppen, P., Welters, M., Essahsah, F., Voet Van Den Brink, A., Lantrua, M. et al. (2009) Induction of P53-specific immunity by a P53 synthetic long peptide vaccine in patients treated for metastatic colorectal cancer. Clin Cancer Res 15: 1086–1095.
76. Starck, S. and Shastri, N. (2011) Non-conventional sources of peptides presented by MHC class I. Cell Mol Life Sci 68: 1471–1479.
77. Stevanovic, S. (2002) Identification of tumourassociated T cell epitopes for vaccine development. Nat Rev Cancer 2: 514–520.
78. Testa, J., Shetty, V., Hafner, J., Nickens, Z., Kamal, S., Sinnathamby, G. et al. (2012a) MHC class I-presented T cell epitopes identified by immunoproteomics analysis are targets for a cross reactive influenza-specific T cell response. PLoS One 7: e48484.
79. Testa, J., Shetty, V., Sinnathamby, G., Nickens, Z., Hafner, J., Kamal, S. et al. (2012b) Conserved MHC class I-presented dengue virus epitopes identified by immunoproteomics analysis are targets for crossserotype reactive T cell response. J Infect Dis 205: 647–655.
80. Thomas, P., Brown, S., Keating, R., Yue, W., Morris, M., So, J. et al. (2007) Hidden epitopes emerge in secondary influenza virus-specific CD8+ T cell responses. J Immunol 178: 3091–3098.
81. Traversari, C., Van Der Bruggen, P., Luescher, I., Lurquin, C., Chomez, P., Van Pel, A. et al. (1992) A nonapeptide encoded by human gene MAGE-1 is recognized on HLA-A1 by cytolytic T lymphocytes directed against tumor antigen MZ2-E. J Exp Med 176: 1453–1457.
82. Tsuruma, T., Hata, F., Torigoe, T., Furuhata, T., Idenoue, S., Kurotaki, T. et al. (2004) Phase I clinical study of anti-apoptosis protein, survivinderived peptide vaccine therapy for patients with advanced or recurrent colorectal cancer. J Transl Med 2: 19.
83. Tsuruma, T., Iwayama, Y., Ohmura, T., Katsuramaki, T., Hata, F., Furuhata, T. et al. (2008) Clinical and immunological evaluation of antiapoptosis protein, survivin-derived peptide vaccine in phase I clinical study for patients with advanced or recurrent breast cancer. J Transl Med 6: 24.
84. Van Der Bruggen, P., Traversari, C., Chomez, P., Lurquin, C., De Plaen, E., Van Den Eynde, B. et al. (1991) A gene encoding an antigen recognized by cytolytic T lymphocytes on a human melanoma. Science 254: 1643–1647.
85. Van Els, C., Herberts, C., Van Der Heeft, E., Poelen, M., Van Gaans-Van Den Brink, J., Van Der Kooi, A. et al. (2000) A single naturally processed measles virus peptide fully dominates the HLA-A*0201- associated peptide display and is mutated at its anchor position in persistent viral strains. Eur J Immunol 30: 1172–1181.
86. Walter, S., Weinschenk, T., Stenzl, A., Zdrojowy, R., Pluzanska, A., Szczylik, C. et al. (2012) Multipeptide immune response to cancer vaccine IMA901 after single-dose cyclophosphamide associates with longer patient survival. Nat Med 18: 1254–1261.
87. Wherry, E. (2011) T cell exhaustion. Nat Immunol 12: 492–499.
88. Woo, E., Chu, C., Goletz, T., Schlienger, K., Yeh, H., Coukos, G. et al. (2001) Regulatory CD4(+) CD25(+) T cells in tumors from patients with earlystage non-small cell lung cancer and late-stage ovarian cancer. Cancer Res 61: 4766–4772.
89. Yoshimura, K., Minami, T., Nozawa, M. and Uemura, H. (2013) Phase I clinical trial of human vascular endothelial growth factor receptor 1 peptide vaccines for patients with metastatic renal cell carcinoma. Br J Cancer 108: 1260–1266.
90. Zarling, A., Polefrone, J., Evans, A., Mikesh, L., Shabanowitz, J., Lewis, S. et al. (2006) Identification of class I MHC-associated phosphopeptides as targets for cancer immunotherapy. Proc Natl Acad Sci U S A 103: 14889–14894.
91. Zeeberg Iversen, T., Engell-Noerregaard, L., Ellebaek, E., Andersen, R., Kiaer Larsen, S., Bjoern, J. et al. (2013) Long-lasting disease stabilization in the absence of toxicity in metastatic lung cancer patients vaccinated with an epitope derived from indoleamine 2,3 dioxygenase. Clin Cancer Res:
92. Zeestraten, E., Speetjens, F., Welters, M., Saadatmand, S., Stynenbosch, L., Jongen, R. et al. (2013) Addition of interferon-alpha to the P53- SLP(R) vaccine results in increased production of interferon-gamma in vaccinated colorectal cancer patients: a phase I/II clinical trial. Int J Cancer 132: 1581–1591.
93. Zhang, X., Huang, Y., Li, Z., Lin, H. and Sui, Y. (2010) Prediction and analysis of HLA-A2/A24- restricted cytotoxic T-lymphocyte epitopes of the tumor antigen MAGE-N using the artificial neural networks method on NETCTL1.2 Server. Oncol Lett 1: 1097–1100.
94. Zhong, W., Reche, P., Lai, C., Reinhold, B. and Reinherz, E. (2003) Genome-wide characterization of a viral cytotoxic T lymphocyte epitope repertoire. J Biol Chem 278: 45135–45144.
95. Zhu, B., Chen, Z., Cheng, X., Lin, Z., Guo, J., Jia, Z. et al. (2003) Identification of HLA-A*0201-restricted cytotoxic T lymphocyte epitope from TRAG-3 antigen. Clin Cancer Res 9: 1850–1857.