Skip to main content

Advertisement

SpringerLink
Log in

An Update on the Role of Immunotherapy and Vaccine Strategies for Primary Brain Tumors

  • Neuro-oncology (GJ Lesser, Section Editor)
  • Published:
Current Treatment Options in Oncology Aims and scope Submit manuscript

Opinion statement

Existing therapies for glioblastoma (GBM), the most common malignant primary brain tumor in adults, have fallen short of improving the dismal patient outcomes, with an average 14–16-month median overall survival. The biological complexity and adaptability of GBM, redundancy of dysregulated signaling pathways, and poor penetration of therapies through the blood–brain barrier contribute to poor therapeutic progress. The current standard of care for newly diagnosed GBM consists of maximal safe resection, followed by fractionated radiotherapy combined with concurrent temozolomide (TMZ) and 6–12 cycles of adjuvant TMZ. At progression, bevacizumab with or without additional chemotherapy is an option for salvage therapy. The recent FDA approval of sipuleucel-T for prostate cancer and ipilumimab, nivolumab, and pembrolizumab for select solid tumors and the ongoing trials showing clinical efficacy and response durability herald a new era of cancer treatment with the potential to change standard-of-care treatment across multiple cancers. The evaluation of various immunotherapeutics is advancing for GBM, putting into question the dogma of the CNS as an immuno-privileged site. While the field is yet young, both active immunotherapy involving vaccine strategies and cellular therapy as well as reversal of GBM-induced global immune-suppression through immune checkpoint blockade are showing promising results and revealing essential immunological insights regarding kinetics of the immune response, immune evasion, and correlative biomarkers. The future holds exciting promise in establishing new treatment options for GBM that harness the patients’ own immune system by activating it with immune checkpoint inhibitors, providing specificity using vaccine therapy, and allowing for modulation and enhancement by combinatorial approaches.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Ostrom QT, Gittleman H, Liao P, Rouse C, Chen Y, Dowling J, et al. CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2007–2011. Neuro-Oncology. 2014;16 Suppl 4:iv1–63. doi:10.1093/neuonc/nou223.

    Article  PubMed Central  PubMed  Google Scholar 

  2. Ostrom QT, Gittleman H, Stetson L, Virk SM, Barnholtz-Sloan JS. Epidemiology of gliomas. Cancer Treat Res. 2015;163:1–14. doi:10.1007/978-3-319-12048-5_1.

    Article  PubMed  Google Scholar 

  3. Wen PY, Kesari S. Malignant gliomas in adults. N Engl J Med. 2008;359(5):492–507. doi:10.1056/NEJMra0708126.

    Article  CAS  PubMed  Google Scholar 

  4. Schiff D, Lee EQ, Nayak L, Norden AD, Reardon DA, Wen PY. Medical management of brain tumors and the sequelae of treatment. Neuro-Oncology. 2014. doi:10.1093/neuonc/nou304.

    Google Scholar 

  5. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352(10):987–96. doi:10.1056/NEJMoa043330.

    Article  CAS  PubMed  Google Scholar 

  6. Bauchet L, Mathieu-Daude H, Fabbro-Peray P, Rigau V, Fabbro M, Chinot O, et al. Oncological patterns of care and outcome for 952 patients with newly diagnosed glioblastoma in 2004. Neuro-Oncology. 2010;12(7):725–35. doi:10.1093/neuonc/noq030.

    Article  PubMed Central  PubMed  Google Scholar 

  7. Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC, et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol. 2009;10(5):459–66. doi:10.1016/S1470-2045(09)70025-7.

    Article  CAS  PubMed  Google Scholar 

  8. Chinot OL, Wick W, Cloughesy T. Bevacizumab for newly diagnosed glioblastoma. N Engl J Med. 2014;370(21):2049.

    Article  PubMed  Google Scholar 

  9. Friedman HS, Prados MD, Wen PY, Mikkelsen T, Schiff D, Abrey LE, et al. Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol : Off J Am Soc Clin Oncol. 2009;27(28):4733–40. doi:10.1200/JCO.2008.19.8721.

    Article  CAS  Google Scholar 

  10. Gilbert MR, Dignam JJ, Armstrong TS, Wefel JS, Blumenthal DT, Vogelbaum MA, et al. A randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl J Med. 2014;370(8):699–708. doi:10.1056/NEJMoa1308573.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Taal W, Oosterkamp HM, Walenkamp AM, Dubbink HJ, Beerepoot LV, Hanse MC, et al. Single-agent bevacizumab or lomustine versus a combination of bevacizumab plus lomustine in patients with recurrent glioblastoma (BELOB trial): a randomised controlled phase 2 trial. Lancet Oncol. 2014;15(9):943–53. doi:10.1016/S1470-2045(14)70314-6.

    Article  CAS  PubMed  Google Scholar 

  12. Grupp SA, Kalos M, Barrett D, Aplenc R, Porter DL, Rheingold SR, et al. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med. 2013;368(16):1509–18. doi:10.1056/NEJMoa1215134. This study shows the first clinical efficacy of adoptive CAR T cell transfer.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  13. Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363(8):711–23. doi:10.1056/NEJMoa1003466.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. Kantoff PW, Higano CS, Shore ND, Berger ER, Small EJ, Penson DF, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363(5):411–22. doi:10.1056/NEJMoa1001294.

    Article  CAS  PubMed  Google Scholar 

  15. Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015;372(4):320–30. doi:10.1056/NEJMoa1412082. This study shows durable and robust anti-tumor effects of PD-1 blockade in melanoma.

    Article  CAS  PubMed  Google Scholar 

  16. Robert C, Ribas A, Wolchok JD, Hodi FS, Hamid O, Kefford R, et al. Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Lancet. 2014;384(9948):1109–17. doi:10.1016/S0140-6736(14)60958-2.

    Article  CAS  PubMed  Google Scholar 

  17. Fecci PE, Heimberger AB, Sampson JH. Immunotherapy for primary brain tumors: no longer a matter of privilege. Clin Cancer Res : Off J Am Assoc Cancer Res. 2014;20(22):5620–9. doi:10.1158/1078-0432.CCR-14-0832.

    Article  CAS  Google Scholar 

  18. Reardon DA, Freeman G, Wu C, Chiocca EA, Wucherpfennig KW, Wen PY, et al. Immunotherapy advances for glioblastoma. Neuro-Oncology. 2014;16(11):1441–58. doi:10.1093/neuonc/nou212.

    Article  PubMed  Google Scholar 

  19. Constam DB, Philipp J, Malipiero UV, ten Dijke P, Schachner M, Fontana A. Differential expression of transforming growth factor-beta 1, -beta 2, and -beta 3 by glioblastoma cells, astrocytes, and microglia. J Immunol. 1992;148(5):1404–10.

    CAS  PubMed  Google Scholar 

  20. Crane CA, Ahn BJ, Han SJ, Parsa AT. Soluble factors secreted by glioblastoma cell lines facilitate recruitment, survival, and expansion of regulatory T cells: implications for immunotherapy. Neuro-Oncology. 2012;14(5):584–95. doi:10.1093/neuonc/nos014.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Facoetti A, Nano R, Zelini P, Morbini P, Benericetti E, Ceroni M, et al. Human leukocyte antigen and antigen processing machinery component defects in astrocytic tumors. Clin Cancer Res : Off J Am Assoc Cancer Res. 2005;11(23):8304–11. doi:10.1158/1078-0432.CCR-04-2588.

    Article  CAS  Google Scholar 

  22. Gabrilovich DI, Ishida T, Nadaf S, Ohm JE, Carbone DP. Antibodies to vascular endothelial growth factor enhance the efficacy of cancer immunotherapy by improving endogenous dendritic cell function. Clin Cancer Res : Off J Am Assoc Cancer Res. 1999;5(10):2963–70.

    CAS  Google Scholar 

  23. Heimberger AB, Abou-Ghazal M, Reina-Ortiz C, Yang DS, Sun W, Qiao W, et al. Incidence and prognostic impact of FoxP3+ regulatory T cells in human gliomas. Clin Cancer Res : Off J Am Assoc Cancer Res. 2008;14(16):5166–72. doi:10.1158/1078-0432.CCR-08-0320.

    Article  CAS  Google Scholar 

  24. Huettner C, Paulus W, Roggendorf W. Messenger RNA expression of the immunosuppressive cytokine IL-10 in human gliomas. Am J Pathol. 1995;146(2):317–22.

    PubMed Central  CAS  PubMed  Google Scholar 

  25. Hussain SF, Yang D, Suki D, Aldape K, Grimm E, Heimberger AB. The role of human glioma-infiltrating microglia/macrophages in mediating antitumor immune responses. Neuro-Oncology. 2006;8(3):261–79. doi:10.1215/15228517-2006-008.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. Jacobs JF, Idema AJ, Bol KF, Grotenhuis JA, de Vries IJ, Wesseling P, et al. Prognostic significance and mechanism of Treg infiltration in human brain tumors. J Neuroimmunol. 2010;225(1-2):195–9. doi:10.1016/j.jneuroim.2010.05.020.

    Article  CAS  PubMed  Google Scholar 

  27. Jansen T, Tyler B, Mankowski JL, Recinos VR, Pradilla G, Legnani F, et al. FasL gene knock-down therapy enhances the antiglioma immune response. Neuro-Oncology. 2010;12(5):482–9. doi:10.1093/neuonc/nop052.

    PubMed Central  CAS  PubMed  Google Scholar 

  28. Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol. 2008;26:677–704. doi:10.1146/annurev.immunol.26.021607.090331.

    Article  CAS  PubMed  Google Scholar 

  29. Schartner JM, Hagar AR, Van Handel M, Zhang L, Nadkarni N, Badie B. Impaired capacity for upregulation of MHC class II in tumor-associated microglia. Glia. 2005;51(4):279–85. doi:10.1002/glia.20201.

    Article  PubMed  Google Scholar 

  30. Walker DG, Chuah T, Rist MJ, Pender MP. T-cell apoptosis in human glioblastoma multiforme: implications for immunotherapy. J Neuroimmunol. 2006;175(1–2):59–68. doi:10.1016/j.jneuroim.2006.03.006.

    Article  CAS  PubMed  Google Scholar 

  31. Schijns VE, Pretto C, Devillers L, Pierre D, Hofman FM, Chen TC, et al. First clinical results of a personalized immunotherapeutic vaccine against recurrent, incompletely resected, treatment-resistant glioblastoma multiforme (GBM) tumors, based on combined allo- and auto-immune tumor reactivity. Vaccine. 2015;33(23):2690–6. doi:10.1016/j.vaccine.2015.03.095.

    Article  CAS  PubMed  Google Scholar 

  32. Reardon DA, Wucherpfennig KW, Freeman G, Wu CJ, Chiocca EA, Wen PY, et al. An update on vaccine therapy and other immunotherapeutic approaches for glioblastoma. Expert Rev Vaccines. 2013;12(6):597–615. doi:10.1586/erv.13.41.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. Sayegh ET, Oh T, Fakurnejad S, Bloch O, Parsa AT. Vaccine therapies for patients with glioblastoma. J Neuro-Oncol. 2014;119(3):531–46. doi:10.1007/s11060-014-1502-6.

    Article  CAS  Google Scholar 

  34. Mitchell DA, Batich KA, Gunn MD, Huang MN, Sanchez-Perez L, Nair SK, et al. Tetanus toxoid and CCL3 improve dendritic cell vaccines in mice and glioblastoma patients. Nature. 2015;519(7543):366–9. doi:10.1038/nature14320. This is elegant study demonstrates that tetanus toxoid can significantly augment anti-glioma immune responses from vaccination.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  35. Abecassis IJ, Morton RP, Nerva JD, Kim LJ. Immunotherapy for secondary glioblastoma multiforme: toward an isocitrate dehydrogenase vaccine. World Neurosurg. 2014;82(6):933–5. doi:10.1016/j.wneu.2014.10.006.

    Article  PubMed  Google Scholar 

  36. Schumacher T, Bunse L, Pusch S, Sahm F, Wiestler B, Quandt J, et al. A vaccine targeting mutant IDH1 induces antitumour immunity. Nature. 2014;512(7514):324–7. doi:10.1038/nature13387. A systematic approach to creating an anti-IDH-1 R132H petide vaccine, which may in time allow for targeting lower grade gliomas. This paper also shows that IDH-1R132H may be an inherently immunogenic target in patients.

    Article  CAS  PubMed  Google Scholar 

  37. Akiyama Y, Oshita C, Kume A, Iizuka A, Miyata H, Komiyama M, et al. alpha-type-1 polarized dendritic cell-based vaccination in recurrent high-grade glioma: a phase I clinical trial. BMC Cancer. 2012;12:623. doi:10.1186/1471-2407-12-623.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  38. Prins RM, Wang X, Soto H, Young E, Lisiero DN, Fong B, et al. Comparison of glioma-associated antigen peptide-loaded versus autologous tumor lysate-loaded dendritic cell vaccination in malignant glioma patients. J Immunother. 2013;36(2):152–7. doi:10.1097/CJI.0b013e3182811ae4.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  39. Sampson JH, Archer GE, Mitchell DA, Heimberger AB, Herndon 2nd JE, Lally-Goss D, et al. An epidermal growth factor receptor variant III-targeted vaccine is safe and immunogenic in patients with glioblastoma multiforme. Mol Cancer Ther. 2009;8(10):2773–9. doi:10.1158/1535-7163.MCT-09-0124.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  40. Phuphanich S, Wheeler CJ, Rudnick JD, Mazer M, Wang H, Nuno MA, et al. Phase I trial of a multi-epitope-pulsed dendritic cell vaccine for patients with newly diagnosed glioblastoma. Cancer Immunol, Immunother : CII. 2013;62(1):125–35. doi:10.1007/s00262-012-1319-0. This multi-epitope vaccine has now shown promising results in Phase 2 trials.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  41. Del Vecchio CA, Li G, Wong AJ. Targeting EGF receptor variant III: tumor-specific peptide vaccination for malignant gliomas. Expert Rev Vaccines. 2012;11(2):133–44. doi:10.1586/erv.11.177.

    Article  PubMed  CAS  Google Scholar 

  42. Neagu MR, Reardon DA. Rindopepimut vaccine and bevacizumab combination therapy: improving survival rates in relapsed glioblastoma patients? Immunotherapy. 2015. doi:10.2217/imt.15.39.

    PubMed  Google Scholar 

  43. Patel MA, Kim JE, Ruzevick J, Li G, Lim M. The future of glioblastoma therapy: synergism of standard of care and immunotherapy. Cancers. 2014;6(4):1953–85. doi:10.3390/cancers6041953.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  44. Swartz AM, Batich KA, Fecci PE, Sampson JH. Peptide vaccines for the treatment of glioblastoma. J Neuro-Oncol. 2014. doi:10.1007/s11060-014-1676-y.

    Google Scholar 

  45. Heimberger AB, Crotty LE, Archer GE, Hess KR, Wikstrand CJ, Friedman AH, et al. Epidermal growth factor receptor VIII peptide vaccination is efficacious against established intracerebral tumors. Clin Cancer Res : Off J Am Assoc Cancer Res. 2003;9(11):4247–54.

    CAS  Google Scholar 

  46. Sampson JH, Heimberger AB, Archer GE, Aldape KD, Friedman AH, Friedman HS, et al. 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 : Off J Am Soc Clin Oncol. 2010;28(31):4722–9. doi:10.1200/JCO.2010.28.6963.

    Article  Google Scholar 

  47. Reardon DA, Schuster J, Tran DD, Fink KL, Nabors LB, Li G, et al. ReACT: overall survival from a randomized phase II study of rindopepimut (CDX-110) plus bevacizumab in relapsed glioblastoma. Journal of Clinical Oncology: official journal of the American Society of Clinical Oncology. 2015;33(suppl;abstr 2009) Rindopepimut is the most advanced vaccine in development for glioblastoma. The ReACT study is the first randomized trial to demonstrate a survival benefit for any immunotherapeutic among GBM patients.

  48. Sampson JH, Aldape KD, Archer GE, Coan A, Desjardins A, Friedman AH, et al. Greater chemotherapy-induced lymphopenia enhances tumor-specific immune responses that eliminate EGFRvIII-expressing tumor cells in patients with glioblastoma. Neuro-Oncology. 2011;13(3):324–33. doi:10.1093/neuonc/noq157.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  49. Babu R, Adamson DC. Rindopepimut: an evidence-based review of its therapeutic potential in the treatment of EGFRvIII-positive glioblastoma. Core Evid. 2012;7:93–103. doi:10.2147/CE.S29001.

    PubMed Central  CAS  PubMed  Google Scholar 

  50. Ampie L, Choy W, Lamano JB, Fakurnejad S, Bloch O, Parsa AT. Heat shock protein vaccines against glioblastoma: from bench to bedside. J Neuro-Oncol. 2015;123(3):441–8. doi:10.1007/s11060-015-1837-7.

    Article  CAS  Google Scholar 

  51. Crane CA, Han SJ, Ahn B, Oehlke J, Kivett V, Fedoroff A, et al. 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 : Off J Am Assoc Cancer Res. 2013;19(1):205–14. doi:10.1158/1078-0432.CCR-11-3358.

    Article  CAS  Google Scholar 

  52. Bloch O, Crane CA, Fuks Y, Kaur R, Aghi MK, Berger MS, et al. Heat-shock protein peptide complex-96 vaccination for recurrent glioblastoma: a phase II, single-arm trial. Neuro-Oncology. 2014;16(2):274–9. doi:10.1093/neuonc/not203. This autologous heat-shock protein vaccine shows intriguing results.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  53. Bloch O, Raizer JJ, Lim M, Sughrue M, Komotar R, Abrahams J, O’Rourke D, D’Ambrosio A, Bruce JN, Parsa A. Newly diagnosed glioblastoma patients treated with an autologous heat shock protein peptide vaccine: PD-L1 expression and response to therapy. Journal of clinical oncology: official journal of the American Society of Clinical Oncology. 2015;33(suppl; abstr 2011).

  54. Lawler SE. Cytomegalovirus and glioblastoma: controversies and opportunities. J Neuro-Oncol. 2015;123(3):465–71. doi:10.1007/s11060-015-1734-0.

    Article  CAS  Google Scholar 

  55. Mitchell DA, Xie W, Schmittling R, Learn C, Friedman A, McLendon RE, et al. Sensitive detection of human cytomegalovirus in tumors and peripheral blood of patients diagnosed with glioblastoma. Neuro-Oncology. 2008;10(1):10–8. doi:10.1215/15228517-2007-035.

    Article  PubMed Central  PubMed  Google Scholar 

  56. Priel E, Wohl A, Teperberg M, Nass D, Cohen ZR. Human cytomegalovirus viral load in tumor and peripheral blood samples of patients with malignant gliomas. J Clin Neurosci : Off J Neurosurg Soc Australasia. 2015;22(2):326–30. doi:10.1016/j.jocn.2014.06.099.

    Article  Google Scholar 

  57. Izumoto S, Tsuboi A, Oka Y, Suzuki T, Hashiba T, Kagawa N, et al. Phase II clinical trial of Wilms tumor 1 peptide vaccination for patients with recurrent glioblastoma multiforme. J Neurosurg. 2008;108(5):963–71. doi:10.3171/JNS/2008/108/5/0963.

    Article  CAS  PubMed  Google Scholar 

  58. Yajima N, Yamanaka R, Mine T, Tsuchiya N, Homma J, Sano M, et al. Immunologic evaluation of personalized peptide vaccination for patients with advanced malignant glioma. Clin Cancer Res : Off J Am Assoc Cancer Res. 2005;11(16):5900–11. doi:10.1158/1078-0432.CCR-05-0559.

    Article  CAS  Google Scholar 

  59. Lennerz V, Fatho M, Gentilini C, Frye RA, Lifke A, Ferel D, et al. The response of autologous T cells to a human melanoma is dominated by mutated neoantigens. Proc Natl Acad Sci U S A. 2005;102(44):16013–8. doi:10.1073/pnas.0500090102.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  60. Rajasagi M, Shukla SA, Fritsch EF, Keskin DB, DeLuca D, Carmona E, et al. Systematic identification of personal tumor-specific neoantigens in chronic lymphocytic leukemia. Blood. 2014;124(3):453–62. doi:10.1182/blood-2014-04-567933.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  61. Zhang GL, Ansari HR, Bradley P, Cawley GC, Hertz T, Hu X, et al. Machine learning competition in immunology—prediction of HLA class I binding peptides. J Immunol Methods. 2011;374(1–2):1–4. doi:10.1016/j.jim.2011.09.010.

    CAS  PubMed  Google Scholar 

  62. Castle JC, Kreiter S, Diekmann J, Lower M, van de Roemer N, de Graaf J, et al. Exploiting the mutanome for tumor vaccination. Cancer Res. 2012;72(5):1081–91. doi:10.1158/0008-5472.CAN-11-3722.

    Article  CAS  PubMed  Google Scholar 

  63. Prieto PA, Yang JC, Sherry RM, Hughes MS, Kammula US, White DE, et al. CTLA-4 blockade with ipilimumab: long-term follow-up of 177 patients with metastatic melanoma. Clin Cancer Res : Off J Am Assoc Cancer Res. 2012;18(7):2039–47. doi:10.1158/1078-0432.CCR-11-1823.

    Article  CAS  Google Scholar 

  64. Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366(26):2455–65. doi:10.1056/NEJMoa1200694.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  65. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366(26):2443–54. doi:10.1056/NEJMoa1200690.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  66. Robert C, Thomas L, Bondarenko I, O’Day S, Weber J, Garbe C, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011;364(26):2517–26. doi:10.1056/NEJMoa1104621.

    Article  CAS  PubMed  Google Scholar 

  67. Weber JS, Kahler KC, Hauschild A. Management of immune-related adverse events and kinetics of response with ipilimumab. J Clin Oncol : Off J Am Soc Clin Oncol. 2012;30(21):2691–7. doi:10.1200/JCO.2012.41.6750.

    Article  CAS  Google Scholar 

  68. Margolin K, Ernstoff MS, Hamid O, Lawrence D, McDermott D, Puzanov I, et al. Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial. Lancet Oncol. 2012;13(5):459–65. doi:10.1016/S1470-2045(12)70090-6.

    Article  CAS  PubMed  Google Scholar 

  69. Fecci PE, Ochiai H, Mitchell DA, Grossi PM, Sweeney AE, Archer GE, et al. Systemic CTLA-4 blockade ameliorates glioma-induced changes to the CD4+ T cell compartment without affecting regulatory T-cell function. Clin Cancer Res : Off J Am Assoc Cancer Res. 2007;13(7):2158–67. doi:10.1158/1078-0432.CCR-06-2070.

    Article  CAS  Google Scholar 

  70. Vom Berg J, Vrohlings M, Haller S, Haimovici A, Kulig P, Sledzinska A, et al. Intratumoral IL-12 combined with CTLA-4 blockade elicits T cell-mediated glioma rejection. J Exp Med. 2013;210(13):2803–11. doi:10.1084/jem.20130678.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  71. Zeng J, See AP, Phallen J, Jackson CM, Belcaid Z, Ruzevick J, et al. Anti-PD-1 blockade and stereotactic radiation produce long-term survival in mice with intracranial gliomas. Int J Radiat Oncol Biol Phys. 2013;86(2):343–9. doi:10.1016/j.ijrobp.2012.12.025.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  72. Reardon D, Gokhale P, Ligon K, Liao X, Rodig S, Zhou J, et al. Immune checkpoint blockade for glioblastoma: preclinical activity of single agent and combinagtorial therapy. Neuro-Oncology. 2014;16:v110–8. doi:10.1093/neuonc/nou258.

    Article  Google Scholar 

  73. Suryadevara CM, Verla T, Sanchez-Perez L, Reap EA, Choi BD, Fecci PE, et al. Immunotherapy for malignant glioma. Surg Neurol Int. 2015;6 Suppl 1:S68–77. doi:10.4103/2152-7806.151341.

    Article  PubMed Central  PubMed  Google Scholar 

  74. Rosenberg SA, Lotze MT, Muul LM, Chang AE, Avis FP, Leitman S, et al. A progress report on the treatment of 157 patients with advanced cancer using lymphokine-activated killer cells and interleukin-2 or high-dose interleukin-2 alone. N Engl J Med. 1987;316(15):889–97. doi:10.1056/NEJM198704093161501.

    Article  CAS  PubMed  Google Scholar 

  75. Rosenberg SA, Yang JC, Sherry RM, Kammula US, Hughes MS, Phan GQ, et al. Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy. Clin Cancer Res : Off J Am Assoc Cancer Res. 2011;17(13):4550–7. doi:10.1158/1078-0432.CCR-11-0116.

    Article  CAS  Google Scholar 

  76. Dudley ME, Wunderlich JR, Yang JC, Sherry RM, Topalian SL, Restifo NP, et al. Adoptive cell transfer therapy following non-myeloablative but lymphodepleting chemotherapy for the treatment of patients with refractory metastatic melanoma. J Clin Oncol : Off J Am Soc Clin Oncol. 2005;23(10):2346–57. doi:10.1200/JCO.2005.00.240.

    Article  CAS  Google Scholar 

  77. Heslop HE, Slobod KS, Pule MA, Hale GA, Rousseau A, Smith CA, et al. Long-term outcome of EBV-specific T-cell infusions to prevent or treat EBV-related lymphoproliferative disease in transplant recipients. Blood. 2010;115(5):925–35. doi:10.1182/blood-2009-08-239186.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  78. Schuessler A, Smith C, Beagley L, Boyle GM, Rehan S, Matthews K, et al. Autologous T-cell therapy for cytomegalovirus as a consolidative treatment for recurrent glioblastoma. Cancer Res. 2014;74(13):3466–76. doi:10.1158/0008-5472.CAN-14-0296. This approach uses autologous T cell transfer to target CMV epitopes expressed by glioma cells.

    Article  CAS  PubMed  Google Scholar 

  79. Sanchez-Perez LA, Choi BD, Archer GE, Cui X, Flores C, Johnson LA, et al. Myeloablative temozolomide enhances CD8(+) T-cell responses to vaccine and is required for efficacy against brain tumors in mice. PLoS One. 2013;8(3), e59082. doi:10.1371/journal.pone.0059082.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  80. Kochenderfer JN, Dudley ME, Feldman SA, Wilson WH, Spaner DE, Maric I, et al. B-cell depletion and remissions of malignancy along with cytokine-associated toxicity in a clinical trial of anti-CD19 chimeric-antigen-receptor-transduced T cells. Blood. 2012;119(12):2709–20. doi:10.1182/blood-2011-10-384388.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  81. Pule MA, Savoldo B, Myers GD, Rossig C, Russell HV, Dotti G, et al. Virus-specific T cells engineered to coexpress tumor-specific receptors: persistence and antitumor activity in individuals with neuroblastoma. Nat Med. 2008;14(11):1264–70. doi:10.1038/nm.1882.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  82. Chow KK, Naik S, Kakarla S, Brawley VS, Shaffer DR, Yi Z, et al. T cells redirected to EphA2 for the immunotherapy of glioblastoma. Mol Ther : J Am Soc Gene Ther. 2013;21(3):629–37. doi:10.1038/mt.2012.210.

    Article  CAS  Google Scholar 

  83. Hegde M, Corder A, Chow KK, Mukherjee M, Ashoori A, Kew Y, et al. Combinational targeting offsets antigen escape and enhances effector functions of adoptively transferred T cells in glioblastoma. Mol Ther : J Am Soc Gene Ther. 2013;21(11):2087–101. doi:10.1038/mt.2013.185.

    Article  CAS  Google Scholar 

  84. Miao H, Choi BD, Suryadevara CM, Sanchez-Perez L, Yang S, De Leon G, et al. 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. 2014;9(4), e94281. doi:10.1371/journal.pone.0094281.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  85. Morgan RA, Johnson LA, Davis JL, Zheng Z, Woolard KD, Reap EA, et al. Recognition of glioma stem cells by genetically modified T cells targeting EGFRvIII and development of adoptive cell therapy for glioma. Hum Gene Ther. 2012;23(10):1043–53. doi:10.1089/hum.2012.041.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  86. Brown CE, Badie B, Barish ME, Weng L, Ostberg JR, Chang WC, et al. Bioactivity and safety of IL13Ralpha2-redirected chimeric antigen receptor CD8+ T cells in patients with recurrent glioblastoma. Clin Cancer Res : Off J Am Assoc Cancer Res. 2015. doi:10.1158/1078-0432.CCR-15-0428.

    Google Scholar 

  87. Wen PY, Macdonald DR, Reardon DA, Cloughesy TF, Sorensen AG, Galanis E, et al. Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group. J Clin Oncol : Off J Am Soc Clin Oncol. 2010;28(11):1963–72. doi:10.1200/JCO.2009.26.3541.

    Article  Google Scholar 

  88. Wolchok JD, Hoos A, O’Day S, Weber JS, Hamid O, Lebbe C, et al. Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res : Off J Am Assoc Cancer Res. 2009;15(23):7412–20. doi:10.1158/1078-0432.CCR-09-1624.

    Article  CAS  Google Scholar 

  89. Okada H, Weller, M., Huang, R. et. al. Immunotherapy Response Assessment in Neuro-Oncology (iRANO): a report of the RANO Working Group Lancet Oncology. 2015;In Press.The iRANO Working Group redefines response criteria for immunotherapy among neuro-oncology patients in this manuscript.

  90. Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013;369(2):122–33. doi:10.1056/NEJMoa1302369. This work shows enhanced efficacy of combination CTLA-4 and PD-1 blockade in treatment of melanoma.

    Article  CAS  PubMed  Google Scholar 

  91. Weathers SP, Gilbert MR. Current challenges in designing GBM trials for immunotherapy. J Neuro-Oncol. 2015;123(3):331–7. doi:10.1007/s11060-015-1716-2.

    Article  CAS  Google Scholar 

  92. Agarwalla P, Barnard Z, Fecci P, Dranoff G, Curry Jr WT. Sequential immunotherapy by vaccination with GM-CSF-expressing glioma cells and CTLA-4 blockade effectively treats established murine intracranial tumors. J Immunother. 2012;35(5):385–9. doi:10.1097/CJI.0b013e3182562d59.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  93. Duraiswamy J, Freeman GJ, Coukos G. Dual blockade of PD-1 and CTLA-4 combined with tumor vaccine effectively restores T-cell rejection function in tumors—response. Cancer Res. 2014;74(2):633–4. doi:10.1158/0008-5472.CAN-13-2752. discussion 5.

    Article  CAS  PubMed  Google Scholar 

  94. Chow KK, Hara W, Lim M, Li G. Combining immunotherapy with radiation for the treatment of glioblastoma. J Neuro-Oncol. 2015;123(3):459–64. doi:10.1007/s11060-015-1762-9.

    Article  CAS  Google Scholar 

  95. Postow MA, Callahan MK, Barker CA, Yamada Y, Yuan J, Kitano S, et al. Immunologic correlates of the abscopal effect in a patient with melanoma. N Engl J Med. 2012;366(10):925–31. doi:10.1056/NEJMoa1112824.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  96. Lee Y, Auh SL, Wang Y, Burnette B, Wang Y, Meng Y, et al. Therapeutic effects of ablative radiation on local tumor require CD8+ T cells: changing strategies for cancer treatment. Blood. 2009;114(3):589–95. doi:10.1182/blood-2009-02-206870.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  97. Lugade AA, Sorensen EW, Gerber SA, Moran JP, Frelinger JG, Lord EM. Radiation-induced IFN-gamma production within the tumor microenvironment influences antitumor immunity. J Immunol. 2008;180(5):3132–9.

    Article  CAS  PubMed  Google Scholar 

  98. Reits EA, Hodge JW, Herberts CA, Groothuis TA, Chakraborty M, Wansley EK, et al. Radiation modulates the peptide repertoire, enhances MHC class I expression, and induces successful antitumor immunotherapy. J Exp Med. 2006;203(5):1259–71. doi:10.1084/jem.20052494.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  99. Sims JS, Ung TH, Neira JA, Canoll P, Bruce JN. Biomarkers for glioma immunotherapy: the next generation. J Neuro-Oncol. 2015;123(3):359–72. doi:10.1007/s11060-015-1746-9.

    Article  CAS  Google Scholar 

  100. Gustafson MP, Lin Y, LaPlant B, Liwski CJ, Maas ML, League SC, et al. Immune monitoring using the predictive power of immune profiles. J Immunother Cancer. 2013;1:7. doi:10.1186/2051-1426-1-7.

    Article  PubMed Central  PubMed  Google Scholar 

  101. Stricker TP, Morales La Madrid A, Chlenski A, Guerrero L, Salwen HR, Gosiengfiao Y, et al. Validation of a prognostic multi-gene signature in high-risk neuroblastoma using the high throughput digital NanoString nCounter system. Mol Oncol. 2014;8(3):669–78. doi:10.1016/j.molonc.2014.01.010.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  102. Nielsen T, Wallden B, Schaper C, Ferree S, Liu S, Gao D, et al. Analytical validation of the PAM50-based Prosigna Breast Cancer Prognostic Gene Signature Assay and nCounter Analysis System using formalin-fixed paraffin-embedded breast tumor specimens. BMC Cancer. 2014;14:177. doi:10.1186/1471-2407-14-177.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  103. Tumeh PC, Harview CL, Yearley JH, Shintaku IP, Taylor EJ, Robert L, et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature. 2014;515(7528):568–71. doi:10.1038/nature13954.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  104. Verhaak RG, Hoadley KA, Purdom E, Wang V, Qi Y, Wilkerson MD, et al. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell. 2010;17(1):98–110. doi:10.1016/j.ccr.2009.12.020.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

Download references

Compliance with Ethics Guidelines

Conflict of Interest

Martha R. Neagu has received financial support through a grant from the National Institutes of Health (K12CA090354).

David A. Reardon has served on advisory boards for AbbVie, Amgen, Bristol-Myers Squibb, Cavion, Genentech/Roche, Merck, Midatech, Regeneron, and Stemline Therapeutics and has conducted lectures on behalf of Genentech/Roche and Merck.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Author information

Authors and Affiliations

  1. Dana-Farber Cancer Institute, G4200, 44 Binney St, Boston, MA, 02115, USA

    Martha R. Neagu MD, PhD & David A. Reardon MD

  2. Pappas Center for Neuro-Oncology, Massachusetts General Hospital, WACC 8-835m 55 Fruit St, Boston, MA, 02114, USA

    Martha R. Neagu MD, PhD

Authors
  1. Martha R. Neagu MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. David A. Reardon MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to David A. Reardon MD.

Additional information

This article is part of the Topical Collection on Neuro-oncology

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Neagu, M.R., Reardon, D.A. An Update on the Role of Immunotherapy and Vaccine Strategies for Primary Brain Tumors. Curr. Treat. Options in Oncol. 16, 54 (2015). https://doi.org/10.1007/s11864-015-0371-3

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11864-015-0371-3

Keywords

Search

Navigation