Skip to main content

Advertisement

SpringerLink
Log in

Immunological factors influencing clinical outcome in lung cancer patients after telomerase peptide vaccination

  • Original Article
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

We have previously reported two trials in non-small cell lung cancer (NSCLC) evaluating vaccine therapy with the telomerase peptide GV1001. The studies demonstrated considerable differences in survival among immune responders, highlighting that an immune response is not necessarily beneficial. In the present study, we conducted long-term clinical follow-up and investigated immunological factors hypothesized to influence clinical efficacy. Peripheral blood mononuclear cells from 33 NSCLC trial patients and 15 healthy donors were analyzed by flow cytometry for T regulatory cells (Tregs, CD4+CD25+CD127low/−FOXP3+) and two types of myeloid-derived suppressor cells (MDSCs, HLA-DR low CD14 + or Lin −/lo HLA-DR − CD33 + CD11b +). T cell cultures were analyzed for 17 cytokines. The results demonstrated that immune responders had increased overall survival (OS, p < 0.001) and progression-free survival (p = 0.003), compared to subjects without immunological response. The mean OS advantage was 54 versus 13 months. Six patients were still alive at the last clinical update, all belonging to the immune responders. No serious toxicity had developed (maximum observation 13 years). Most patients developed a polyfunctional cytokine profile, with high IFNγ/IL-4 and IFNγ/IL-10 ratios. Low Treg levels were associated with improved OS (p = 0.037) and a favorable cytokine profile, including higher IFNγ/IL-10 ratios. High CD33+ MDSC levels were associated with poorer immune response rate (p = 0.005). The levels of CD14+ MDSC were significantly higher in patients than in healthy controls (p = 0.012). We conclude that a randomized GV1001 trial in NSCLC is warranted. The findings suggest that Tregs and MDSCs are associated with a tolerogenic cytokine milieu and impaired clinical efficacy of vaccine responses.

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
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Abbreviations

MCP:

Monocyte chemoattractant protein

MDSC:

Myeloid-derived suppressor cell

MIP:

Macrophage inflammatory protein

NSCLC:

Non-small cell lung cancer

OS:

Overall survival

PFS:

Progression-free survival

Th:

T helper

Treg:

T regulatory cell

References

  1. Brambilla E, Travis WD (2014) World cancer report. Lung cancer, World Health Organization, Lyon

    Google Scholar 

  2. Garon EB, Rizvi NA, Hui R, Leighl N, Balmanoukian AS, Eder JP, Patnaik A, Aggarwal C, Gubens M, Horn L et al (2015) Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med 372(21):2018–2028

    Article  PubMed  Google Scholar 

  3. Melero I, Gaudernack G, Gerritsen W, Huber C, Parmiani G, Scholl S, Thatcher N, Wagstaff J, Zielinski C, Faulkner I et al (2014) Therapeutic vaccines for cancer: an overview of clinical trials. Nat Rev Clin Oncol 11(9):509–524

    Article  CAS  PubMed  Google Scholar 

  4. Kyte JA (2009) Cancer vaccination with telomerase peptide GV1001. Expert Opin Investig Drugs 18(5):687–694

    Article  CAS  PubMed  Google Scholar 

  5. Bernhardt SL, Gjertsen MK, Trachsel S, Moller M, Eriksen JA, Meo M, Buanes T, Gaudernack G (2006) Telomerase peptide vaccination of patients with non-resectable pancreatic cancer: a dose escalating phase I/II study. Br J Cancer 95(11):1474–1482

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  6. Brunsvig PF, Kyte JA, Kersten C, Sundstrom S, Moller M, Nyakas M, Hansen GL, Gaudernack G, Aamdal S (2011) Telomerase peptide vaccination in NSCLC: a phase II trial in stage III patients vaccinated after chemoradiotherapy and an 8-year update on a phase I/II trial. Clin Cancer Res 17(21):6847–6857

    Article  CAS  PubMed  Google Scholar 

  7. Kyte JA, Gaudernack G, Dueland S, Trachsel S, Julsrud L, Aamdal S (2011) Telomerase peptide vaccination combined with temozolomide: a clinical trial in stage IV melanoma patients. Clin Cancer Res 17(13):4568–4580

    Article  CAS  PubMed  Google Scholar 

  8. Greten TF, Forner A, Korangy F, N’Kontchou G, Barget N, Ayuso C, Ormandy LA, Manns MP, Beaugrand M, Bruix J (2010) A phase II open label trial evaluating safety and efficacy of a telomerase peptide vaccination in patients with advanced hepatocellular carcinoma. BMC Cancer 10:209

    Article  PubMed Central  PubMed  Google Scholar 

  9. Middleton G, Silcocks P, Cox T, Valle J, Wadsley J, Propper D, Coxon F, Ross P, Madhusudan S, Roques T et al (2014) Gemcitabine and capecitabine with or without telomerase peptide vaccine GV1001 in patients with locally advanced or metastatic pancreatic cancer (TeloVac): an open-label, randomised, phase 3 trial. Lancet Oncol 15(8):829–840

    Article  CAS  PubMed  Google Scholar 

  10. Szostak JW, Blackburn EH (1982) Cloning yeast telomeres on linear plasmid vectors. Cell 29(1):245–255

    Article  CAS  PubMed  Google Scholar 

  11. Greider CW, Blackburn EH (1985) Identification of a specific telomere terminal transferase activity in Tetrahymena extracts. Cell 43(2 Pt 1):405–413

    Article  CAS  PubMed  Google Scholar 

  12. Kim NW, Piatyszek MA, Prowse KR, Harley CB, West MD, Ho PL, Coviello GM, Wright WE, Weinrich SL, Shay JW (1994) Specific association of human telomerase activity with immortal cells and cancer. Science 266(5193):2011–2015

    Article  CAS  PubMed  Google Scholar 

  13. Fernandez-Garcia I, Ortiz-de-Solorzano C, Montuenga LM (2008) Telomeres and telomerase in lung cancer. J Thorac Oncol 3(10):1085–1088

    Article  PubMed  Google Scholar 

  14. Parkhurst MR, Riley JP, Igarashi T, Li Y, Robbins PF, Rosenberg SA (2004) Immunization of patients with the hTERT: 540–548 peptide induces peptide-reactive T lymphocytes that do not recognize tumors endogenously expressing telomerase. Clin Cancer Res 10(14):4688–4698

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. Bolonaki I, Kotsakis A, Papadimitraki E, Aggouraki D, Konsolakis G, Vagia A, Christophylakis C, Nikoloudi I, Magganas E, Galanis A et al (2007) Vaccination of patients with advanced non-small-cell lung cancer with an optimized cryptic human telomerase reverse transcriptase peptide. J Clin Oncol 25(19):2727–2734

    Article  CAS  PubMed  Google Scholar 

  16. Vonderheide RH, Hahn WC, Schultze JL, Nadler LM (1999) The telomerase catalytic subunit is a widely expressed tumor-associated antigen recognized by cytotoxic T lymphocytes. Immunity 10(6):673–679

    Article  CAS  PubMed  Google Scholar 

  17. Brunsvig P, Aamdal S, Gjertsen MK, Kvalheim G, Markowski-Grimsrud CJ, Sve I, Dyrhaug M, Trachsel S, Moeller M, Eriksen JA et al (2006) Telomerase peptide vaccination: a phase I/II study in patients with non-small cell lung cancer. Cancer Immunol Immunother 55(12):1553–1564

    Article  CAS  PubMed  Google Scholar 

  18. Kyte JA, Trachsel S, Risberg B, thor Straten P, Lislerud K, Gaudernack G (2009) Unconventional cytokine profiles and development of T cell memory in long-term survivors after cancer vaccination. Cancer Immunol Immunother 58(10):1609–1626

    Article  CAS  PubMed  Google Scholar 

  19. Knutson KL, Disis ML (2005) Tumor antigen-specific T helper cells in cancer immunity and immunotherapy. Cancer Immunol Immunother 54(8):721–728

    Article  CAS  PubMed  Google Scholar 

  20. Mougiakakos D, Choudhury A, Lladser A, Kiessling R, Johansson CC (2010) Regulatory T cells in cancer. Adv Cancer Res 107:57–117

    Article  CAS  PubMed  Google Scholar 

  21. Ostrand-Rosenberg S, Sinha P (2009) Myeloid-derived suppressor cells: linking inflammation and cancer. J Immunol 182(8):4499–4506

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  22. Gabrilovich DI, Nagaraj S (2009) Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol 9(3):162–174

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Almand B, Clark JI, Nikitina E, van Beynen J, English NR, Knight SC, Carbone DP, Gabrilovich DI (2001) Increased production of immature myeloid cells in cancer patients: a mechanism of immunosuppression in cancer. J Immunol 166(1):678–689

    Article  CAS  PubMed  Google Scholar 

  24. Lechner MG, Megiel C, Russell SM, Bingham B, Arger N, Woo T, Epstein AL (2011) Functional characterization of human Cd33+ and Cd11b+ myeloid-derived suppressor cell subsets induced from peripheral blood mononuclear cells co-cultured with a diverse set of human tumor cell lines. J Transl Med 9:90

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  25. Gabitass RF, Annels NE, Stocken DD, Pandha HA, Middleton GW (2011) Elevated myeloid-derived suppressor cells in pancreatic, esophageal and gastric cancer are an independent prognostic factor and are associated with significant elevation of the Th2 cytokine interleukin-13. Cancer Immunol Immunother 60(10):1419–1430

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. 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(18):2546–2553

    Article  CAS  PubMed  Google Scholar 

  27. Brimnes MK, Vangsted AJ, Knudsen LM, Gimsing P, Gang AO, Johnsen HE, Svane IM (2010) Increased level of both CD4+FOXP3+ regulatory T cells and CD14+HLA-DR(−)/low myeloid-derived suppressor cells and decreased level of dendritic cells in patients with multiple myeloma. Scand J Immunol 72(6):540–547

    Article  CAS  PubMed  Google Scholar 

  28. Hoechst B, Ormandy LA, Ballmaier M, Lehner F, Kruger C, Manns MP, Greten TF, Korangy F (2008) A new population of myeloid-derived suppressor cells in hepatocellular carcinoma patients induces CD4(+)CD25(+)Foxp3(+) T cells. Gastroenterology 135(1):234–243

    Article  CAS  PubMed  Google Scholar 

  29. Kyte JA, Kvalheim G, Aamdal S, Saebøe-Larssen S, Gaudernack G (2005) Preclinical full-scale evaluation of dendritic cells transfected with autologous tumor-mRNA for melanoma vaccination. Cancer Gene Ther 12(6):579–591

    Article  CAS  PubMed  Google Scholar 

  30. Annunziato F, Cosmi L, Santarlasci V, Maggi L, Liotta F, Mazzinghi B, Parente E, Fili L, Ferri S, Frosali F et al (2007) Phenotypic and functional features of human Th17 cells. J Exp Med 204(8):1849–1861

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  31. Martin-Orozco N, Muranski P, Chung Y, Yang XO, Yamazaki T, Lu S, Hwu P, Restifo NP, Overwijk WW, Dong C (2009) T helper 17 cells promote cytotoxic T cell activation in tumor immunity. Immunity 31(5):787–798

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  32. Kyte JA, Kvalheim G, Lislerud K, Thor Straten P, Dueland S, Aamdal S, Gaudernack G (2007) T cell responses in melanoma patients after vaccination with tumor-mRNA transfected dendritic cells. Cancer Immunol Immunother 56(5):659–675

    Article  CAS  PubMed  Google Scholar 

  33. Ruffell B, Chang-Strachan D, Chan V, Rosenbusch A, Ho CM, Pryer N, Daniel D, Hwang ES, Rugo HS, Coussens LM (2014) Macrophage IL-10 blocks CD8+ T cell-dependent responses to chemotherapy by suppressing IL-12 expression in intratumoral dendritic cells. Cancer Cell 26(5):623–637

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  34. Zou W (2006) Regulatory T cells, tumour immunity and immunotherapy. Nat Rev Immunol 6(4):295–307

    Article  CAS  PubMed  Google Scholar 

  35. Woo EY, Yeh H, Chu CS, Schlienger K, Carroll RG, Riley JL, Kaiser LR, June CH (2002) Cutting edge: regulatory T cells from lung cancer patients directly inhibit autologous T cell proliferation. J Immunol 168(9):4272–4276

    Article  CAS  PubMed  Google Scholar 

  36. Woo EY, Chu CS, Goletz TJ, Schlienger K, Yeh H, Coukos G, Rubin SC, Kaiser LR, June CH (2001) Regulatory CD4(+)CD25(+) T cells in tumors from patients with early-stage non-small cell lung cancer and late-stage ovarian cancer. Cancer Res 61(12):4766–4772

    CAS  PubMed  Google Scholar 

  37. Elkord E, Alcantar-Orozco EM, Dovedi SJ, Tran DQ, Hawkins RE, Gilham DE (2010) T regulatory cells in cancer: recent advances and therapeutic potential. Expert Opin Biol Ther 10(11):1573–1586

    Article  CAS  PubMed  Google Scholar 

  38. Walter S, Weinschenk T, Stenzl A, Zdrojowy R, Pluzanska A, Szczylik C, Staehler M, Brugger W, Dietrich PY, Mendrzyk R et al (2012) Multipeptide immune response to cancer vaccine IMA901 after single-dose cyclophosphamide associates with longer patient survival. Nat Med 18(8):1254–1261

    Article  CAS  PubMed  Google Scholar 

  39. Inderberg-Suso EM, Trachsel S, Lislerud K, Rasmussen AM, Gaudernack G (2012) Widespread CD4+ T-cell reactivity to novel hTERT epitopes following vaccination of cancer patients with a single hTERT peptide GV1001. Oncoimmunology 1(5):670–686

    Article  PubMed Central  PubMed  Google Scholar 

  40. Diaz-Montero CM, Salem ML, Nishimura MI, Garrett-Mayer E, Cole DJ, Montero AJ (2009) Increased circulating myeloid-derived suppressor cells correlate with clinical cancer stage, metastatic tumor burden, and doxorubicin–cyclophosphamide chemotherapy. Cancer Immunol Immunother 58(1):49–59

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  41. Liu CY, Wang YM, Wang CL, Feng PH, Ko HW, Liu YH, Wu YC, Chu Y, Chung FT, Kuo CH et al (2010) Population alterations of L-arginase- and inducible nitric oxide synthase-expressed CD11b+/CD14(−)/CD15+/CD33+ myeloid-derived suppressor cells and CD8+ T lymphocytes in patients with advanced-stage non-small cell lung cancer. J Cancer Res Clin Oncol 136(1):35–45

    Article  CAS  PubMed  Google Scholar 

  42. Huang A, Zhang B, Wang B, Zhang F, Fan KX, Guo YJ (2013) Increased CD14(+)HLA-DR (-/low) myeloid-derived suppressor cells correlate with extrathoracic metastasis and poor response to chemotherapy in non-small cell lung cancer patients. Cancer Immunol Immunother 62(9):1439–1451

    Article  CAS  PubMed  Google Scholar 

  43. Iclozan C, Antonia S, Chiappori A, Chen DT, Gabrilovich D (2013) Therapeutic regulation of myeloid-derived suppressor cells and immune response to cancer vaccine in patients with extensive stage small cell lung cancer. Cancer Immunol Immunother 62(5):909–918

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  44. Ridolfi L, Petrini M, Granato AM, Gentilcore G, Simeone E, Ascierto PA, Pancisi E, Ancarani V, Fiammenghi L, Guidoboni M et al (2013) Low-dose temozolomide before dendritic-cell vaccination reduces (specifically) CD4+ CD25++ Foxp3+ regulatory T-cells in advanced melanoma patients. J Transl Med 11:135

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  45. Simpson TR, Li F, Montalvo-Ortiz W, Sepulveda MA, Bergerhoff K, Arce F, Roddie C, Henry JY, Yagita H, Wolchok JD et al (2013) Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti-CTLA-4 therapy against melanoma. J Exp Med 210(9):1695–1710

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  46. Marabelle A, Kohrt H, Sagiv-Barfi I, Ajami B, Axtell RC, Zhou G, Rajapaksa R, Green MR, Torchia J, Brody J et al (2013) Depleting tumor-specific Tregs at a single site eradicates disseminated tumors. J Clin Invest 123(6):2447–2463

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  47. Mosmann TR, Cherwinski H, Bond MW, Giedlin MA, Coffman RL (1986) Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol 136(7):2348–2357

    CAS  PubMed  Google Scholar 

  48. Kyte JA, Mu L, Aamdal S, Kvalheim G, Dueland S, Hauser M, Gullestad HP, Ryder T, Lislerud K, Hammerstad H et al (2006) Phase I/II trial of melanoma therapy with dendritic cells transfected with autologous tumor-mRNA. Cancer Gene Ther 13(10):905–918

    Article  CAS  PubMed  Google Scholar 

  49. Duvall MG, Precopio ML, Ambrozak DA, Jaye A, McMichael AJ, Whittle HC, Roederer M, Rowland-Jones SL, Koup RA (2008) Polyfunctional T cell responses are a hallmark of HIV-2 infection. Eur J Immunol 38(2):350–363

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  50. Darrah PA, Patel DT, De Luca PM, Lindsay RW, Davey DF, Flynn BJ, Hoff ST, Andersen P, Reed SG, Morris SL et al (2007) Multifunctional TH1 cells define a correlate of vaccine-mediated protection against Leishmania major. Nat Med 13(7):843–850

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The work was supported by the Norwegian Health Region South-East and the Faculty of Medicine, University of Oslo. Pharmexa (Denmark) supplied GV1001 free of charge. The authors thank Sissel Trachsel and Mira Roness for valuable technical assistance. We also thank doctors and nurses at the study hospitals for excellent clinical follow-up and patient care. Special thanks to Steinar Aamdal, Christian Kersten, Stein Sundstrøm, Else Marit Suso, Svein Dueland, Odd Terje Brustugun, Kristin Øwre, and Ingun Sve.

Author information

Authors and Affiliations

  1. Department of Immunology, Radiumhospitalet, Oslo University Hospital, Oslo, Norway

    Gaute Lund Hansen, Gustav Gaudernack & Jon Amund Kyte

  2. The Clinical Trial Unit, Department of Clinical Cancer Research, Radiumhospitalet, Oslo University Hospital, Oslo, Norway

    Paal Fredrik Brunsvig

  3. National Resource Center for Late Effects, Department of Oncology, Radiumhospitalet, Oslo University Hospital, Oslo, Norway

    Milada Cvancarova

  4. Department of Oncology, Radiumhospitalet, Oslo University Hospital, Mail Box 4950, Nydalen, 0424, Oslo, Norway

    Jon Amund Kyte

Authors
  1. Gaute Lund Hansen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gustav Gaudernack
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Paal Fredrik Brunsvig
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Milada Cvancarova
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jon Amund Kyte
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jon Amund Kyte.

Ethics declarations

Conflict of interest

J.A. Kyte has received research support (≈10,000 Euro) from Kael-Gemvax. G. Gaudernack is a member of Kael-Gemvax advisory board. The other authors declare that they have no conflict of interest.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 423 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hansen, G.L., Gaudernack, G., Brunsvig, P.F. et al. Immunological factors influencing clinical outcome in lung cancer patients after telomerase peptide vaccination. Cancer Immunol Immunother 64, 1609–1621 (2015). https://doi.org/10.1007/s00262-015-1766-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-015-1766-5

Keywords

Search

Navigation