Abstract
A fundamental challenge in administering immunotherapies for cancer is the establishment of biomarkers that can predict patients’ responsiveness to treatment. In this study, our aim was to predict the immunologic and clinical responses of vaccination therapy with an Ii-key-modified HER-2/neu peptide (Ii-key/HER-2(776–790) or AE37), applied in our recent phase I study in patients with prostate cancer. To this end, we retrospectively analyzed our data derived from immunologic determinations before, during and after primary series of vaccinations with AE37, as well as after one AE37 booster injection. Using the obtained data, we then observed the relationship between the immunologic parameters and clinical outcome of patients. We found that preexisting levels of transforming growth factor beta (TGF-β) had an inverse correlation with in vivo and in vitro immunologic responses to the AE37 vaccine which were measured as delayed-type hypersensitivity (DTH) and interferon gamma (IFN-γ) production in response to the native HER-2(776–790) (or AE36) peptide, respectively. Patients with preexistent IFN-γ immunity to AE36 developed positive DTH reactions after primary vaccinations and booster. Moreover, we could detect a direct correlation between IFN-γ production and DTH reactions in response to AE36 challenge in our vaccinated patients. DTH reactions were a stronger indicator for patients’ overall survival (OS) than preexistent or vaccine-induced IFN-γ immunity. In contrast, we found that preexisting TGF-β levels were correlated with shorter patients’ OS. These retrospective analyses suggest that the above biomarkers at the time-points measured offer promise for evaluating immunologic and clinical responses to AE37-based vaccinations.
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1007%2Fs00262-014-1582-3/MediaObjects/262_2014_1582_Fig1_HTML.gif)
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1007%2Fs00262-014-1582-3/MediaObjects/262_2014_1582_Fig2_HTML.gif)
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1007%2Fs00262-014-1582-3/MediaObjects/262_2014_1582_Fig3_HTML.gif)
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1007%2Fs00262-014-1582-3/MediaObjects/262_2014_1582_Fig4_HTML.gif)
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1007%2Fs00262-014-1582-3/MediaObjects/262_2014_1582_Fig5_HTML.gif)
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1007%2Fs00262-014-1582-3/MediaObjects/262_2014_1582_Fig6_HTML.gif)
Similar content being viewed by others
Abbreviations
- DTH:
-
Delayed-type hypersensitivity
- FDA:
-
Food and drug administration
- GM-CSF:
-
Granulocyte–macrophage colony-stimulating factor
- IFN-γ:
-
Interferon gamma
- LT:
-
Long term
- LTB:
-
Long-term booster
- LTI:
-
Long-term immunity
- OS:
-
Overall survival
- TGF-β:
-
Transforming growth factor beta
References
Di Lorenzo G, Buonerba C, Kantoff PW (2011) Immunotherapy for the treatment of prostate cancer. Nat Rev Clin Oncol 8:551–561. doi:10.1038/nrclinonc.2011.72
Cheng ML, Fong L (2014) Beyond sipuleucel-T: immune approaches to treating prostate cancer. Curr Treat Options Oncol 15:115–126. doi:10.1007/s11864-013-0267-z
May KF Jr, Gulley JL, Drake CG, Dranoff G, Kantoff PW (2011) Prostate cancer immunotherapy. Clin Cancer Res 17:5233–5238. doi:10.1158/1078-0432.CCR-10-3402
Schlom J (2012) Therapeutic cancer vaccines: current status and moving forward. J Natl Cancer Inst 104:599–613. doi:10.1093/jnci/djs033
Baxevanis CN (2012) Outlining novel scenarios for improved therapeutic cancer vaccines: the PANVAC paradigm. Expert Rev Vaccines. 11:275–277. doi:10.1586/erv.11.193
Cowen D, Troncoso P, Khoo VS, Zagars GK, von Eschenbach AC, Meistrich ML, Pollack A (2002) Ki-67 staining is an independent correlate of biochemical failure in prostate cancer treated with radiotherapy. Clin Cancer Res 8:1148–1154
Khor LY, Bae K, Paulus R et al (2009) MDM2 and Ki-67 predict for distant metastasis and mortality in men treated with radiotherapy and androgen deprivation for prostate cancer: RTOG 92-02. J Clin Oncol 27:3177–3184. doi:10.1200/JCO.2008.19.8267
Travis MA, Sheppard D (2014) TGF-beta activation and function in immunity. Annu Rev Immunol 32:51–82. doi:10.1146/annurev-immunol-032713-120257
Bierie B, Moses HL (2006) Tumour microenvironment: TGFbeta: the molecular Jekyll and Hyde of cancer. Nat Rev Cancer 6:506–520. doi:10.1038/nrc1926
Steiner MS, Zhou ZZ, Tonb DC, Barrack ER (1994) Expression of transforming growth factor-beta 1 in prostate cancer. Endocrinology 135:2240–2247. doi:10.1210/endo.135.5.7956947
Barrack ER (1997) TGF beta in prostate cancer: a growth inhibitor that can enhance tumorigenicity. Prostate 31:61–70
Disis ML, Schiffman K, Gooley TA, McNeel DG, Rinn K, Knutson KL (2000) Delayed-type hypersensitivity response is a predictor of peripheral blood T-cell immunity after HER-2/neu peptide immunization. Clin Cancer Res 6:1347–1350
Holmes JP, Benavides LC, Gates JD et al (2008) Results of the first phase I clinical trial of the novel II-key hybrid preventive HER-2/neu peptide (AE37) vaccine. J Clin Oncol 26:3426–3433. doi:10.1200/JCO.2007.15.7842
Lesterhuis WJ, Schreibelt G, Scharenborg NM 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. doi:10.1007/s00262-010-0942-x
Lopez MN, Pereda C, Segal G et al (2009) Prolonged survival of dendritic cell-vaccinated melanoma patients correlates with tumor-specific delayed type IV hypersensitivity response and reduction of tumor growth factor beta-expressing T cells. J Clin Oncol 27:945–952. doi:10.1200/JCO.2008.18.0794
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 16:3495–3506. doi:10.1158/1078-0432.CCR-10-0085
Hoos A, Eggermont AM, Janetzki S et al (2010) Improved endpoints for cancer immunotherapy trials. J Natl Cancer Inst 102:1388–1397. doi:10.1093/jnci/djq310
Ishikawa T, Kokura S, Sakamoto N et al (2013) Whole blood interferon-gamma levels predict the therapeutic effects of adoptive T-cell therapy in patients with advanced pancreatic cancer. Int J Cancer 133:1119–1125. doi:10.1002/ijc.28117
Zamarron BF, Chen W (2011) Dual roles of immune cells and their factors in cancer development and progression. Int J Biol Sci. 7:651–658
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
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 56:601–613. doi:10.1007/s00262-006-0213-z
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
Perez SA, Anastasopoulou EA, Tzonis P, Gouttefangeas C, Kalbacher H, Papamichail M, Baxevanis CN (2013) AE37 peptide vaccination in prostate cancer: a 4-year immunological assessment updates on a phase I trial. Cancer Immunol Immunother 62:1599–1608. doi:10.1007/s00262-013-1461-3
Reyes D, Salazar L, Espinoza E et al (2013) Tumour cell lysate-loaded dendritic cell vaccine induces biochemical and memory immune response in castration-resistant prostate cancer patients. Br J Cancer 109:1488–1497. doi:10.1038/bjc.2013.494
Prud’homme GJ (2007) Pathobiology of transforming growth factor beta in cancer, fibrosis and immunologic disease, and therapeutic considerations. Lab Invest 87:1077–1091. doi:10.1038/labinvest.3700669
Lippitz BE (2013) Cytokine patterns in patients with cancer: a systematic review. Lancet Oncol. 14:e218–e228. doi:10.1016/S1470-2045(12)70582-X
de Vries IJ, Bernsen MR, Lesterhuis WJ et al (2005) Immunomonitoring tumor-specific T cells in delayed-type hypersensitivity skin biopsies after dendritic cell vaccination correlates with clinical outcome. J Clin Oncol 23:5779–5787. doi:10.1200/JCO.2005.06.478
Coulie PG, Karanikas V, Colau D, Lurquin C, Landry C, Marchand M, Dorval T, Brichard V, Boon T (2001) A monoclonal cytolytic T-lymphocyte response observed in a melanoma patient vaccinated with a tumor-specific antigenic peptide encoded by gene MAGE-3. Proc Natl Acad Sci USA 98:10290–10295. doi:10.1073/pnas.161260098
Vukmanovic-Stejic M, Reed JR, Lacy KE, Rustin MH, Akbar AN (2006) Mantoux test as a model for a secondary immune response in humans. Immunol Lett 107:93–101. doi:10.1016/j.imlet.2006.08.002
Nacher M, Blazquez AB, Shao B, Matesanz A, Prophete C, Berin MC, Frenette PS, Hidalgo A (2011) Physiological contribution of CD44 as a ligand for E-selectin during inflammatory T-cell recruitment. Am J Pathol 178:2437–2446. doi:10.1016/j.ajpath.2011.01.039
Singh SK, Tummers B, Schumacher TN et al (2013) The development of standard samples with a defined number of antigen-specific T cells to harmonize T cell assays: a proof-of-principle study. Cancer Immunol Immunother 62:489–501. doi:10.1007/s00262-012-1351-0
Conflict of interest
The authors declare that they have no conflict of interest.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Perez, S.A., Anastasopoulou, E.A., Papamichail, M. et al. AE37 peptide vaccination in prostate cancer: identification of biomarkers in the context of prognosis and prediction. Cancer Immunol Immunother 63, 1141–1150 (2014). https://doi.org/10.1007/s00262-014-1582-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00262-014-1582-3