Summary
The type III variant of the epidermal growth factor receptor (EGFRvIII) mutation is present in 20–25% of patients with glioblastoma multiforme (GBM). EGFRvIII is not expressed in normal tissue and is therefore a suitable candidate antigen for dendritic cell (DC) based immunotherapy of GBM. To identify the antigenic epitope(s) that may serve as targets for EGFRvIII-specific cytotoxic T lymphocytes (CTLs), the peptide sequence of EGFRvIII was screened with two software programs to predict candidate epitopes restricted by the major histocompatibility complex class I subtype HLA-A0201, which is the predominant subtype in most ethnic groups. Three predicted peptides were constructed and loaded to mature human DCs generated from peripheral blood monocytes. Autologous CD8+ T cells were stimulated in vitro with the EGFRvIII peptide-pulsed DCs. One of the three peptides was found to induce EGFRvIII-specific CTLs as demonstrated by IFN-γ production and cytotoxicity against HLA-A0201+ EGFRvIII transfected U87 glioma cells. These results suggest that vaccination with EGFRvIII peptide-pulsed DCs or adoptive transfer of in vitro elicited EGFRvIII-specific CTLs by EGFRvIII peptide-pulsed DCs are potential approaches to the treatment of glioma patients.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
IF Parney C Hao KC Petruk (2000) ArticleTitleGlioma immunology and immunotherapy Neurosurgery 46 IssueID4 778–791 Occurrence Handle10764250 Occurrence Handle1:STN:280:DC%2BD3c3isFehsg%3D%3D
NK Garlie RE Siebenlist AV Lefever (2001) ArticleTitleT cells activated in vitro as immunotherapy for renal cell carcinoma: characterization of 2 effector T-cell populations J Urol 166 IssueID1 299–303 Occurrence Handle11435890 Occurrence Handle1:STN:280:DC%2BD3MznslCqtQ%3D%3D
HT Ni SR Spellman WC Jean WA Hall WC Low (2001) ArticleTitleImmunization with dendritic cells pulsed with tumor extract increases survival of mice bearing intracranial gliomas J Neuro-Oncol 51 IssueID1 1–9 Occurrence Handle10.1023/A:1006452726391 Occurrence Handle1:STN:280:DC%2BD3M3ltFKhug%3D%3D
M Schnurr P Galambos C Scholz F Then M Dauer S Endres A Eigler (2001) ArticleTitleTumor cell lysate-pulsed human dendritic cells induce a T-cell response against pancreatic carcinoma cells: an in vitro model for the assessment of tumor vaccines Cancer Res 61 IssueID17 6445–6450 Occurrence Handle11522639 Occurrence Handle1:CAS:528:DC%2BD3MXmsF2jsb8%3D
WE Schmitt MJ Stassar W Schmitt M Little B Cochlovius (2001) ArticleTitleIn vitro induction of a bladder cancer-specific T-cell response by mRNA-transfected dendritic cells J Cancer Res Clin Oncol 127 IssueID3 203–206 Occurrence Handle11260867 Occurrence Handle10.1007/s004320000201 Occurrence Handle1:CAS:528:DC%2BD3MXhtVGgt70%3D
JS Yu CJ Wheeler PM Zeltzer H Ying DN Finger PK Lee WH Yong F Incardona RC Thompson MS Riedinger W Zhang RM Prins KL Black (2001) ArticleTitleVaccination of malignant glioma patients with peptide-pulsed dendritic cells elicits systemic cytotoxicity and intracranial T-cell infiltration Cancer Res 61 IssueID3 842–847 Occurrence Handle11221866 Occurrence Handle1:CAS:528:DC%2BD3MXhsFSrtLs%3D
D Ridgway (2003) ArticleTitleThe first 1000 dendritic cell vaccines Cancer Investigation 21 873–886 Occurrence Handle14735692 Occurrence Handle10.1081/CNV-120025091
SH Bigner PA Humphrey AJ Wong B Vogelstein J Mark HS Friedman DD Bigner (1990) ArticleTitleCharacterization of the epidermal growth factor receptor in human glioma cell lines and xenografts Cancer Res 50 IssueID24 8017–8022 Occurrence Handle2253244 Occurrence Handle1:CAS:528:DyaK3MXls1ejuw%3D%3D
CT Kuan CJ Wikstrand DD Bigner (2001) ArticleTitleEGF mutant receptor vIII as a molecular target in cancer therapy Endocr-Relat Cancer 8 IssueID2 83–96 Occurrence Handle11397666 Occurrence Handle1:CAS:528:DC%2BD3MXls1Kqtbk%3D
H-JS Huang M Nagane CK Klingbeil H Lin R Nishikawa X-D Ji C-M Huang GN Gill HS Wiley WK Cavenee (1997) ArticleTitleThe enhanced tumorigenic activity of a mutant epidermal growth factor receptor common in human cancers is mediated by threshold levels of constitutive tyrosine phosphorylation and unattenuated signalling J Biol Chem 272 2927–2935 Occurrence Handle9006938 Occurrence Handle1:CAS:528:DyaK2sXpslGitQ%3D%3D
CJ Wikstrand CJ Reist GE Archer MR Zalutsky DD Bigner (1998) ArticleTitleThe class III variant of the epidermal growth factor receptor (EGFRvIII): characterization and utilization as an immunotherapeutic target J Neurovirol 4 IssueID2 148–158 Occurrence Handle9584952 Occurrence Handle1:CAS:528:DyaK1cXis1Wnsrk%3D Occurrence Handle10.3109/13550289809114515
AB Heimberger GE Archer LE Crotty RE McLendon AH Friedman HS Friedman DD Bigner JH Sampson (2002) ArticleTitleDendritic cells pulsed with a tumor-specific peptide induce long-lasting immunity and are effective against murine intracerebral melanoma Neurosurgery 50 IssueID1 158–164 Occurrence Handle11844246
DK Moscatello G Ramirez AJ Wong (1997) ArticleTitleA naturally occurring mutant human epidermal growth factor receptor as a target for peptide vaccine immunotherapy of tumors Cancer Res 57 IssueID8 1419–1424 Occurrence Handle9108438 Occurrence Handle1:CAS:528:DyaK2sXis12lsrw%3D
AB Heimberger LE Crotty AE Archer KR Hess CJ Wikstrand AH Friedman HS Friedman DD Bigner JH Sampson (2003) ArticleTitleEpidermal growth factor receptor VIII peptide vaccination is efficacious against established intracerebral tumors Clin Cancer Res 9 4247–4254 Occurrence Handle14519652 Occurrence Handle1:CAS:528:DC%2BD3sXns1Ojuro%3D
I Mellman RM Steinman (2001) ArticleTitleDendritic cells: specialized and regulated antigen processing machines Cell 106 IssueID3 255–258 Occurrence Handle11509172 Occurrence Handle10.1016/S0092-8674(01)00449-4 Occurrence Handle1:CAS:528:DC%2BD3MXmtFKnsL4%3D
N Romani S Gruner D Brang E Kampgen A Lenz B Trockenbacher G Konwalinka PO Fritsch RM Steinman G Schuler (1994) ArticleTitleProliferating dendritic cell progenitors in human blood J Exp Med 180 83–93 Occurrence Handle8006603 Occurrence Handle10.1084/jem.180.1.83 Occurrence Handle1:CAS:528:DyaK2cXkvVSrurw%3D
F Sallusto A Lanzavecchia (1994) ArticleTitleEfficient presentation of soluble antigen by cultured human dendritic cells is maintained by granulocyte/macrophage colony-stimulating factor plus interleukin 4 and downregulated by tumor necrosis factor alpha J Exp Med 179 1109–1118 Occurrence Handle8145033 Occurrence Handle10.1084/jem.179.4.1109 Occurrence Handle1:CAS:528:DyaK2cXhs1Wjurg%3D
C Caux C Massacrier C Vanbervliet B Dubois I Durand M Cella A Lanzavecchia J Banchereau (1997) ArticleTitleCD34+ hematopoietic progenitors from human cord blood differentiate along two independent dendritic cell pathways in response to granulocyte-macrophage colony-stimulating factor plus tumor necrosis factor alpha: II. Functional analysis Blood 90 1458–1470 Occurrence Handle9269763 Occurrence Handle1:CAS:528:DyaK2sXltlOkur4%3D
BA Tjoa SJ Erickson VA Bowes H Ragde GM Kenny OE Cobb RC Ireton MJ Troychak AL Boynton GP Murphy (1997) ArticleTitleFollow-up evaluation of prostate cancer patients infused with autologous dendritic cells pulsed with PSMA peptides Prostate 32 IssueID4 272–278 Occurrence Handle9288186 Occurrence Handle10.1002/(SICI)1097-0045(19970901)32:4<272::AID-PROS7>3.0.CO;2-L Occurrence Handle1:CAS:528:DyaK2sXmtVGns70%3D
SE Alters JR Gadea M Sorich G O’Donoghue S Talib R Philip (1998) ArticleTitleDendritic cells pulsed with CEA peptide induce CEA-specific CTL with restricted TCR repertoire J Immunother 21 IssueID1 17–26 Occurrence Handle9456432 Occurrence Handle1:CAS:528:DyaK1cXmtVyqtA%3D%3D
J Banchereau AK Palucka M Dhodapkar S Burkeholder N Taquet A Rolland S Taquet S Coquery KM Wittkowski N Bhardwaj L Pineiro R Steinman J Fay (2001) ArticleTitleImmune and clinical responses in patients with metastatic melanoma to CD34(+) progenitor-derived dendritic cell vaccine Cancer Res 61 6451–6458 Occurrence Handle11522640 Occurrence Handle1:CAS:528:DC%2BD3MXmsF2jsbw%3D
DW Mullins TN Bullock TA Colella VV Robila VH Engelhard (2001) ArticleTitleImmune responses to the HLA-A*0201-restricted epitopes of tyrosinase and glycoprotein 100 enable control of melanoma outgrowth in HLA-A*0201-transgenic mice. J Immunol 167 IssueID9 4853–4860 Occurrence Handle11673489 Occurrence Handle1:CAS:528:DC%2BD3MXotVSqurw%3D
ES Schultz B Schuler-Thurner V Stroobant L Jenne TG Berger K Thielemanns P Bruggen Particlevan der G Schuler (2004) ArticleTitleFunctional analysis of tumor-specific Th cell responses detected I melanoma patients after dendritic cell-based immunotherapy J Immunol 172 1304–1310 Occurrence Handle14707109 Occurrence Handle1:CAS:528:DC%2BD2cXnvVam
X Hu NG Chakraborty JR Sporn SH Kurtzman MT Ergin B Mukherji (1996) ArticleTitleEnhancement of cytolytic T lymphocyte precursor frequency in melanoma patients following immunization with the MAGE-1 peptide loaded antigen presenting cell-based vaccine Cancer Res 56 IssueID11 2479–2483 Occurrence Handle8653680 Occurrence Handle1:CAS:528:DyaK28XjtlCgtLw%3D
MR Parkhurst EB Fitzgerald S Southwood A Sette SA Rosenberg Y Kawakami (1998) ArticleTitleIdentification of a shared HLA-A*0201-restricted T-cell epitope from the melanoma antigen tyrosinase-related protein 2 (TRP2) Cancer Res 58 IssueID21 4895–4901 Occurrence Handle9809996 Occurrence Handle1:CAS:528:DyaK1cXnt1yis7Y%3D
MH Andersen P Keikavoussi EB Brocker B Schuler-Thurner M Jonassen I Sondergaard PT Straten JC Becker E Kampgen (2001) ArticleTitleInduction of systemic CTL responses in melanoma patients by dendritic cell vaccination: cessation of CTL responses is associated with disease progression Int J Cancer 94 IssueID6 820–824 Occurrence Handle11745484 Occurrence Handle10.1002/ijc.1536 Occurrence Handle1:CAS:528:DC%2BD3MXotFOkurY%3D
S Reker JC Becker IM Svane E Ralfkiaer P thor Straten MH Andersen (2004) ArticleTitleHLA-B35-restricted immune responses against surviving in cancer patients Int J Cancer 108 937–941 Occurrence Handle14712500 Occurrence Handle10.1002/ijc.11634 Occurrence Handle1:CAS:528:DC%2BD2cXht1Citbw%3D
An-hua Wu WA Hall WC Low (2004) ArticleTitleIdentification of HLA a*0201 glioblastoma multiforme cell lines for immunotherapy by PCR-SSP and DNA sequencing J Neuro-Oncol 66 1–8 Occurrence Handle10.1023/B:NEON.0000013460.53527.28
ML Disis E Calenoff AE Murphy W Chen B Groner M Jescke N Lydon E McGlynn RB Livingston R Moe MA Cheever (1994) ArticleTitleExistent T cell and antibody immunity to HER-2/neu protein in patients with breast cancer Cancer Res 54 16–20 Occurrence Handle7505195 Occurrence Handle1:STN:280:DyaK2c%2FosVKrtQ%3D%3D
J Lu E Celis (2000) ArticleTitleUse of two predictive algorithms of the world wide web for the identification of tumor-reactive T-cell epitopes Cancer Res 60 IssueID18 5223–5227 Occurrence Handle11016651 Occurrence Handle1:CAS:528:DC%2BD3cXntVamu74%3D
L Piriou S Chilmonczyk N Genetet E Albina (2000) ArticleTitleDesign of a flow cytometric assay for the determination of natural killer and cytotoxic T-lymphocyte activity in human and in different animal species Cytometry 41 IssueID4 289–297 Occurrence Handle11084614 Occurrence Handle10.1002/1097-0320(20001201)41:4<289::AID-CYTO7>3.0.CO;2-5 Occurrence Handle1:STN:280:DC%2BD3M%2Fot1agsg%3D%3D
LM Liau KL Black RM Prins SN Sykes PL DiPatre TF Cloughesy DP Becker JM Bronstein (1999) ArticleTitleTreatment of intracranial gliomas with bone marrow-derived dendritic cells pulsed with tumor antigens J Neurosurg 90 IssueID6 1115–1124 Occurrence Handle10350260 Occurrence Handle1:STN:280:DyaK1M3nslOlsQ%3D%3D
T Kikuchi Y Akasaki M Irie S Homma T Abe T Ohno (2001) ArticleTitleResults of a phase I clinical trial of vaccination of glioma patients with fusions of dendritic and glioma cells Cancer Immunol Immunother 50 337–344 Occurrence Handle11676393 Occurrence Handle10.1007/s002620100205 Occurrence Handle1:STN:280:DC%2BD3MrntVSjtQ%3D%3D
R Yamanaka T Abe N Yajima N Tsuchiya J Homma T Kobayashi M Narita M Takahashi R Tanaka (2003) ArticleTitleVaccination of recurrent glioma patients with tumor lysate-pulsed dendritic cells elicits immune responses: results of a clinical phase I/II trial Brit J Cancer 89 1172–1179 Occurrence Handle14520441 Occurrence Handle1:CAS:528:DC%2BD3sXns1Cmu7k%3D
LA Morford AR Dix WH Brooks TL Roszman (1999) ArticleTitleApoptotic elimination of peripheral T lymphocytes in patients with primary intracranial tumors J Neurosurg 91 IssueID6 935–946 Occurrence Handle10584838 Occurrence Handle1:STN:280:DC%2BD3c%2FkvFGgsQ%3D%3D
MA Cheever ML Disis H Bernhard JR Gralow SL Hand ES Huseby HL Qin M Takahashi W Chen (1995) ArticleTitleImmunity to oncogenic proteins Immunol Rev 145 33–59 Occurrence Handle7590829 Occurrence Handle1:CAS:528:DyaK2MXnsVemurw%3D
DJ Peace W Chen H Nelson MA Cheever (1991) ArticleTitleT cell recognition of transforming proteins encoded by mutated ras proto-oncogenes J Immunol 146 2059–2065 Occurrence Handle2005390 Occurrence Handle1:CAS:528:DyaK3MXltFahur4%3D
W Chen DJ Peace DK Rovira SG You MA Cheever (1992) ArticleTitleT cell immunity to the joining region of p210bcr-abl protein Proc Natl Acad Sci USA 89 1468–1472 Occurrence Handle1346932 Occurrence Handle1:CAS:528:DyaK38XhslWrs7Y%3D
DJ Peace JW Smith W Chen SG You WL Cosand J Blake MA Cheever (1994) ArticleTitleLysis of ras oncogene-transformed cells by specific cytotoxic T lymphocytes elicited by primary in vitro immunization with mutated ras peptide J Exp Med 179 473–479 Occurrence Handle8294861 Occurrence Handle10.1084/jem.179.2.473 Occurrence Handle1:CAS:528:DyaK2cXhtlahu70%3D
HL Qin W Chen M Takahashi ML Disis DR Byrd L McCahill KA Bertram RG Fenton DJ Peace MA Cheever (1995) ArticleTitleCD4+ T cell immunity to mutated ras protein in pancreas and colon cancer patients Cancer Res 55 2984–2987 Occurrence Handle7606715 Occurrence Handle1:CAS:528:DyaK2MXmvVyisbY%3D
CJ Wikstrand LP Hale SK Batra ML Hill PA Humphrey SN Kurpad RE McLendon D Moscatello CN Pegram CJ Reist et al. (1995) ArticleTitleMonoclonal antibodies against EGFRvIII are tumor specific and react with breast and lung carcinomas, and malignant gliomas Cancer Res 55 3140–3148 Occurrence Handle7606735 Occurrence Handle1:CAS:528:DyaK2MXmvVyitLo%3D
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Wu, Ah., Xiao, J., Anker, L. et al. Identification of EGFRvIII-derived CTL Epitopes Restricted by HLA A0201 for Dendritic Cell Based Immunotherapy of Gliomas. J Neurooncol 76, 23–30 (2006). https://doi.org/10.1007/s11060-005-3280-7
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11060-005-3280-7