Skip to main content

AE37 peptide vaccination in prostate cancer: a 4-year immunological assessment updates on a phase I trial

Abstract

In our recent phase I trial, we demonstrated that the AE37 vaccine is safe and induces HER-2/neu-specific immunity in a heterogeneous population of HER-2/neu + prostate cancer patients. Herein, we tested whether one AE37 boost can induce long-lasting immunological memory in these patients. Twenty-three patients from the phase I study received one AE37 boost 6-month post-primary vaccinations. Local/systemic toxicities were evaluated following the booster injection. Immunological responses were monitored 1-month (long-term booster; LTB) and 3-year (long-term immunity; LTI) post-booster by delayed-type hypersensitivity, IFN-γ ELISPOT and proliferation assays. Regulatory T cell (Treg) frequencies, plasma transforming growth factor-β (TGF-β) and indoleamine 2,3-deoxygenase (IDO) activity levels were also determined at the same time points. The AE37 booster was safe and well tolerated. Immunological monitoring revealed vaccine-specific long-term immunity in most of the evaluated patients during both LTB and LTI, although individual levels of immunity during LTI were decreased compared with those measured 3 years earlier during LTB. This was paralleled with increased Tregs, TGF-β levels and IDO activity. One AE37 booster generated long-term immunological memory in HER-2/neu + prostate cancer patients, which was detectable 3 years later, albeit with a tendency to decline. Boosted patients had favorable clinical outcome in terms of overall and/or metastasis-free survival compared with historical groups with similar clinical characteristics at diagnosis. We suggest that more boosters and/or concomitant disarming of suppressor circuits may be necessary to sustain immunological memory, and therefore, further studies to optimize the AE37 booster schedule are warranted.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

References

  1. 1.

    Drake CG (2010) Prostate cancer as a model for tumour immunotherapy. Nat Rev Immunol 10:580–593. doi:10.1038/nri2817

    PubMed  Article  CAS  Google Scholar 

  2. 2.

    Baxevanis CN, Voutsas IF, Gritzapis AD, Perez SA, Papamichail M (2010) HER-2/neu as a target for cancer vaccines. Immunotherapy 2:213–226. doi:10.2217/imt.09.89

    PubMed  Article  CAS  Google Scholar 

  3. 3.

    Carles J, Lloreta J, Salido M, Font A, Suarez M, Baena V, Nogue M, Domenech M, Fabregat X (2004) Her-2/neu expression in prostate cancer: a dynamic process? Clinical cancer research : an official journal of the American Association for Cancer Research 10:4742–4745. doi:10.1158/1078-0432.CCR-04-0115

    Article  CAS  Google Scholar 

  4. 4.

    Shi Y, Brands FH, Chatterjee S, Feng AC, Groshen S, Schewe J, Lieskovsky G, Cote RJ (2001) Her-2/neu expression in prostate cancer: high level of expression associated with exposure to hormone therapy and androgen independent disease. J Urol 166:1514–1519

    PubMed  Article  CAS  Google Scholar 

  5. 5.

    Signoretti S, Montironi R, Manola J et al (2000) Her-2-neu expression and progression toward androgen independence in human prostate cancer. J Natl Cancer Inst 92:1918–1925

    PubMed  Article  CAS  Google Scholar 

  6. 6.

    Agus DB, Sweeney CJ, Morris MJ et al (2007) Efficacy and safety of single-agent pertuzumab (rhuMAb 2C4), a human epidermal growth factor receptor dimerization inhibitor, in castration-resistant prostate cancer after progression from taxane-based therapy. J Clin Oncolo Off J Am Soc Clin Oncol 25:675–681. doi:10.1200/JCO.2006.07.0649

    Article  CAS  Google Scholar 

  7. 7.

    de Bono JS, Bellmunt J, Attard G et al (2007) Open-label phase II study evaluating the efficacy and safety of two doses of pertuzumab in castrate chemotherapy-naive patients with hormone-refractory prostate cancer. J Clin Oncol Off J Am Soc Clin Oncol 25:257–262. doi:10.1200/JCO.2006.07.0888

    Article  Google Scholar 

  8. 8.

    Salazar LG, Fikes J, Southwood S, Ishioka G, Knutson KL, Gooley TA, Schiffman K, Disis ML (2003) Immunization of cancer patients with HER-2/neu-derived peptides demonstrating high-affinity binding to multiple class II alleles. Clin Cancer Res Off J Am Assoc Cancer Res 9:5559–5565

    CAS  Google Scholar 

  9. 9.

    Sotiriadou R, Perez SA, Gritzapis AD et al (2001) Peptide HER2(776-788) represents a naturally processed broad MHC class II-restricted T cell epitope. Br J Cancer 85:1527–1534. doi:10.1054/bjoc.2001.2089

    PubMed  Article  CAS  Google Scholar 

  10. 10.

    Gillogly ME, Kallinteris NL, Xu M, Gulfo JV, Humphreys RE, Murray JL (2004) Ii-Key/HER-2/neu MHC class-II antigenic epitope vaccine peptide for breast cancer. Cancer immunol immunotherapy CII 53:490–496. doi:10.1007/s00262-003-0463-y

    Article  CAS  Google Scholar 

  11. 11.

    Perez SA, von Hofe E, Kallinteris NL, Gritzapis AD, Peoples GE, Papamichail M, Baxevanis CN (2010) A new era in anticancer peptide vaccines. Cancer 116:2071–2080. doi:10.1002/cncr.24988

    Google Scholar 

  12. 12.

    Sotiriadou NN, Kallinteris NL, Gritzapis AD et al (2007) Ii-Key/HER-2/neu(776-790) hybrid peptides induce more effective immunological responses over the native peptide in lymphocyte cultures from patients with HER-2/neu + tumors. Cancer Immunol Immunother CII 56:601–613. doi:10.1007/s00262-006-0213-z

    Article  CAS  Google Scholar 

  13. 13.

    Voutsas IF, Gritzapis AD, Mahaira LG, Salagianni M, von Hofe E, Kallinteris NL, Baxevanis CN (2007) Induction of potent CD4 + T cell-mediated antitumor responses by a helper HER-2/neu peptide linked to the Ii-Key moiety of the invariant chain. Int J Cancer 121:2031–2041. doi:10.1002/ijc.22936

    PubMed  Article  CAS  Google Scholar 

  14. 14.

    Perez SA, Kallinteris NL, Bisias S et al (2010) Results from a phase I clinical study of the novel Ii-Key/HER-2/neu(776-790) hybrid peptide vaccine in patients with prostate cancer. Clin Cancer Res Off J Am Assoc Cancer Res 16:3495–3506. doi:10.1158/1078-0432.CCR-10-0085

    Article  CAS  Google Scholar 

  15. 15.

    Sperner-Unterweger B, Neurauter G, Klieber M, Kurz K, Meraner V, Zeimet A, Fuchs D (2011) Enhanced tryptophan degradation in patients with ovarian carcinoma correlates with several serum soluble immune activation markers. Immunobiology 216:296–301. doi:10.1016/j.imbio.2010.07.010

    PubMed  Article  CAS  Google Scholar 

  16. 16.

    Widner B, Werner ER, Schennach H, Wachter H, Fuchs D (1997) Simultaneous measurement of serum tryptophan and kynurenine by HPLC. Clin Chem 43:2424–2426

    PubMed  CAS  Google Scholar 

  17. 17.

    Pound CR, Partin AW, Eisenberger MA, Chan DW, Pearson JD, Walsh PC (1999) Natural history of progression after PSA elevation following radical prostatectomy. JAMA J Am Med Assoc 281:1591–1597

    Article  CAS  Google Scholar 

  18. 18.

    Cheever MA, Higano CS (2011) PROVENGE (Sipuleucel-T) in prostate cancer: the first FDA-approved therapeutic cancer vaccine. Clin Cancer Res Off J Am Assoc Cancer Res 17:3520–3526. doi:10.1158/1078-0432.CCR-10-3126

    Article  Google Scholar 

  19. 19.

    Halabi S, Small EJ, Kantoff PW, Kattan MW, Kaplan EB, Dawson NA, Levine EG, Blumenstein BA, Vogelzang NJ (2003) Prognostic model for predicting survival in men with hormone-refractory metastatic prostate cancer. J Clin Oncol Off J Am Soc Clin Oncol 21:1232–1237

    Article  Google Scholar 

  20. 20.

    Sartor O (2011) Combination therapy: abiraterone prolongs survival in metastatic prostate cancer. Nat Rev Clin Oncol 8:515–516. doi:10.1038/nrclinonc.2011.111

    PubMed  Article  CAS  Google Scholar 

  21. 21.

    Knutson KL, Disis ML (2005) Tumor antigen-specific T helper cells in cancer immunity and immunotherapy. Cancer Immunol Immunother CII 54:721–728. doi:10.1007/s00262-004-0653-2

    Article  CAS  Google Scholar 

  22. 22.

    Melief CJ, van der Burg SH (2008) Immunotherapy of established (pre)malignant disease by synthetic long peptide vaccines. Nat Rev Cancer 8:351–360. doi:10.1038/nrc2373

    PubMed  Article  CAS  Google Scholar 

  23. 23.

    Ebert LM, MacRaild SE, Zanker D, Davis ID, Cebon J, Chen W (2012) A cancer vaccine induces expansion of NY-ESO-1-specific regulatory T cells in patients with advanced melanoma. PLoS ONE 7:e48424. doi:10.1371/journal.pone.0048424

    PubMed  Article  CAS  Google Scholar 

  24. 24.

    Francois V, Ottaviani S, Renkvist N et al (2009) The CD4(+) T-cell response of melanoma patients to a MAGE-A3 peptide vaccine involves potential regulatory T cells. Cancer Res 69:4335–4345. doi:10.1158/0008-5472.CAN-08-3726

    PubMed  Article  CAS  Google Scholar 

  25. 25.

    Welters MJ, Kenter GG, Piersma SJ et al (2008) Induction of tumor-specific CD4 + and CD8 + T-cell immunity in cervical cancer patients by a human papillomavirus type 16 E6 and E7 long peptides vaccine. Clin Cancer Res Off J Am Assoc Cancer Res 14:178–187. doi:10.1158/1078-0432.CCR-07-1880

    Article  CAS  Google Scholar 

  26. 26.

    Ayyoub M, Dojcinovic D, Pignon P, Raimbaud I, Schmidt J, Luescher I, Valmori D (2010) Monitoring of NY-ESO-1 specific CD4 + T cells using molecularly defined MHC class II/His-tag-peptide tetramers. Proc Natl Acad Sci USA 107:7437–7442. doi:10.1073/pnas.1001322107

    PubMed  Article  CAS  Google Scholar 

  27. 27.

    Derhovanessian E, Adams V, Hahnel K, Groeger A, Pandha H, Ward S, Pawelec G (2009) Pretreatment frequency of circulating IL-17 + CD4 + T-cells, but not Tregs, correlates with clinical response to whole-cell vaccination in prostate cancer patients. Int J Cancer 125:1372–1379. doi:10.1002/ijc.24497

    PubMed  Article  CAS  Google Scholar 

  28. 28.

    Jandus C, Bioley G, Dojcinovic D et al (2009) Tumor antigen-specific FOXP3 + CD4 T cells identified in human metastatic melanoma: peptide vaccination results in selective expansion of Th1-like counterparts. Cancer Res 69:8085–8093. doi:10.1158/0008-5472.CAN-09-2226

    PubMed  Article  CAS  Google Scholar 

  29. 29.

    Gates JD, Clifton GT, Benavides LC et al (2010) Circulating regulatory T cells (CD4+ CD25+ FOXP3+) decrease in breast cancer patients after vaccination with a modified MHC class II HER2/neu (AE37) peptide. Vaccine 28:7476–7482. doi:10.1016/j.vaccine.2010.09.029

    PubMed  Article  CAS  Google Scholar 

  30. 30.

    Angell H, Galon J (2013) From the immune contexture to the Immunoscore: the role of prognostic and predictive immune markers in cancer. Curr Opin Immunol 25:261–267. doi:10.1016/j.coi.2013.03.004

    PubMed  Article  CAS  Google Scholar 

  31. 31.

    Fridman WH, Pages F, Sautes-Fridman C, Galon J (2012) The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer 12:298–306. doi:10.1038/nrc3245

    PubMed  Article  CAS  Google Scholar 

  32. 32.

    Flammiger A, Weisbach L, Huland H et al (2013) High tissue density of FOXP3+ T cells is associated with clinical outcome in prostate cancer. Eur J Cancer 49:1273–1279. doi:10.1016/j.ejca.2012.11.035

    PubMed  Article  CAS  Google Scholar 

  33. 33.

    Huen NY, Pang AL, Tucker JA et al (2013) Up-regulation of proliferative and migratory genes in regulatory T cells from patients with metastatic castration-resistant prostate cancer. Int J Cancer. doi:10.1002/ijc.28026

    PubMed  Google Scholar 

  34. 34.

    Gulley JL, Arlen PM, Madan RA et al (2010) Immunologic and prognostic factors associated with overall survival employing a poxviral-based PSA vaccine in metastatic castrate-resistant prostate cancer. Cancer Immunol Immunother CII 59:663–674. doi:10.1007/s00262-009-0782-8

    Article  CAS  Google Scholar 

  35. 35.

    Degl’Innocenti E, Grioni M, Capuano G, Jachetti E, Freschi M, Bertilaccio MT, Hess-Michelini R, Doglioni C, Bellone M (2008) Peripheral T-cell tolerance associated with prostate cancer is independent from CD4+ CD25+ regulatory T cells. Cancer Res 68:292–300. doi:10.1158/0008-5472.CAN-07-2429

    PubMed  Article  Google Scholar 

  36. 36.

    Wan YY, Flavell RA (2007) ‘Yin-Yang’ functions of transforming growth factor-beta and T regulatory cells in immune regulation. Immunol Rev 220:199–213. doi:10.1111/j.1600-065X.2007.00565.x

    PubMed  Article  CAS  Google Scholar 

  37. 37.

    Beriou G, Bradshaw EM, Lozano E et al (2010) TGF-beta induces IL-9 production from human Th17 cells. J Immunol 185:46–54. doi:10.4049/jimmunol.1000356

    PubMed  Article  CAS  Google Scholar 

  38. 38.

    Lu Y, Hong S, Li H et al (2012) Th9 cells promote antitumor immune responses in vivo. J Clin Invest 122:4160–4171. doi:10.1172/JCI65459

    PubMed  Article  CAS  Google Scholar 

  39. 39.

    Smeltz RB, Chen J, Shevach EM (2005) Transforming growth factor-beta1 enhances the interferon-gamma-dependent, interleukin-12-independent pathway of T helper 1 cell differentiation. Immunology 114:484–492. doi:10.1111/j.1365-2567.2005.02115.x

    PubMed  Article  CAS  Google Scholar 

  40. 40.

    Rabinowitz KM, Wang Y, Chen EY et al (2013) Transforming growth factor beta signaling controls activities of human intestinal CD8(+)T suppressor cells. Gastroenterology 144(601–12):e1. doi:10.1053/j.gastro.2012.12.001

    PubMed  Google Scholar 

  41. 41.

    Bierie B, Chung CH, Parker JS, Stover DG, Cheng N, Chytil A, Aakre M, Shyr Y, Moses HL (2009) Abrogation of TGF-beta signaling enhances chemokine production and correlates with prognosis in human breast cancer. J Clin Invest 119:1571–1582. doi:10.1172/JCI37480

    PubMed  Article  CAS  Google Scholar 

  42. 42.

    Godin-Ethier J, Pelletier S, Hanafi LA et al (2009) Human activated T lymphocytes modulate IDO expression in tumors through Th1/Th2 balance. J Immunol 183:7752–7760. doi:10.4049/jimmunol.0901004

    PubMed  Article  CAS  Google Scholar 

  43. 43.

    Riley JL (2013) Combination checkpoint blockade: taking melanoma immunotherapy to the next level. The New England journal of medicine. doi:10.1056/NEJMe1305484

    Google Scholar 

Download references

Acknowledgments

We are indebted to our patients for their voluntary participation in this study. We thank Dr Eric von Hofe for critical reading of the manuscript. We also thank Joanne Kalogeropoulou and Efi Pappou for excellent technical assistance, Dr. Stratos Bissias for helping in patients’ follow-up and C. Zeyher for expert assistance with Trp/Kyn measurements. This study was supported by Antigen Express, Inc. Worcester, Massachusetts, and a grant from OPAP SA to Michael Papamichail.

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Sonia A. Perez.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material (PDF 165 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Perez, S.A., Anastasopoulou, E.A., Tzonis, P. et al. AE37 peptide vaccination in prostate cancer: a 4-year immunological assessment updates on a phase I trial. Cancer Immunol Immunother 62, 1599–1608 (2013). https://doi.org/10.1007/s00262-013-1461-3

Download citation

Keywords

  • HER-2/neu
  • AE37 vaccine
  • Prostate cancer
  • Immunological memory