Skip to main content

Advertisement

SpringerLink
Log in

Modified peptides in anti-cancer vaccines: are we eventually improving anti-tumour immunity?

  • Symposium Paper
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

The discovery of tumour antigens recognized by T cells and the features of immune responses directed against them has paved the way to a multitude of clinical studies aimed at boosting anti-tumour T cell immunity as a therapeutic tool for cancer patients. One of the different strategies explored to ameliorate the immunogenicity of tumour antigens in vaccine protocols is represented by the use of optimized peptides or altered peptide ligands, whose amino acid sequence has been modified for improving HLA binding or TCR interaction with respect to native epitopes. However, despite the promising results achieved with preclinical studies, the clinical efficacy of this approach has not yet met the expectations. Although multiple reasons could explain the relative failure of altered peptide ligands as more effective cancer vaccines, the possibility that T cells primed by modified tumour peptides might may be unable to effectively cross-recognize tumour cells has not been sufficiently addressed. Indeed, the introduction of conservative amino acid substitutions may still produce diverse and unpredictable changes in the HLA/peptide interface, with consequent modifications of the TCR repertoire that can interact with the complex. This could lead to the expansion of a broad array of T cells whose TCRs may not necessarily react with equivalent affinity with the original antigenic epitope. Considering the results presently achieved with this vaccine approach, and the emerging availability of alternative strategies for boosting anti-tumour immunity, the use of modified tumour peptides could be reconsidered.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Parmiani G, Castelli C, Santinami M, Rivoltini L (2007) Melanoma immunology: past, present and future. Curr Opin Oncol 19:121–127

    Article  PubMed  Google Scholar 

  2. Rosenberg SA, Yang JC, Restifo NP (2004) Cancer immunotherapy: moving beyond current vaccines. Nat Med 10(9):909–915

    Article  PubMed  CAS  Google Scholar 

  3. Rivoltini L, Canese P, Huber V, Iero M, Pilla L, Valenti R, Fais S, Lozupone F, Casati C, Castelli C, Parmiani G (2005) Escape strategies and reasons for failure in the interaction between tumour cells and the immune system: how can we tilt the balance towards immune-mediated cancer control? Expert Opin Biol Ther 5:463–476

    Article  PubMed  CAS  Google Scholar 

  4. Zippelius A, Pittet MJ, Batard P, Rufer N, de Smedt M, Guillaume P, Ellefsen K, Valmori D, Lienard D, Plum J, MacDonald HR, Speiser DE, Cerottini JC, Romero P (2002) Thymic selection generates a large T cell pool recognizing a self-peptide in humans. J Exp Med 195:485–494

    Article  PubMed  CAS  Google Scholar 

  5. Sprent J, Lo D, Gao EK, Ron Y (1988) T cell selection in the thymus. Immunol Rev 101:173–190

    Article  PubMed  CAS  Google Scholar 

  6. Huseby ES, White J, Crawford F, Vass T, Becker D, Pinilla C, Marrack P, Kappler JW (2005) How the T cell repertoire becomes peptide and MHC specific. Cell 122:247–260

    Article  PubMed  CAS  Google Scholar 

  7. Marincola FM, Jaffee EM, Hicklin DJ, Ferrone S (2000) Escape of human solid tumors from T-cell recognition: molecular mechanisms and functional significance. Adv Immunol 74:181–273

    Article  PubMed  CAS  Google Scholar 

  8. Marincola FM, Wang E, Herlyn M, Seliger B, Ferrone S (2003) Tumors as elusive targets of T-cell-based active immunotherapy. Trends Immunol 24:335–342

    Article  PubMed  CAS  Google Scholar 

  9. Rogers PR, Grey HM, Croft M (1998) Modulation of naive CD4 T cell activation with altered peptide ligands: the nature of the peptide and presentation in the context of costimulation are critical for a sustained response. J Immunol 160:3698–3704

    PubMed  CAS  Google Scholar 

  10. Dressel A, Chin JL, Sette A, Gausling R, Hollsberg P, Hafler DA (1997) Autoantigen recognition by human CD8 T cell clones: enhanced agonist response induced by altered peptide ligands. J Immunol 159:4943–4951

    PubMed  CAS  Google Scholar 

  11. Vergelli M, Hemmer B, Kalbus M, Vogt AB, Ling N, Conlon P, Coligan JE, McFarland H, Martin R (1997) Modifications of peptide ligands enhancing T cell responsiveness imply large numbers of stimulatory ligands for autoreactive T cells. J Immunol 158:3746–3752

    PubMed  CAS  Google Scholar 

  12. Nicholson LB, Waldner H, Carrizosa AM, Sette A, Collins M, Kuchroo VK (1998) Heteroclitic proliferative responses and changes in cytokine profile induced by altered peptides: implications for autoimmunity. Proc Nat Acad Sci USA 95:264–269

    Article  PubMed  CAS  Google Scholar 

  13. Valmori D, Fonteneau JF, Lizana CM, Gervois N, Lienard D, Rimoldi D, Jongeneel V, Jotereau F, Cerottini JC, Romero P (1998) Enhanced generation of specific tumor-reactive CTL in vitro by selected Melan-A/MART-1 immunodominant peptide analogues. J Immunol 160:1750–1758

    PubMed  CAS  Google Scholar 

  14. Parkhurst MR, Salgaller ML, Southwood S, Robbins PF, Sette A, Rosenberg SA, Kawakami Y (1996) Improved induction of melanoma-reactive CTL with peptides from the melanoma antigen gp100 modified at HLA-A*0201-binding residues. J Immunol 157:2539–2548

    PubMed  CAS  Google Scholar 

  15. Fong L, Hou Y, Rivas A, Benike C, Yuen A, Fisher GA, Davis MM, Engleman EG (2001) Altered peptide ligand vaccination with Flt3 ligand expanded dendritic cells for tumor immunotherapy. Proc Natl Acad Sci USA 98:8809–8814

    Article  PubMed  CAS  Google Scholar 

  16. Morse MA, Hobeika AC, Osada T, Serra D, Niedzwiecki D, Lyerly HK, Clay TM (2008) Depletion of human regulatory T cells specifically enhances antigen specific immune responses to cancer vaccines. Blood 112:610–618

    Article  PubMed  CAS  Google Scholar 

  17. Rivoltini L, Squarcina P, Loftus DJ, Castelli C, Tarsini P, Mazzocchi A, Rini F, Viggiano V, Belli F, Parmiani G (1999) 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 59:301–306

    PubMed  CAS  Google Scholar 

  18. Novellino L, Castelli C, Parmiani G (2005) A listing of human tumor antigens recognized by T cells: March 2004 update. Cancer Immunol Immunother 54:187–207

    Article  PubMed  CAS  Google Scholar 

  19. Slingluff CL Jr, Engelhard VH, Ferrone S (2006) Peptide and dendritic cell vaccines. Clin Cancer Res 12:2342s–2345s

    Article  PubMed  CAS  Google Scholar 

  20. Kersh GJ, Allen PM (1996) Essential flexibility in the T-cell recognition of antigen. Nature 380:495–498

    Article  PubMed  CAS  Google Scholar 

  21. Evavold BD, Sloan-Lancaster J, Wilson KJ, Rothbard JB, Allen PM (1995) Specific T cell recognition of minimally homologous peptides: evidence for multiple endogenous ligands. Immunity 2:663–665

    Article  Google Scholar 

  22. Shih FF, Allen PM (2004) T cells are not as degenerate as you think, once you get to know them. Mol Immunol 40:1041–1046

    Article  PubMed  CAS  Google Scholar 

  23. Hennecke J, Wiley DC (2001) T cell receptor-MHC interactions up close. Cell 104:1–4

    Article  PubMed  CAS  Google Scholar 

  24. Sloan-Lancaster J, Paul MA (1995) Significance of T-cell stimulation by altered peptide ligands in T cell biology. Curr Op Immunol 7:103–109

    Article  CAS  Google Scholar 

  25. Huseby ES, Crawford F, White J, Marrack P, Kappler JW (2006) Interface-disrupting amino acids establish specificity between T cell receptors and complexes of major histocompatibility complex and peptide. Nat Immunol 7:1191–1199

    Article  PubMed  CAS  Google Scholar 

  26. Kawakami Y, Eliyahu S, Sakaguchi K, Robbins PF, Rivoltini L, Yannelli JR, Appella E, Rosenberg SA (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

    Article  PubMed  CAS  Google Scholar 

  27. Valmori D, Gervois N, Rimoldi D, Fonteneau JF, Bonelo A, Liénard D, Rivoltini L, Jotereau F, Cerottini JC, Romero P (1998) Diversity of the fine specificity displayed by HLA-A*0201-restricted CTL specific for the immunodominant Melan-A/MART-1 antigenic peptide. J Immunol 161:6956–6962

    PubMed  CAS  Google Scholar 

  28. Jäger E, Chen YT, Drijfhout JW, Karbach J, Ringhoffer M, Jäger D, Arand M, Wada H, Noguchi Y, Stockert E, Old LJ, Knuth A (1998) Simultaneous humoral and cellular immune response against cancer-testis antigen NY-ESO-1: definition of human histocompatibility leukocyte antigen (HLA)-A2-binding peptide epitopes. J Exp Med 187:265–270

    Article  PubMed  Google Scholar 

  29. Romero P, Dutoit V, Rubio-Godoy V, Liénard D, Speiser D, Guillaume P, Servis K, Rimoldi D, Cerottini JC, Valmori D (2001) CD8+ T-cell response to NY-ESO-1: relative antigenicity and in vitro immunogenicity of natural and analogue sequences. Clin Cancer Res 7:766s–772s

    PubMed  CAS  Google Scholar 

  30. Bownds S, Tong-On P, Rosenberg SA, Parkhurst M (2001) Induction of tumor-reactive cytotoxic T-lymphocytes using a peptide from NY-ESO-1 modified at the carboxy-terminus to enhance HLA-A2.1 binding affinity and stability in solution. J Immunother 24:1–9

    Article  PubMed  CAS  Google Scholar 

  31. Chen JL, Dunbar PR, Gileadi U, Jäger E, Gnjatic S, Nagata Y, Stockert E, Panicali DL, Chen YT, Knuth A, Old LJ, Cerundolo V (2000) Identification of NY-ESO-1 peptide analogues capable of improved stimulation of tumor-reactive CTL. J Immunol 165:948–955

    PubMed  CAS  Google Scholar 

  32. Chen JL, Stewart-Jones G, Bossi G, Lissin NM, Wooldridge L, Choi EM, Held G, Dunbar PR, Esnouf RM, Sami M, Boulter JM, Rizkallah P, Renner C, Sewell A, van der Merwe PA, Jakobsen BK, Griffiths G, Jones EY, Cerundolo V (2005) Structural and kinetic basis for heightened immunogenicity of T cell vaccines. J Exp Med 201:1243–1255

    Article  PubMed  CAS  Google Scholar 

  33. Cole DJ, Weil DP, Shamamian P, Rivoltini L, Kawakami Y, Topalian S, Jennings C, Eliyahu S, Rosenberg SA, Nishimura MI (1994) Identification of MART-1-specific T-cell receptors: T cells utilizing distinct T-cell receptor variable and joining regions recognize the same tumor epitope. Cancer Res 54:5265–5268

    PubMed  CAS  Google Scholar 

  34. Zaremba S, Barzaga E, Zhu M, Soares N, Tsang KY, Schlom J (1997) Identification of an enhancer agonist cytotoxic T lymphocyte peptide from human carcinoembryonic antigen. Cancer Res 57:4570–4577

    PubMed  CAS  Google Scholar 

  35. Iero M, Squarcina P, Romero P, Guillaume P, Scarselli E, Cerino R, Carrabba M, Toutirais O, Parmiani G, Rivoltini L (2007) Low TCR avidity and lack of tumor cell recognition in CD8(+) T cells primed with the CEA-analogue CAP1-6D peptide. Cancer Immunol Immunother 56:1979–1991

    Article  PubMed  CAS  Google Scholar 

  36. Purbhoo MA, Sutton DH, Brewer JE, Mullings RE, Hill ME, Mahon TM, Karbach J, Jäger E, Cameron BJ, Lissin N, Vyas P, Chen JL, Cerundolo V, Jakobsen BK (2006) Quantifying and imaging NY-ESO-1/LAGE-1-derived epitopes on tumor cells using high affinity T cell receptors. J Immunol 176:7308–7316

    PubMed  CAS  Google Scholar 

  37. Ochsenbein AF, Sierro S, Odermatt B, Pericin M, Karrer U, Hermans J, Hemmi S, Hengartner H, Zinkernagel RM (2001) Roles of tumour localization, second signals and cross priming in cytotoxic T-cell induction. Nature 411:1058–1064

    Article  PubMed  CAS  Google Scholar 

  38. Rosenberg SA, Yang JC, Schwartzentruber DJ, Hwu P, Marincola FM, Topalian SL, Restifo NP, Dudley ME, Schwarz SL, Spiess PJ, Wunderlich JR, Parkhurst MR, Kawakami Y, Seipp CA, Einhorn JH, White DE (1998) Immunologic and therapeutic evaluation of a synthetic peptide vaccine for the treatment of patients with metastatic melanoma. Nat Med 4:321–327

    Article  PubMed  CAS  Google Scholar 

  39. Speiser DE, Baumgaertner P, Voelter V, Devevre E, Barbey C, Rufer N, Romero P (2008) Unmodified self antigen triggers human CD8 T cells with stronger tumor reactivity than altered antigen. Proc Natl Acad Sci USA 105:3849–3854

    Article  PubMed  CAS  Google Scholar 

  40. Lurquin C, Lethé B, De Plaen E, Corbière V, Théate I, van Baren N, Coulie PG, Boon T (2005) Contrasting frequencies of antitumor and anti-vaccine T cells in metastases of a melanoma patient vaccinated with a MAGE tumor antigen. J Exp Med 201:249–257

    Article  PubMed  CAS  Google Scholar 

  41. Babatz J, Rollig C, Lobel B, Folprecht G, Haack M, Gunther H, Kohne CH, Ehninger G, Schmitz M, Bornhauser M (2006) Induction of cellular immune responses against carcinoembryonic antigen in patients with metastatic tumors after vaccination with altered peptide ligand-loaded dendritic cells. Cancer Immunol Immunother 55:268–276

    Article  PubMed  CAS  Google Scholar 

  42. Clay TM, Custer MC, McKee MD, Parkhurst M, Robbins PF, Kerstann K, Wunderlich J, Rosenberg SA, Nishimura MI (1999) 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 162:1749–1755

    PubMed  CAS  Google Scholar 

  43. Stuge TB, Holmes SP, Saharan S, Tuettenberg A, Roederer M, Weber JS, Lee PP (2004) Diversity and recognition efficiency of T cell responses to cancer. PLoS Med 1(2):e28, 149–160

    Google Scholar 

  44. Fazilleau N, Bachelez H, Gougeon ML, Viguier M (2007) Cutting edge: size and diversity of CD4+ CD25 high Foxp3+ regulatory T cell repertoire in humans: evidence for similarities and partial overlapping with CD4+ CD25- T cells. J Immunol 179:3412–3416

    PubMed  CAS  Google Scholar 

  45. Kiniwa Y, Miyahara Y, Wang HY, Peng W, Peng G, Wheeler TM, Thompson TC, Old LJ, Wang RF (2007) CD8+ Foxp3+ regulatory T cells mediate immunosuppression in prostate cancer. Clin Cancer Res 13:6947–6958

    Article  PubMed  CAS  Google Scholar 

  46. Tangri S, Ishioka GY, Huang X, Sidney J, Southwood S, Fikes J, Sette A (2001) 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 194:833–846

    Article  PubMed  CAS  Google Scholar 

  47. Houghton CS, Engelhorn ME, Liu C, Song D, Gregor P, Livingston PO, Orlandi F, Wolchok JD, McCracken J, Houghton AN, Guevara-Patiño JA (2007) Immunological validation of the EpitOptimizer program for streamlined design of heteroclitic epitopes. Vaccine 25:5330–5342

    Article  PubMed  CAS  Google Scholar 

  48. Singh-Jasuja H, Emmerich NP, Rammensee HG (2004) The Tübingen approach: identification, selection, and validation of tumor-associated HLA peptides for cancer therapy. Cancer Immunol Immunother 53:187–195

    Article  PubMed  CAS  Google Scholar 

  49. Hamid O, Solomon JC, Scotland R, Garcia M, Sian S, Ye W, Groshen SL, Weber JS (2007) Alum with interleukin-12 augments immunity to a melanoma peptide vaccine: correlation with time to relapse in patients with resected high-risk disease. Clin Cancer Res 13:215–222

    Article  PubMed  CAS  Google Scholar 

  50. Casati C, Camisaschi C, Rini F, Arienti F, Rivoltini L, Triebel F, Parmiani G, Castelli C (2006) Soluble human LAG-3 molecule amplifies the in vitro generation of type 1 tumor-specific immunity. Cancer Res 66:4450–4460

    Article  PubMed  CAS  Google Scholar 

  51. Kim M, Moon HB, Kim K, Lee KY (2006) Antigen dose governs the shaping of CTL repertoires in vitro and in vivo. Int Immunol 18:435–444

    Article  PubMed  CAS  Google Scholar 

  52. Yang S, Linette GP, Longerich S, Haluska FG (2002) Antimelanoma activity of CTL generated from peripheral blood mononuclear cells after stimulation with autologous dendritic cells pulsed with melanoma gp100 peptide G209-2 M is correlated to TCR avidity. J Immunol 169:531–539

    PubMed  CAS  Google Scholar 

  53. Colombo MP, Piconese S (2007) Regulatory-T-cell inhibition versus depletion: the right choice in cancer immunotherapy. Nat Rev Cancer 7:880–887

    Article  PubMed  CAS  Google Scholar 

  54. Serafini P, Borrello I, Bronte V (2006) Myeloid suppressor cells in cancer: recruitment, phenotype, properties, and mechanisms of immune suppression. Semin Cancer Biol 16:53–65

    Article  PubMed  CAS  Google Scholar 

  55. Filipazzi P, Valenti R, Huber V, Pilla L, Canese P, Iero M, Castelli C, Mariani L, Parmiani G, Rivoltini L (2007) Identification of a new subset of myeloid suppressor cells in peripheral blood of melanoma patients with modulation by a granulocyte-macrophage colony-stimulation factor-based antitumor vaccine. J Clin Oncol 25:2546–2553

    Article  PubMed  CAS  Google Scholar 

  56. Schabowsky RH, Madireddi S, Sharma R, Yolcu ES, Shirwan H (2007) Targeting CD4+ CD25+ FoxP3+ regulatory T-cells for the augmentation of cancer immunotherapy. Curr Opin Investig Drugs 8:1002–1008

    PubMed  CAS  Google Scholar 

  57. De Santo C, Serafini P, Marigo I, Dolcetti L, Bolla M, Del Soldato P, Melani C, Guiducci C, Colombo MP, Iezzi M, Musiani P, Zanovello P, Bronte V (2005) Nitroaspirin corrects immune dysfunction in tumor-bearing hosts and promotes tumor eradication by cancer vaccination. Proc Natl Acad Sci USA 102:4185–4190

    Article  PubMed  Google Scholar 

  58. Nefedova Y, Fishman M, Sherman S, Wang X, Beg AA, Gabrilovich DI (2007) Mechanism of all-trans retinoic acid effect on tumor-associated myeloid-derived suppressor cells. Cancer Res 67:11021–11028

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors are grateful to Agata Cova, Paola Squarcina, Francesca Rini and Valeria Beretta, for the skilful work on the immunological monitoring of vaccinated patients. This work was in part supported by grants of Italian Association for Cancer Research (AIRC, Milan), Italian Ministry of Health-Rome (contracts #70 and 72), the European Community (Cancerimmunotherapy), Istituto Superiore di Sanità-Rome (contracts # ACC2/R2.5 and 7OAF2), and Fondazione Italo Monzino-Milano.

Author information

Authors and Affiliations

  1. Unit of Immunotherapy of Human Tumours, Fondazione IRCCS Istituto Nazionale Tumori, Via Venezian 1, 20133, Milan, Italy

    Manuela Iero, Paola Filipazzi, Chiara Castelli & Licia Rivoltini

  2. Unit of Colo-rectal Surgery, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy

    Filiberto Belli

  3. Unit of Prostate Cancer Program, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy

    Riccardo Valdagni

  4. Unit of Immunobiotherapy of Solid Tumours, San Raffaele Scientific Institute, Milan, Italy

    Giorgio Parmiani

  5. Unit of Melanoma and Sarcoma Surgery, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy

    Roberto Patuzzo & Mario Santinami

Authors
  1. Manuela Iero
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Paola Filipazzi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chiara Castelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Filiberto Belli
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Riccardo Valdagni
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Giorgio Parmiani
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Roberto Patuzzo
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Mario Santinami
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Licia Rivoltini
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Licia Rivoltini.

Additional information

This article is a symposium paper from the conference “Immunotherapy—From Basic Research to Clinical Applications”, Symposium of the Collaborative Research Center (SFB) 685, held in Tübingen, Germany, 6–7 March 2008.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Iero, M., Filipazzi, P., Castelli, C. et al. Modified peptides in anti-cancer vaccines: are we eventually improving anti-tumour immunity?. Cancer Immunol Immunother 58, 1159–1167 (2009). https://doi.org/10.1007/s00262-008-0610-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-008-0610-6

Keywords

Search

Navigation