The Rational Design of T-Cell Epitopes With Enhanced Immunogenicity

  • John Fikes
Part of the Cancer Drug Discovery and Development book series (CDD&D)


For all cancer vaccine strategies, a major challenge facing efforts to induce a clinically effective T-cell response is the necessity to break tolerance to normal, “self” antigens. To control auto-reactivity, some T cells with high avidity for tumor-associated antigen (TAA) epitope—major histocompatibility (MHCs) complexes are deleted in the thymus and the remaining T cells are controlled by peripheral tolerance (1). However, several groups have demonstrated using in vitro systems that thymic-deletion of TAA-specific cytolytic T cell (CTL) is not complete (2–4). More importantly, it is clear that in some patients, natural exposure to tumor or immunization with wild-type antigens or epitopes can induce CTL of sufficient avidity and functionality to infiltrate tumors in vivo and/or recognize tumor cells in vitro. Therefore, although the fundamental vaccine strategy of targeting TAA to mount tumor-specific immune responses is supported, it remains a significant challenge to design cancer vaccine strategies that consistently overcome immunological tolerance in order to effectively activate and maintain therapeutic T-cell responses. Experimentation in the late 1980s and 1990s has resulted in a detailed understanding of the molecular mechanisms controlling T-cell activation and effector function. It is now appreciated that the interaction of a T-cell receptor with a peptide epitope presented by an antigen-presenting cell (APC) in the context of an MHC molecule generates the central event (referred to as “signal 1”) in the activation of naïve or memory T cells.


Cancer Vaccine Single Amino Acid Substitution Altered Peptide Ligand Anchor Position Human Carcinoembryonic Antigen 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Yu Z, Restifo NP. Cancer vaccines: progress reveals new complexities. J Clin Invest 2002; 110:289–294.PubMedGoogle Scholar
  2. 2.
    Keogh E, Fikes J, Southwood S, Celis E, Chesnut R, Sette A. Identification of new epitopes from four different tumor-associated antigens: recognition of naturally processed epitopes correlates with HLAA*0201-binding affinity. J Immunol 2001; 167:787–796.PubMedGoogle Scholar
  3. 3.
    Rosenberg SA, Yang JC, Schwartzentruber DJ, Hwu P, Marincola FM, Topalian SL, 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.PubMedCrossRefGoogle Scholar
  4. 4.
    Reynolds SR, Celis E, Sette A, Oratz R, Shapiro RL, Johnston D, et al. Identification of HLA-A*03, A*11 and B*07-restricted melanoma-associated peptides that are immunogenic in vivo by vaccineinduced immune response (VIIR) analysis. J Immunol Methods 2000; 244:59–67.PubMedCrossRefGoogle Scholar
  5. 5.
    Ruppert J, Sidney J, Celis E, Kubo RT, Grey HM, Sette A. Prominent role of secondary anchor residues in peptide binding to HLA-A2.1 molecules. Cell 1993; 74:929–937.PubMedCrossRefGoogle Scholar
  6. 6.
    Sette A, Vitiello A, Reherman B, Fowler P, Nayersina R, Kast WM, et al. The relationship between class I binding affinity and immunogenicity of potential cytotoxic T cell epitopes. J Immunol 1994; 153:5586–5592.PubMedGoogle Scholar
  7. 7.
    Cibotti R, Kanellopoulos JM, Cabaniols JP, Halle-Panenko 0, Kosmatopoulos K, Sercarz E, et al. Tolerance to a self-protein involves its immunodominant but does not involve its subdominant determinants. Proc Natl Acad Sci USA 1992; 89:416–420.PubMedCrossRefGoogle Scholar
  8. 8.
    Parkhurst MR, Salgaller ML, Southwood S, Robbins PF, Sette A, Rosenberg SA, et al. Improved induction of melanoma-reactive CTL with peptides from the melanoma antigen gp100 modified at HLAA*0201-binding residues. J Immunol 1996; 157:2539–2548.PubMedGoogle Scholar
  9. 9.
    Fisk B, Savary C, Hudson JM, O’Brian CA , Murray JL, Wharton JT, et al. Changes in an HER-2 peptide upregulating HLA-A2 expression affect both conformational epitopes and CTL recognition: implications for optimization of antigen presentation and tumor-specific CTL induction. J Immunother 1996; 18:197–209.CrossRefGoogle Scholar
  10. 10.
    Kawashima I, Hudson SJ, Tsai V, Southwood S, Takesako K, Appella E, et al. The multi-epitope approach for immunotherapy for cancer: identification of several CTL epitopes from various tumorassociated antigens expressed on solid epithelial tumors. Hum Immunol 1998; 59:1–14.PubMedCrossRefGoogle Scholar
  11. 11.
    Kappler JW, Roehm N, Marrack P. T cell tolerance by clonal elimination in the thymus. Cell 1987; 49:273–280.PubMedCrossRefGoogle Scholar
  12. 12.
    Rivoltini L, Squarcina P, Loftus DJ, Castelli C, Tarsini P, Mazzocchi A, et al. A superagonist variant of peptide MART1/Me1an A27–35 elicits anti-melanoma CD8+ T cells with enhanced functional characteristics: implication for more effective immunotherapy. Cancer Res 1999; 59:301–306.PubMedGoogle Scholar
  13. 13.
    Chen JL, Dunbar PR, Gileadi U, Jager E, Gnjatic S, Nagata Y, et al. Identification of NY-ESO-1 peptide analogues capable of improved stimulation of tumor-reactive CTL. J Immunol 2000; 165:948–955.PubMedGoogle Scholar
  14. 14.
    Trojan A, Witzens M, Schultze JL, Vonderheide RH, Hang S, Krackhardt AM, et al. Generation of cytotoxic T lymphocytes against native and altered peptides of human leukocyte antigen-A*0201 restricted epitopes from the human epithelial cell adhesion molecule. Cancer Res 2001; 61:4761–4765.PubMedGoogle Scholar
  15. 15.
    Lee P, Wang F, Kuniyoshi J, Rubio V, Stuges T, Groshen S, et al. Effects of interleukin-12 on the immune response to a multipeptide vaccine for resected metastatic melanoma. J Clin Oncol 2001; 19:3836–3847.PubMedGoogle Scholar
  16. 16.
    Banchereau J, Palucka AK, Dhodapkar M, Burkeholder S, Taquet N, Rolland A, et al. Immune and clinical responses in patients with metastatic melanoma to CD34(+) progenitor-derived dendritic cell vaccine. Cancer Res 2001; 61:6451–6458.PubMedGoogle Scholar
  17. 17.
    Yang S, Linette GP, Longerich S, Haluska FG. Antimelanoma activity of CTL generated from peripheral blood mononuclear cells after stimulation with autologous dendritic cells pulsed with melanoma gp100 peptide G209–2M is correlated to TCR avidity. J Immunol 2002; 169:531–539.PubMedGoogle Scholar
  18. 18.
    Lee KH, Wang E, Nielsen MB, Wunderlich J, Migueles S, Connors M, et al. 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 1999; 163:6292–6300.PubMedGoogle Scholar
  19. 19.
    Sette A, Sidney J. Nine major HLA class I supertypes account for the vast preponderance of HLA-A and -B polymorphism. Immunogenetics 1999; 50:201–212.PubMedCrossRefGoogle Scholar
  20. 20.
    Slansky JE, Rattis FM, Boyd LF, Fahmy T , Jaffee EM, Schneck JP, et al. Enhanced antigen-specific antitumor immunity with altered peptide ligands that stabilize the MHC-peptide-TCR complex. Immunity 2000; 13:529–538.PubMedCrossRefGoogle Scholar
  21. 21.
    England RD, Kullberg MC, Cornette JL, Berzofsky JA. Molecular analysis of a heteroclitic T cell response to the immunodominant epitope of sperm whale myoglobin. Implications for peptide partial agonists. J Immunol 1995; 155:4295–4306.PubMedGoogle Scholar
  22. 22.
    Salazar E, Zaremba S, Arlen PM, Tsang KY, Schlom J. Agonist peptide from a cytotoxic T-lymphocyte epitope of human carcinoembryonic antigen stimulates production of TC1-type cytokines and increases tyrosine phosphorylation more efficiently than cognate peptide. Int J Cancer 2000; 85:829–838.PubMedCrossRefGoogle Scholar
  23. 23.
    Tangri S, Ishioka GY, Huang X, Sidney J , Southwood S, Fikes J, et al. Structural features of peptide analogs of human histocompatibility leukocyte antigen class I epitopes that are more potent and immunogenic than wild-type peptide. J Exp Med 2001; 194:833–846.PubMedCrossRefGoogle Scholar
  24. 24.
    Zaremba S, Barzaga E, Zhu MZ, Soares N, Tsang KY, Schlom J. Identification of an enhancer agonist cytotoxic T lymphocyte peptide from human carcinoembryonic antigen. Cancer Res 1997; 57:4570–4577.PubMedGoogle Scholar
  25. 25.
    Fong L, Hou Y, Rivas A, Benike C, Yuen A, Fisher GA, et al. Altered peptide ligand vaccination with F1t3 ligand expanded dendritic cells for tumor immunotherapy. Proc Natl Acad Sci USA 2001; 98:8809–8814.PubMedCrossRefGoogle Scholar
  26. 26.
    Morse MA, Deng Y, Coleman D, Hull S, Kitrell-Fisher E, Nair S, Schlon J, Ryback ME, Lyerly HK. A Phase I study of active immunotherapy with carcinoembryonic antigen peptide (CAP-1)-pulsed, autologous human cultured dendritic cells in patients with metastatic malignancies expressing carcinoembryonic antigen. Clin Cancer Res. 1999;5:1331–1338.PubMedGoogle Scholar

Copyright information

© Humana Press Inc. 2004

Authors and Affiliations

  • John Fikes

There are no affiliations available

Personalised recommendations