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Heat shock protein vaccines against glioblastoma: from bench to bedside

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Abstract

Current adjuvant treatment regimens available for the treatment of glioblastoma are widely ineffective and offer a dismal prognosis. Advancements in conventional treatment strategies have only yielded modest improvements in overall survival. Immunotherapy remains a promising adjuvant in the treatment of GBM through eliciting tumor specific immune responses capable of producing sustained antitumor response while minimizing systemic toxicity. Heat shock proteins (HSP) function as intracellular chaperones and have been implicated in the activation of both innate and adaptive immune systems. Vaccines formulated from HSP-peptide complexes, derived from autologous tumor, have been applied to the field of immunotherapy for glioblastoma. The results from the phase I and II clinical trials have been promising. Here we review the role of HSP in cellular function and immunity, and its application in the treatment of glioblastoma.

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References

  1. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO, European Organisation for R, Treatment of Cancer Brain T, Radiotherapy G, National Cancer Institute of Canada Clinical Trials G (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987–996. doi:10.1056/NEJMoa043330

    Article  CAS  PubMed  Google Scholar 

  2. Hussain SF, Yang D, Suki D, Aldape K, Grimm E, Heimberger AB (2006) The role of human glioma-infiltrating microglia/macrophages in mediating antitumor immune responses. Neuro Oncol 8:261–279. doi:10.1215/15228517-2006-008

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  3. Parsa AT, Waldron JS, Panner A, Crane CA, Parney IF, Barry JJ, Cachola KE, Murray JC, Tihan T, Jensen MC, Mischel PS, Stokoe D, Pieper RO (2007) Loss of tumor suppressor PTEN function increases B7-H1 expression and immunoresistance in glioma. Nat Med 13:84–88. doi:10.1038/nm1517

    Article  CAS  PubMed  Google Scholar 

  4. Waziri A (2010) Glioblastoma-derived mechanisms of systemic immunosuppression. Neurosurg Clin N Am 21:31–42. doi:10.1016/j.nec.2009.08.005

    Article  PubMed  Google Scholar 

  5. Ampie L, Woolf EC, Dardis C (2015) Immunotherapeutic advancements for glioblastoma. Front Oncol 5:12. doi:10.3389/fonc.2015.00012

    Article  PubMed Central  PubMed  Google Scholar 

  6. 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

    Article  PubMed Central  PubMed  Google Scholar 

  7. Schirrmacher V, Haas C, Bonifer R, Ahlert T, Gerhards R, Ertel C (1999) Human tumor cell modification by virus infection: an efficient and safe way to produce cancer vaccine with pleiotropic immune stimulatory properties when using Newcastle disease virus. Gene Ther 6:63–73. doi:10.1038/sj.gt.3300787

    Article  CAS  PubMed  Google Scholar 

  8. Prins RM, Soto H, Konkankit V, Odesa SK, Eskin A, Yong WH, Nelson SF, Liau LM (2011) Gene expression profile correlates with T-cell infiltration and relative survival in glioblastoma patients vaccinated with dendritic cell immunotherapy. Clin Cancer Res 17:1603–1615. doi:10.1158/1078-0432.CCR-10-2563

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Young JC, Agashe VR, Siegers K, Hartl FU (2004) Pathways of chaperone-mediated protein folding in the cytosol. Nat Rev Mol Cell Biol 5:781–791. doi:10.1038/nrm1492

    Article  CAS  PubMed  Google Scholar 

  10. Craig E, Weissman JS (1994) Heat shock proteins and molecular chaperones: mediators of protein conformation and turnover in the cell. Cell 78:365–372

    Article  CAS  PubMed  Google Scholar 

  11. Graner MW, Bigner DD (2005) Chaperone proteins and brain tumors: potential targets and possible therapeutics. Neuro Oncol 7:260–278. doi:10.1215/s1152851704001188

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Ciocca DR, Calderwood SK (2005) Heat shock proteins in cancer: diagnostic, prognostic, predictive, and treatment implicaitons. Cell Stress Chaperones 10:86–103

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Schmitt E, Gehrmann M, Brunet M, Multhoff G, Garrido C (2007) Intracellular and extracellular functions of heat shock proteins: repercussions in cancer therapy. J Leukoc Biol 81:15–27. doi:10.1189/jlb.0306167

    Article  CAS  PubMed  Google Scholar 

  14. Binder RJ (2006) Heat shock protein vaccines: from bench to bedside. Int Rev Immunol 25:353–375

    Article  CAS  PubMed  Google Scholar 

  15. Hermisson M, Strik H, Rieger J, Dichgans J, Meyermann R, Weller M (2000) Expression and functional activity of heat shock proteins in human glioblastoma multiforme. Neurology 54:1357–1365

    Article  CAS  PubMed  Google Scholar 

  16. Graner MW, Cumming RI, Bigner DD (2007) The heat shock response and chaperones/heat shock proteins in brain tumors: surface expression, release, and possible immune consequences. J Neurosci 27:11214–11227

    Article  CAS  PubMed  Google Scholar 

  17. Beaman GM, Dennison SR, Chatfield LK, Phoenix DA (2014) Reliability of HSP70 (HSPA) expression as a prognostic marker in glioma. Mol Cell Biochem 393:301–307

    Article  CAS  PubMed  Google Scholar 

  18. Flynn GC, Chappell TG, Rothman JE (1989) Peptide binding and release by proteins implicated as catalysts of protein assembly. Science 245:385–390

    Article  CAS  PubMed  Google Scholar 

  19. Srivastava PK, DeLeo AB, Old LJ (1986) Tumor rejection antigens of chemically induced sarcomas of inbred mice. Proc Natl Acad Sci 83:3407–3411

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Ullrich SJ, Robinson EA, Law LW, Willingham M, Appella E (1986) A mouse tumor-specific transplantation antigen is a heat shock-related protein. Proc Natl Acad Sci 83:3121–3125

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  21. Srivastava PK, DeLeo AB, Old LJ (1986) Tumor rejection antigens of chemically induced sarcomas of inbred mice. Proc Natl Acad Sci USA 83:3407–3411

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Ullrich SJ, Robinson EA, Law LW, Willingham M, Appella E (1986) A mouse tumor-specific transplantation antigen is a heat shock-related protein. Proc Natl Acad Sci USA 83:3121–3125

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Srivastava PK, Maki RG (1991) Stress-induced proteins in immune response to cancer. Curr Top Microbiol Immunol 167:109–123

    CAS  PubMed  Google Scholar 

  24. Blachere NE, Li Z, Chandawarkar RY, Suto R, Jaikaria NS, Basu S, Udono H, Srivastava PK (1997) Heat shock protein-peptide complexes, reconstituted in vitro, elicit peptide-specific cytotoxic T lymphocyte response and tumor immunity. J Exp Med 186:1315–1322

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. 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

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. Basu S, Binder RJ, Ramalingam T, Srivastava PK (2001) CD91 is a common receptor for heat shock proteins gp96, hsp90, hsp70, and calreticulin. Immunity 14:303–313

    Article  CAS  PubMed  Google Scholar 

  27. Castellino F, Boucher PE, Eichelberg K, Mayhew M, Rothman JE, Houghton AN, Germain RN (2000) Receptor-mediated uptake of antigen/heat shock protein complexes results in major histocompatibility complex class I antigen presentation via two distinct processing pathways. J Exp Med 191:1957–1964

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. Matsutake T, Sawamura T, Srivastava PK (2010) High efficiency CD91- and LOX-1-mediated re-presentation of gp96-chaperoned peptides by MHC II molecules. Cancer Immun 10:7

    PubMed Central  PubMed  Google Scholar 

  29. Berwin B, Hart JP, Pizzo SV, Nicchitta CV (2002) Cutting edge: CD91-independent cross-presentation of GRP94(gp96)-associated peptides. J Immunol 168:4282–4286

    Article  CAS  PubMed  Google Scholar 

  30. Panjwani NN, Popova L, Srivastava PK (2002) Heat shock proteins gp96 and hsp70 activate the release of nitric oxide by APCs. J Immunol 168:2997–3003

    Article  CAS  PubMed  Google Scholar 

  31. Srivastava P (2002) Roles of heat-shock proteins in innate and adaptive immunity. Nat Rev Immunol 2:185–194. doi:10.1038/nri749

    Article  CAS  PubMed  Google Scholar 

  32. 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 164:63–72

    Article  CAS  PubMed  Google Scholar 

  33. Srivastava PK (1997) Purification of heat shock protein-peptide complexes for use in vaccination against cancers and intracellular pathogens. Methods 12(2):165–171

    Article  CAS  PubMed  Google Scholar 

  34. See AP, Pradilla G, Yang I, Han S, Parsa AT, Lim M (2011) Heat shock protein-peptide complex in the treatment of glioblastoma. Expert Rev Vaccines 10:721–731. doi:10.1586/erv.11.49

    Article  CAS  PubMed  Google Scholar 

  35. Belli F, Testori A, Rivoltini L, Maio M, Andreola G, Sertoli MR, Gallino G, Piris A (2002) Vaccination of metastatic melanoma patients with autologous tumor-derived heat shock protein gp96-peptide complexes: clinical and immunologic findings. J Clin Oncol 20:4169–4180. doi:10.1200/JCO.2002.09.134

    Article  CAS  PubMed  Google Scholar 

  36. Janetzki S, Palla D, Rosenhauer V, Lochs H, Lewis JJ, Srivastava PK (2000) Immunization of cancer patients with autologous cancer-derived heat shock protein gp96 preparations: a pilot study. Int J Cancer 88:232–238

    Article  CAS  PubMed  Google Scholar 

  37. Hishii M, Andrews D, Boyle LA, Wong JT, Pandolfi F, van den Elsen PJ, Kurnick JT (1997) In vivo accumulation of the same anti-melanoma T cell clone in two different metastatic sites. Proc Natl Acad Sci USA 94:1378–1383

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  38. Jager E, Ringhoffer M, Dienes HP, Arand M, Karbach J, Jager D, Ilsemann C, Hagedorn M, Oesch F, Knuth A (1996) Granulocyte-macrophage-colony-stimulating factor enhances immune responses to melanoma-associated peptides in vivo. Int J Cancer 67:54–62. doi:10.1002/(SICI)1097-0215(19960703)67

    Article  CAS  PubMed  Google Scholar 

  39. Rivoltini L, Castelli C, Carrabba M, Mazzaferro V, Pilla L, Huber V, Coppa J, Gallino G, Scheibenbogen C, Squarcina P, Cova A, Camerini R, Lewis JJ, Srivastava PK, Parmiani G (2003) Human tumor-derived heat shock protein 96 mediates in vitro activation and in vivo expansion of melanoma- and colon carcinoma-specific T cells. J Immunol 171:3467–3474

    Article  CAS  PubMed  Google Scholar 

  40. Mazzaferro V, Coppa J, Carrabba MG, Rivoltini L, Schiavo M, Regalia E, Mariani L, Camerini T, Marchiano A, Andreola S, Camerini R, Corsi M, Lewis JJ, Srivastava PK, Parmiani G (2003) Vaccination with autologous tumor-derived heat-shock protein gp96 after liver resection for metastatic colorectal cancer. Clin Cancer Res 9:3235–3245

    CAS  PubMed  Google Scholar 

  41. Santis G, Senzer NN, Champagne P, Isakov L, Teofilovici F (2008) Phase II feasibility study of autologous vaccine (HSPPC-96) in patients with resectable lung cancer. J Clin Oncol 26(15):7584

    Google Scholar 

  42. Maki RG, Livingston PO, Lewis JJ, Janetzki S, Klimstra D, Desantis D, Srivastava PK, Brennan MF (2007) A phase I pilot study of autologous heat shock protein vaccine HSPPC-96 in patients with resected pancreatic adenocarcinoma. Dig Dis Sci 52:1964–1972. doi:10.1007/s10620-006-9205-2

    Article  CAS  PubMed  Google Scholar 

  43. Pilla L, Patuzzo R, Rivoltini L, Maio M, Pennacchioli E, Lamaj E, Maurichi A, Massarut S, Marchiano A, Santantonio C, Tosi D, Arienti F, Cova A, Sovena G, Piris A, Nonaka D, Bersani I, Di Florio A, Luigi M, Srivastava PK, Hoos A, Santinami M, Parmiani G (2006) A phase II trial of vaccination with autologous, tumor-derived heat-shock protein peptide complexes Gp96, in combination with GM-CSF and interferon-alpha in metastatic melanoma patients. Cancer Immunol Immunother 55:958–968. doi:10.1007/s00262-005-0084-8

    Article  CAS  PubMed  Google Scholar 

  44. Oki Y, McLaughlin P, Fayad LE, Pro B, Mansfield PF, Clayman GL, Medeiros LJ, Kwak LW, Srivastava PK, Younes A (2007) Experience with heat shock protein-peptide complex 96 vaccine therapy in patients with indolent non-Hodgkin lymphoma. Cancer 109:77–83. doi:10.1002/cncr.22389

    Article  CAS  PubMed  Google Scholar 

  45. Testori A, Richards J, Whitman E, Mann GB, Lutzky J, Camacho L, Parmiani G, Tosti G, Kirkwood JM, Hoos A, Yuh L, Gupta R, Srivastava PK, Group CS (2008) Phase III comparison of vitespen, an autologous tumor-derived heat shock protein gp96 peptide complex vaccine, with physician’s choice of treatment for stage IV melanoma: the C-100-21 Study Group. J Clin Oncol 26:955–962. doi:10.1200/JCO.2007.11.9941

    Article  CAS  PubMed  Google Scholar 

  46. Wood C, Srivastava P, Bukowski R, Lacombe L, Gorelov AI, Gorelov S, Mulders P, Zielinski H, Hoos A, Teofilovici F, Isakov L, Flanigan R, Figlin R, Gupta R, Escudier B, Group CRS (2008) An adjuvant autologous therapeutic vaccine (HSPPC-96; vitespen) versus observation alone for patients at high risk of recurrence after nephrectomy for renal cell carcinoma: a multicentre, open-label, randomised phase III trial. Lancet 372:145–154. doi:10.1016/S0140-6736(08)60697-2

    Article  CAS  PubMed  Google Scholar 

  47. Messing EM, Manola J, Wilding G, Propert K, Fleischmann J, Crawford ED, Pontes JE, Hahn R, Trump D, Eastern Cooperative Oncology Group/Intergroup trail (2003) Phase III study of interferon alfa-NL as adjuvant treatment for resectable renal cell carcinoma: an Eastern Cooperative Oncology Group/Intergroup trial. J Clin Oncol 21:1214–1222

    Article  CAS  PubMed  Google Scholar 

  48. Wood CG, Srivastava P, Lacombe L, Gorelov AI, Gorelov S, Mulders P, Zielinski H, Teofilovici F, Isakov L, Escudier B (2009) Survival update from a multicenter, randomized, phase III trial of vitespen versus observation as adjuvant therapy for renal cell carcinoma in patients at high risk of recurrence. J Clin Oncol 27(15S):3009

    Google Scholar 

  49. 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

    Article  CAS  PubMed  Google Scholar 

  50. 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 Oncol 16:274–279. doi:10.1093/neuonc/not203

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  51. 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 Oncol 12:871–881. doi:10.1093/neuonc/nop054

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  52. Bloch O, Kaur R, Aghi M, McDermott M, Berger M, Parsa A (2013) Glioma-induced immunosuppression shortens progression-free survival in a trial of immunotherapy for glioblastoma. J Neurosurg, 119: A565

  53. Khasraw M, Ameratunga MS, Grant R, Wheeler H, Pavlakis N (2014) Antiangiogenic therapy for high-grade glioma. Cochrane Database Syst Rev. doi:10.1002/14651858

    PubMed  Google Scholar 

  54. Chinot OL, Wick W, Mason W, Henriksson R, Saran F, Nishikawa R, Carpentier AF, Hoang-Xuan K, Kavan P, Cernea D, Brandes AA, Hilton M, Abrey L, Cloughesy T (2014) Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. N Engl J Med 370:709–722. doi:10.1056/NEJMoa1308345

    Article  CAS  PubMed  Google Scholar 

  55. Gilbert MR, Dignam JJ, Armstrong TS, Wefel JS, Blumenthal DT, Vogelbaum MA, Colman H, Chakravarti A, Pugh S, Won M, Jeraj R, Brown PD, Jaeckle KA, Schiff D, Stieber VW, Brachman DG, Werner-Wasik M, Tremont-Lukats IW, Sulman EP, Aldape KD, Curran WJ Jr, Mehta MP (2014) A randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl J Med 370:699–708. doi:10.1056/NEJMoa1308573

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  56. Bloch O, Parsa AT (2014) Heat shock protein peptide complex-96 (HSPPC-96) vaccination for recurrent glioblastoma: a phase II, single arm trial. Neuro Oncol 16:758–759. doi:10.1093/neuonc/nou054

    Article  PubMed Central  PubMed  Google Scholar 

  57. Chamberlain MC (2014) Is there a role for vaccine-based therapy in recurrent glioblastoma? Neuro Oncol 16:757. doi:10.1093/neuonc/nou031

    Article  PubMed Central  PubMed  Google Scholar 

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Ampie, L., Choy, W., Lamano, J.B. et al. Heat shock protein vaccines against glioblastoma: from bench to bedside. J Neurooncol 123, 441–448 (2015). https://doi.org/10.1007/s11060-015-1837-7

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