Journal of Neuro-Oncology

, Volume 123, Issue 3, pp 347–358 | Cite as

Glioblastoma antigen discovery—foundations for immunotherapy

  • Tej D. Azad
  • Seyed-Mostafa Razavi
  • Benjamin Jin
  • Karen Lee
  • Gordon Li
Editors' Invited Manuscript


Prognosis for patients with glioblastoma (GBM), the most common high-grade primary central nervous system (CNS) tumor, remains discouraging despite multiple discoveries and clinical advances. Immunotherapy has emerged as a promising approach to GBM therapy as the idea the human CNS is immunoprivileged is being challenged. Early clinical studies of vaccine-based approaches have been encouraging, but further investigation is required before these therapies become clinically meaningful. A key challenge in immunotherapy involves identification of target antigens that are specific and sensitive for GBM. Here we discuss tumor-associated antigens that have been targeted for GBM therapy, strategies for discovery of novel antigens, and the theory of epitope spreading as it applies to GBM immunotherapy.


Glioblastoma Tumor associated antigen Vaccine Epitope spreading 


  1. 1.
    Johnson DR, O’Neill BP (2012) Glioblastoma survival in the United States before and during the temozolomide era. J Neurooncol 107:359–364. doi: 10.1007/s11060-011-0749-4 PubMedCrossRefGoogle Scholar
  2. 2.
    Xu LW, Chow KK, Lim M, Li G (2014) Current vaccine trials in glioblastoma: a review. J Immunol Res 2014:796856. doi: 10.1155/2014/796856 PubMedCentralPubMedCrossRefGoogle Scholar
  3. 3.
    Zhang JG, Kruse CA, Driggers L, Hoa N, Wisoff J, Allen JC, Zagzag D, Newcomb EW, Jadus MR (2008) Tumor antigen precursor protein profiles of adult and pediatric brain tumors identify potential targets for immunotherapy. J Neurooncol 88:65–76. doi: 10.1007/s11060-008-9534-4 PubMedCentralPubMedCrossRefGoogle Scholar
  4. 4.
    Camara-Quintana JQ, Nitta RT, Li G, viii (2012) Pathology: commonly monitored glioblastoma markers: EFGR, EGFRvIII, PTEN, and MGMT. Neurosurg Clin N Am 23:237–246. doi: 10.1016/ 23 PubMedCrossRefGoogle Scholar
  5. 5.
    Reardon DA, Wen PY, Mellinghoff IK (2014) Targeted molecular therapies against epidermal growth factor receptor: past experiences and challenges. Neuro-oncology 16(Suppl 8):viii7–13. doi: 10.1093/neuonc/nou232 PubMedCrossRefGoogle Scholar
  6. 6.
    Parker JJ, Dionne KR, Massarwa R, Klaassen M, Foreman NK, Niswander L, Canoll P, Kleinschmidt-Demasters BK, Waziri A (2013) Gefitinib selectively inhibits tumor cell migration in EGFR-amplified human glioblastoma. Neuro-oncology 15:1048–1057. doi: 10.1093/neuonc/not053 PubMedCentralPubMedCrossRefGoogle Scholar
  7. 7.
    Prados MD, Chang SM, Butowski N, DeBoer R, Parvataneni R, Carliner H, Kabuubi P, Ayers-Ringler J, Rabbitt J, Page M, Fedoroff A, Sneed PK, Berger MS, McDermott MW, Parsa AT, Vandenberg S, James CD, Lamborn KR, Stokoe D, Haas-Kogan DA (2009) Phase II study of erlotinib plus temozolomide during and after radiation therapy in patients with newly diagnosed glioblastoma multiforme or gliosarcoma. J Clin Oncol 27:579–584. doi: 10.1200/JCO.2008.18.9639 PubMedCentralPubMedCrossRefGoogle Scholar
  8. 8.
    Solomon MT, Miranda N, Jorrin E, Chon I, Marinello JJ, Alert J, Lorenzo-Luaces P, Crombet T (2014) Nimotuzumab in combination with radiotherapy in high grade glioma patients: a single institution experience. Cancer Biol Ther 15:504–509. doi: 10.4161/cbt.28021 PubMedCentralPubMedCrossRefGoogle Scholar
  9. 9.
    Mitra S, Li G, Harsh GR (2010) Passive antibody-mediated immunotherapy for the treatment of malignant gliomas. Neurosurg Clin N Am 21:67–76. doi: 10.1016/ PubMedCrossRefGoogle Scholar
  10. 10.
    Bigner DD, Brown MT, Friedman AH, Coleman RE, Akabani G, Friedman HS, Thorstad WL, McLendon RE, Bigner SH, Zhao XG, Pegram CN, Wikstrand CJ, Herndon JE 2nd, Vick NA, Paleologos N, Cokgor I, Provenzale JM, Zalutsky MR (1998) Iodine-131-labeled antitenascin monoclonal antibody 81C6 treatment of patients with recurrent malignant gliomas: phase I trial results. J Clin Oncol 16:2202–2212PubMedGoogle Scholar
  11. 11.
    Reardon DA, Akabani G, Coleman RE, Friedman AH, Friedman HS, Herndon JE 2nd, McLendon RE, Pegram CN, Provenzale JM, Quinn JA, Rich JN, Vredenburgh JJ, Desjardins A, Gururangan S, Badruddoja M, Dowell JM, Wong TZ, Zhao XG, Zalutsky MR, Bigner DD (2006) Salvage radioimmunotherapy with murine iodine-131-labeled antitenascin monoclonal antibody 81C6 for patients with recurrent primary and metastatic malignant brain tumors: phase II study results. J Clin Oncol 24:115–122. doi: 10.1200/JCO.2005.03.4082 PubMedCrossRefGoogle Scholar
  12. 12.
    Reardon DA, Zalutsky MR, Akabani G, Coleman RE, Friedman AH, Herndon JE 2nd, McLendon RE, Pegram CN, Quinn JA, Rich JN, Vredenburgh JJ, Desjardins A, Guruangan S, Boulton S, Raynor RH, Dowell JM, Wong TZ, Zhao XG, Friedman HS, Bigner DD (2008) A pilot study: 131I-antitenascin monoclonal antibody 81c6 to deliver a 44-Gy resection cavity boost. Neuro-oncology 10:182–189. doi: 10.1215/15228517-2007-053 PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    Ahmed N, Salsman VS, Kew Y, Shaffer D, Powell S, Zhang YJ, Grossman RG, Heslop HE, Gottschalk S (2010) HER2-specific T cells target primary glioblastoma stem cells and induce regression of autologous experimental tumors. Clin Cancer Res 16:474–485. doi: 10.1158/1078-0432.CCR-09-1322 PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    Brown CE, Starr R, Aguilar B, Shami AF, Martinez C, D’Apuzzo M, Barish ME, Forman SJ, Jensen MC (2012) Stem-like tumor-initiating cells isolated from IL13Ralpha2 expressing gliomas are targeted and killed by IL13-zetakine-redirected T Cells. Clin Cancer Res 18:2199–2209. doi: 10.1158/1078-0432.CCR-11-1669 PubMedCentralPubMedCrossRefGoogle Scholar
  15. 15.
    Hegde M, Corder A, Chow KK, Mukherjee M, Ashoori A, Kew Y, Zhang YJ, Baskin DS, Merchant FA, Brawley VS, Byrd TT, Krebs S, Wu MF, Liu H, Heslop HE, Gottschalk S, Yvon E, Ahmed N (2013) Combinational targeting offsets antigen escape and enhances effector functions of adoptively transferred T cells in glioblastoma. Mol Ther 21:2087–2101. doi: 10.1038/mt.2013.185 PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    Kawakami M, Kawakami K, Puri RK (2003) Tumor regression mechanisms by IL-13 receptor-targeted cancer therapy involve apoptotic pathways. Int J Cancer 103:45–52. doi: 10.1002/ijc.10778 PubMedCrossRefGoogle Scholar
  17. 17.
    Kunwar S, Chang S, Westphal M, Vogelbaum M, Sampson J, Barnett G, Shaffrey M, Ram Z, Piepmeier J, Prados M, Croteau D, Pedain C, Leland P, Husain SR, Joshi BH, Puri RK, Group PS (2010) Phase III randomized trial of CED of IL13-PE38QQR vs gliadel wafers for recurrent glioblastoma. Neuro-oncology 12:871–881. doi: 10.1093/neuonc/nop054 PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    Stupp R, Hegi ME, Gorlia T, Erridge SC, Perry J, Hong YK, Aldape KD, Lhermitte B, Pietsch T, Grujicic D, Steinbach JP, Wick W, Tarnawski R, Nam DH, Hau P, Weyerbrock A, Taphoorn MJ, Shen CC, Rao N, Thurzo L, Herrlinger U, Gupta T, Kortmann RD, Adamska K, McBain C, Brandes AA, Tonn JC, Schnell O, Wiegel T, Kim CY, Nabors LB, Reardon DA, van den Bent MJ, Hicking C, Markivskyy A, Picard M, Weller M, European Organisation for R, Treatment of C, Canadian Brain Tumor C, team Cs (2014) Cilengitide combined with standard treatment for patients with newly diagnosed glioblastoma with methylated MGMT promoter (CENTRIC EORTC 26071-22072 study): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol 15:1100–1108. doi: 10.1016/S1470-2045(14)70379-1 PubMedCrossRefGoogle Scholar
  19. 19.
    Li G, Mitra S, Wong AJ (2010) The epidermal growth factor variant III peptide vaccine for treatment of malignant gliomas. Neurosurg Clin N Am 21:87–93. doi: 10.1016/ PubMedCrossRefGoogle Scholar
  20. 20.
    Sampson JH, Heimberger AB, Archer GE, Aldape KD, Friedman AH, Friedman HS, Gilbert MR, Herndon JE 2nd, McLendon RE, Mitchell DA, Reardon DA, Sawaya R, Schmittling RJ, Shi W, Vredenburgh JJ, Bigner DD (2010) Immunologic escape after prolonged progression-free survival with epidermal growth factor receptor variant III peptide vaccination in patients with newly diagnosed glioblastoma. J Clin Oncol 28:4722–4729. doi: 10.1200/JCO.2010.28.6963 PubMedCentralPubMedCrossRefGoogle Scholar
  21. 21.
    Sampson JH, Aldape KD, Archer GE, Coan A, Desjardins A, Friedman AH, Friedman HS, Gilbert MR, Herndon JE, McLendon RE, Mitchell DA, Reardon DA, Sawaya R, Schmittling R, Shi W, Vredenburgh JJ, Bigner DD, Heimberger AB (2011) Greater chemotherapy-induced lymphopenia enhances tumor-specific immune responses that eliminate EGFRvIII-expressing tumor cells in patients with glioblastoma. Neuro-oncology 13:324–333. doi: 10.1093/neuonc/noq157 PubMedCentralPubMedCrossRefGoogle Scholar
  22. 22.
    Schuster J, Lai RK, Recht LD, Reardon DA, Paleologos NA, Groves MD, Mrugala MM, Jensen R, Baehring JM, Sloan A, Archer GE, Bigner DD, Cruickshank S, Green JA, Keler T, Davis TA, Heimberger AB, Sampson JH (2015) A phase II, multicenter trial of rindopepimut (CDX-110) in newly diagnosed glioblastoma: the ACT III study. Neuro-oncology. doi: 10.1093/neuonc/nou348 PubMedGoogle Scholar
  23. 23.
    Reardon D, Schuster J, Tran D, Fink F, Nabors L, Li G, Bota D, Lukas R, Desjardins A, Ashby L, Duic JP, Mrugula M, Werner A, Hawthorne T, He Y, Green J, Yellin M, Turner C, Davis T, Sampson J (2014) ReACT.: a phase II study of rindopepimut vaccine (CDX-110) plus bevacizumab in relapsed glioblastoma (GBM). In: Proceedings of the 19th Annual Meeting of the Society for Neuro-Oncology. Oxford Press, Miami, FLGoogle Scholar
  24. 24.
    Johnson LA, Scholler J, Ohkuri T, Kosaka A, Patel PR, McGettigan SE, Nace AK, Dentchev T, Thekkat P, Loew A, Boesteanu AC, Cogdill AP, Chen T, Fraietta JA, Kloss CC, Posey AD, Engels B, Singh R, Ezell T, Idamakanti N, Ramones MH, Li N, Zhou L, Plesa G, Seykora JT, Okada H, June CH, Brogdon JL, Maus MV (2015) Rational development and characterization of humanized anti-EGFR variant III chimeric antigen receptor T cells for glioblastoma. Science translational medicine 7:275ra222. doi: 10.1126/scitranslmed.aaa4963 CrossRefGoogle Scholar
  25. 25.
    Miao H, Choi BD, Suryadevara CM, Sanchez-Perez L, Yang S, De Leon G, Sayour EJ, McLendon R, Herndon JE 2nd, Healy P, Archer GE, Bigner DD, Johnson LA, Sampson JH (2014) EGFRvIII-specific chimeric antigen receptor T cells migrate to and kill tumor deposits infiltrating the brain parenchyma in an invasive xenograft model of glioblastoma. PLoS ONE 9:e94281. doi: 10.1371/journal.pone.0094281 PubMedCentralPubMedCrossRefGoogle Scholar
  26. 26.
    Sampson JH, Choi BD, Sanchez-Perez L, Suryadevara CM, Snyder DJ, Flores CT, Schmittling RJ, Nair SK, Reap EA, Norberg PK, Herndon JE 2nd, Kuan CT, Morgan RA, Rosenberg SA, Johnson LA (2014) EGFRvIII mCAR-modified T-cell therapy cures mice with established intracerebral glioma and generates host immunity against tumor-antigen loss. Clin Cancer Res 20:972–984. doi: 10.1158/1078-0432.CCR-13-0709 PubMedCentralPubMedCrossRefGoogle Scholar
  27. 27.
    Morgan RA, Johnson LA, Davis JL, Zheng Z, Woolard KD, Reap EA, Feldman SA, Chinnasamy N, Kuan CT, Song H, Zhang W, Fine HA, Rosenberg SA (2012) Recognition of glioma stem cells by genetically modified T cells targeting EGFRvIII and development of adoptive cell therapy for glioma. Hum Gene Ther 23:1043–1053. doi: 10.1089/hum.2012.041 PubMedCentralPubMedCrossRefGoogle Scholar
  28. 28.
    Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W, Kos I, Batinic-Haberle I, Jones S, Riggins GJ, Friedman H, Friedman A, Reardon D, Herndon J, Kinzler KW, Velculescu VE, Vogelstein B, Bigner DD (2009) IDH1 and IDH2 mutations in gliomas. N Engl J Med 360:765–773. doi: 10.1056/NEJMoa0808710 PubMedCentralPubMedCrossRefGoogle Scholar
  29. 29.
    Weller M, Felsberg J, Hartmann C, Berger H, Steinbach JP, Schramm J, Westphal M, Schackert G, Simon M, Tonn JC, Heese O, Krex D, Nikkhah G, Pietsch T, Wiestler O, Reifenberger G, von Deimling A, Loeffler M (2009) Molecular predictors of progression-free and overall survival in patients with newly diagnosed glioblastoma: a prospective translational study of the German Glioma Network. J Clin Oncol 27:5743–5750. doi: 10.1200/JCO.2009.23.0805 PubMedCrossRefGoogle Scholar
  30. 30.
    Schumacher T, Bunse L, Wick W, Platten M (2014) Mutant IDH1: an immunotherapeutic target in tumors. Oncoimmunology 3:e974392. doi: 10.4161/2162402X.2014.974392 PubMedCrossRefGoogle Scholar
  31. 31.
    Dziurzynski K, Chang SM, Heimberger AB, Kalejta RF, McGregor Dallas SR, Smit M, Soroceanu L, Cobbs CS, Hcmv Gliomas S (2012) Consensus on the role of human cytomegalovirus in glioblastoma. Neuro-oncology 14:246–255. doi: 10.1093/neuonc/nor227 PubMedCentralPubMedCrossRefGoogle Scholar
  32. 32.
    Lucas KG, Bao L, Bruggeman R, Dunham K, Specht C (2011) The detection of CMV pp65 and IE1 in glioblastoma multiforme. J Neurooncol 103:231–238. doi: 10.1007/s11060-010-0383-6 PubMedCrossRefGoogle Scholar
  33. 33.
    Schuessler A, Smith C, Beagley L, Boyle GM, Rehan S, Matthews K, Jones L, Crough T, Dasari V, Klein K, Smalley A, Alexander H, Walker DG, Khanna R (2014) Autologous T-cell therapy for cytomegalovirus as a consolidative treatment for recurrent glioblastoma. Cancer Res 74:3466–3476. doi: 10.1158/0008-5472.CAN-14-0296 PubMedCrossRefGoogle Scholar
  34. 34.
    Pol JG, Marguerie M, Arulanandam R, Bell JC, Lichty BD (2013) Panorama from the oncolytic virotherapy summit. Mol Ther 21:1814–1818. doi: 10.1038/mt.2013.207 PubMedCentralPubMedCrossRefGoogle Scholar
  35. 35.
    Binder RJ, Srivastava PK (2004) Essential role of CD91 in re-presentation of gp96-chaperoned peptides. Proc Natl Acad Sci USA 101:6128–6133. doi: 10.1073/pnas.0308180101 PubMedCentralPubMedCrossRefGoogle Scholar
  36. 36.
    Crane CA, Han SJ, Ahn B, Oehlke J, Kivett V, Fedoroff A, Butowski N, Chang SM, Clarke J, Berger MS, McDermott MW, Prados MD, Parsa AT (2013) Individual patient-specific immunity against high-grade glioma after vaccination with autologous tumor derived peptides bound to the 96 KD chaperone protein. Clin Cancer Res 19:205–214. doi: 10.1158/1078-0432.CCR-11-3358 PubMedCrossRefGoogle Scholar
  37. 37.
    Bloch O, Crane CA, Fuks Y, Kaur R, Aghi MK, Berger MS, Butowski NA, Chang SM, Clarke JL, McDermott MW, Prados MD, Sloan AE, Bruce JN, Parsa AT (2014) Heat-shock protein peptide complex-96 vaccination for recurrent glioblastoma: a phase II, single-arm trial. Neuro-oncology 16:274–279. doi: 10.1093/neuonc/not203 PubMedCentralPubMedCrossRefGoogle Scholar
  38. 38.
    Okada H, Kalinski P, Ueda R, Hoji A, Kohanbash G, Donegan TE, Mintz AH, Engh JA, Bartlett DL, Brown CK, Zeh H, Holtzman MP, Reinhart TA, Whiteside TL, Butterfield LH, Hamilton RL, Potter DM, Pollack IF, Salazar AM, Lieberman FS (2011) Induction of CD8 + T-cell responses against novel glioma-associated antigen peptides and clinical activity by vaccinations with {alpha}-type 1 polarized dendritic cells and polyinosinic-polycytidylic acid stabilized by lysine and carboxymethylcellulose in patients with recurrent malignant glioma. J Clin Oncol 29:330–336. doi: 10.1200/JCO.2010.30.7744 PubMedCentralPubMedCrossRefGoogle Scholar
  39. 39.
    Phuphanich S, Wheeler CJ, Rudnick JD, Mazer M, Wang H, Nuno MA, Richardson JE, Fan X, Ji J, Chu RM, Bender JG, Hawkins ES, Patil CG, Black KL, Yu JS (2013) Phase I trial of a multi-epitope-pulsed dendritic cell vaccine for patients with newly diagnosed glioblastoma. Cancer Immunol Immunother 62:125–135. doi: 10.1007/s00262-012-1319-0 PubMedCentralPubMedCrossRefGoogle Scholar
  40. 40.
    Pellegatta S, Eoli M, Frigerio S, Antozzi C, Bruzzone MG, Cantini G, Nava S, Anghileri E, Cuppini L, Cuccarini V, Ciusani E, Dossena M, Pollo B, Mantegazza R, Parati EA, Finocchiaro G (2013) The natural killer cell response and tumor debulking are associated with prolonged survival in recurrent glioblastoma patients receiving dendritic cells loaded with autologous tumor lysates. Oncoimmunology 2:e23401. doi: 10.4161/onci.23401 PubMedCentralPubMedCrossRefGoogle Scholar
  41. 41.
    Prins RM, Wang X, Soto H, Young E, Lisiero DN, Fong B, Everson R, Yong WH, Lai A, Li G, Cloughesy TF, Liau LM (2013) Comparison of glioma-associated antigen peptide-loaded versus autologous tumor lysate-loaded dendritic cell vaccination in malignant glioma patients. J Immunother 36:152–157. doi: 10.1097/CJI.0b013e3182811ae4 PubMedCentralPubMedCrossRefGoogle Scholar
  42. 42.
    Fadul CE, Fisher JL, Hampton TH, Lallana EC, Li Z, Gui J, Szczepiorkowski ZM, Tosteson TD, Rhodes CH, Wishart HA, Lewis LD, Ernstoff MS (2011) Immune response in patients with newly diagnosed glioblastoma multiforme treated with intranodal autologous tumor lysate-dendritic cell vaccination after radiation chemotherapy. J Immunother 34:382–389. doi: 10.1097/CJI.0b013e318215e300 PubMedCentralPubMedCrossRefGoogle Scholar
  43. 43.
    Liau LM, Prins RM, Kiertscher SM, Odesa SK, Kremen TJ, Giovannone AJ, Lin JW, Chute DJ, Mischel PS, Cloughesy TF, Roth MD (2005) Dendritic cell vaccination in glioblastoma patients induces systemic and intracranial T-cell responses modulated by the local central nervous system tumor microenvironment. Clin Cancer Res 11:5515–5525. doi: 10.1158/1078-0432.CCR-05-0464 PubMedCrossRefGoogle Scholar
  44. 44.
    Dutoit V, Herold-Mende C, Hilf N, Schoor O, Beckhove P, Bucher J, Dorsch K, Flohr S, Fritsche J, Lewandrowski P, Lohr J, Rammensee HG, Stevanovic S, Trautwein C, Vass V, Walter S, Walker PR, Weinschenk T, Singh-Jasuja H, Dietrich PY (2012) Exploiting the glioblastoma peptidome to discover novel tumour-associated antigens for immunotherapy. Brain 135:1042–1054. doi: 10.1093/brain/aws042 PubMedCrossRefGoogle Scholar
  45. 45.
    Binda E, Visioli A, Giani F, Lamorte G, Copetti M, Pitter KL, Huse JT, Cajola L, Zanetti N, DiMeco F, De Filippis L, Mangiola A, Maira G, Anile C, De Bonis P, Reynolds BA, Pasquale EB, Vescovi AL (2012) The EphA2 receptor drives self-renewal and tumorigenicity in stem-like tumor-propagating cells from human glioblastomas. Cancer Cell 22:765–780. doi: 10.1016/j.ccr.2012.11.005 PubMedCentralPubMedCrossRefGoogle Scholar
  46. 46.
    Chow KK, Naik S, Kakarla S, Brawley VS, Shaffer DR, Yi Z, Rainusso N, Wu MF, Liu H, Kew Y, Grossman RG, Powell S, Lee D, Ahmed N, Gottschalk S (2013) T cells redirected to EphA2 for the immunotherapy of glioblastoma. Mol Ther 21:629–637. doi: 10.1038/mt.2012.210 PubMedCentralPubMedCrossRefGoogle Scholar
  47. 47.
    Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T, Henkelman RM, Cusimano MD, Dirks PB (2004) Identification of human brain tumour initiating cells. Nature 432:396–401. doi: 10.1038/nature03128 PubMedCrossRefGoogle Scholar
  48. 48.
    Akiyama Y, Komiyama M, Miyata H, Yagoto M, Ashizawa T, Iizuka A, Oshita C, Kume A, Nogami M, Ito I, Watanabe R, Sugino T, Mitsuya K, Hayashi N, Nakasu Y, Yamaguchi K (2014) Novel cancer-testis antigen expression on glioma cell lines derived from high-grade glioma patients. Oncol Rep 31:1683–1690. doi: 10.3892/or.2014.3049 PubMedGoogle Scholar
  49. 49.
    Liu G, Yu JS, Zeng G, Yin D, Xie D, Black KL, Ying H (2004) AIM-2: a novel tumor antigen is expressed and presented by human glioma cells. J Immunother 27:220–226PubMedCrossRefGoogle Scholar
  50. 50.
    Cantini G, Pisati F, Pessina S, Finocchiaro G, Pellegatta S (2012) Immunotherapy against the radial glia marker GLAST effectively triggers specific antitumor effectors without autoimmunity. Oncoimmunology 1:884–893. doi: 10.4161/onci.20637 PubMedCentralPubMedCrossRefGoogle Scholar
  51. 51.
    Han A, Glanville J, Hansmann L, Davis MM (2014) Linking T-cell receptor sequence to functional phenotype at the single-cell level. Nat Biotechnol 32:684–692. doi: 10.1038/nbt.2938 PubMedCentralPubMedCrossRefGoogle Scholar
  52. 52.
    Birnbaum ME, Mendoza JL, Sethi DK, Dong S, Glanville J, Dobbins J, Ozkan E, Davis MM, Wucherpfennig KW, Garcia KC (2014) Deconstructing the peptide-MHC specificity of T cell recognition. Cell 157:1073–1087. doi: 10.1016/j.cell.2014.03.047 PubMedCentralPubMedCrossRefGoogle Scholar
  53. 53.
    Hinrichs CS, Restifo NP (2013) Reassessing target antigens for adoptive T-cell therapy. Nat Biotechnol 31:999–1008. doi: 10.1038/nbt.2725 PubMedCentralPubMedCrossRefGoogle Scholar
  54. 54.
    Gros A, Robbins PF, Yao X, Li YF, Turcotte S, Tran E, Wunderlich JR, Mixon A, Farid S, Dudley ME, Hanada K, Almeida JR, Darko S, Douek DC, Yang JC, Rosenberg SA (2014) PD-1 identifies the patient-specific CD8(+) tumor-reactive repertoire infiltrating human tumors. J Clin Investig 124:2246–2259. doi: 10.1172/JCI73639 PubMedCentralPubMedCrossRefGoogle Scholar
  55. 55.
    Matsushita H, Vesely MD, Koboldt DC, Rickert CG, Uppaluri R, Magrini VJ, Arthur CD, White JM, Chen YS, Shea LK, Hundal J, Wendl MC, Demeter R, Wylie T, Allison JP, Smyth MJ, Old LJ, Mardis ER, Schreiber RD (2012) Cancer exome analysis reveals a T-cell-dependent mechanism of cancer immunoediting. Nature 482:400–404. doi: 10.1038/nature10755 PubMedCrossRefGoogle Scholar
  56. 56.
    Yadav M, Jhunjhunwala S, Phung QT, Lupardus P, Tanguay J, Bumbaca S, Franci C, Cheung TK, Fritsche J, Weinschenk T, Modrusan Z, Mellman I, Lill JR, Delamarre L (2014) Predicting immunogenic tumour mutations by combining mass spectrometry and exome sequencing. Nature 515:572–576. doi: 10.1038/nature14001 PubMedCrossRefGoogle Scholar
  57. 57.
    Zhou P, Shaffer DR, Alvarez Arias DA, Nakazaki Y, Pos W, Torres AJ, Cremasco V, Dougan SK, Cowley GS, Elpek K, Brogdon J, Lamb J, Turley SJ, Ploegh HL, Root DE, Love JC, Dranoff G, Hacohen N, Cantor H, Wucherpfennig KW (2014) In vivo discovery of immunotherapy targets in the tumour microenvironment. Nature 506:52–57. doi: 10.1038/nature12988 PubMedCentralPubMedCrossRefGoogle Scholar
  58. 58.
    Jackson C, Ruzevick J, Phallen J, Belcaid Z, Lim M (2011) Challenges in immunotherapy presented by the glioblastoma multiforme microenvironment. Clin Dev Immunol 2011:732413. doi: 10.1155/2011/732413 PubMedCentralPubMedCrossRefGoogle Scholar
  59. 59.
    Fecci PE, Mitchell DA, Whitesides JF, Xie W, Friedman AH, Archer GE, Herndon JE 2nd, Bigner DD, Dranoff G, Sampson JH (2006) Increased regulatory T-cell fraction amidst a diminished CD4 compartment explains cellular immune defects in patients with malignant glioma. Cancer Res 66:3294–3302. doi: 10.1158/0008-5472.CAN-05-3773 PubMedCrossRefGoogle Scholar
  60. 60.
    Schreiber RD, Old LJ, Smyth MJ (2011) Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science 331:1565–1570. doi: 10.1126/science.1203486 PubMedCrossRefGoogle Scholar
  61. 61.
    Koebel CM, Vermi W, Swann JB, Zerafa N, Rodig SJ, Old LJ, Smyth MJ, Schreiber RD (2007) Adaptive immunity maintains occult cancer in an equilibrium state. Nature 450:903–907. doi: 10.1038/nature06309 PubMedCrossRefGoogle Scholar
  62. 62.
    Vanderlugt CL, Miller SD (2002) Epitope spreading in immune-mediated diseases: implications for immunotherapy. Nat Rev Immunol 2:85–95. doi: 10.1038/nri724 PubMedCrossRefGoogle Scholar
  63. 63.
    Vanderlugt CL, Begolka WS, Neville KL, Katz-Levy Y, Howard LM, Eagar TN, Bluestone JA, Miller SD (1998) The functional significance of epitope spreading and its regulation by co-stimulatory molecules. Immunol Rev 164:63–72PubMedCrossRefGoogle Scholar
  64. 64.
    Powell AM, Black MM (2001) Epitope spreading: protection from pathogens, but propagation of autoimmunity? Clin Exp Dermatol 26:427–433PubMedCrossRefGoogle Scholar
  65. 65.
    Brossart P, Wirths S, Stuhler G, Reichardt VL, Kanz L, Brugger W (2000) Induction of cytotoxic T-lymphocyte responses in vivo after vaccinations with peptide-pulsed dendritic cells. Blood 96:3102–3108PubMedGoogle Scholar
  66. 66.
    Mamula MJ (1998) Epitope spreading: the role of self peptides and autoantigen processing by B lymphocytes. Immunol Rev 164:231–239PubMedCrossRefGoogle Scholar
  67. 67.
    Vanderlugt CJ, Miller SD (1996) Epitope spreading. Curr Opin Immunol 8:831–836PubMedCrossRefGoogle Scholar
  68. 68.
    Ranieri E, Kierstead LS, Zarour H, Kirkwood JM, Lotze MT, Whiteside T, Storkus WJ (2000) Dendritic cell/peptide cancer vaccines: clinical responsiveness and epitope spreading. Immunol Invest 29:121–125PubMedCrossRefGoogle Scholar
  69. 69.
    Albert ML, Sauter B, Bhardwaj N (1998) Dendritic cells acquire antigen from apoptotic cells and induce class I-restricted CTLs. Nature 392:86–89. doi: 10.1038/32183 PubMedCrossRefGoogle Scholar
  70. 70.
    Disis ML, Grabstein KH, Sleath PR, Cheever MA (1999) Generation of immunity to the HER-2/neu oncogenic protein in patients with breast and ovarian cancer using a peptide-based vaccine. Clin Cancer Res 5:1289–1297PubMedGoogle Scholar
  71. 71.
    Waki K, Yamada T, Yoshiyama K, Terazaki Y, Sakamoto S, Matsueda S, Komatsu N, Sugawara S, Takamori S, Itoh K, Yamada A (2014) PD-1 expression on peripheral blood T-cell subsets correlates with prognosis in non-small cell lung cancer. Cancer Sci 105:1229–1235. doi: 10.1111/cas.12502 PubMedCrossRefGoogle Scholar
  72. 72.
    Hu Y, Petroni GR, Olson WC, Czarkowski A, Smolkin ME, Grosh WW, Chianese-Bullock KA, Slingluff CL Jr (2014) Immunologic hierarchy, class II MHC promiscuity, and epitope spreading of a melanoma helper peptide vaccine. Cancer Immunol Immunother 63:779–786. doi: 10.1007/s00262-014-1551-x PubMedCrossRefGoogle Scholar
  73. 73.
    Sampson JH, Archer GE, Mitchell DA, Heimberger AB, Herndon JE 2nd, Lally-Goss D, McGehee-Norman S, Paolino A, Reardon DA, Friedman AH, Friedman HS, Bigner DD (2009) An epidermal growth factor receptor variant III-targeted vaccine is safe and immunogenic in patients with glioblastoma multiforme. Mol Cancer Ther 8:2773–2779. doi: 10.1158/1535-7163.MCT-09-0124 PubMedCentralPubMedCrossRefGoogle Scholar
  74. 74.
    Burton A (2002) New glioma vaccine in pipeline. Lancet Oncol 3:327PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Tej D. Azad
    • 1
  • Seyed-Mostafa Razavi
    • 1
  • Benjamin Jin
    • 1
  • Karen Lee
    • 1
  • Gordon Li
    • 1
  1. 1.Department of NeurosurgeryStanford University School of MedicineStanfordUSA

Personalised recommendations