Skip to main content

Advertisement

SpringerLink
Log in

Immunomonitoring in glioma immunotherapy: current status and future perspectives

  • Topic Review
  • Published:
Journal of Neuro-Oncology Aims and scope Submit manuscript

Abstract

Given the continued poor clinical outcomes and refractory nature of glioblastoma multiforme to traditional interventions, immunotherapy is gaining traction due to its potential for specific tumor-targeting and long-term antitumor protective surveillance. Currently, development of glioma immunotherapy relies on overall survival as an endpoint in clinical trials. However, the identification of surrogate immunologic biomarkers can accelerate the development of successful immunotherapeutic strategies. Immunomonitoring techniques possess the potential to elucidate immunological mechanisms of antitumor responses, monitor disease progression, evaluate therapeutic effect, identify candidates for immunotherapy, and serve as prognostic markers of clinical outcome. Current immunomonitoring assays assess delayed-type hypersensitivity, T cell proliferation, cytotoxic T-lymphocyte function, cytokine secretion profiles, antibody titers, and lymphocyte phenotypes. Yet, no single immunomonitoring technique can reliably predict outcomes, relegating immunological markers to exploratory endpoints. In response, the most recent immunomonitoring assays are incorporating emerging technologies and novel analysis techniques to approach the goal of identifying a competent immunological biomarker which predicts therapy responsiveness and clinical outcome. This review addresses the current status of immunomonitoring in glioma vaccine clinical trials with emphasis on correlations with clinical response.

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

  1. Stupp R, Mason WP, Van Den Bent MJ et al (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987–996

    Article  CAS  PubMed  Google Scholar 

  2. Keilholz U, Martus P, Scheibenbogen C (2006) Immune monitoring of T-cell responses in cancer vaccine development. Clin Cancer Res 12:2346s–2352s

    Article  CAS  PubMed  Google Scholar 

  3. Yamanaka R, Homma J, Yajima N et al (2005) Clinical evaluation of dendritic cell vaccination for patients with recurrent glioma: results of a clinical phase I/II trial. Clin Cancer Res 11:4160–4167

    Article  CAS  PubMed  Google Scholar 

  4. Clavreul A, Piard N, Tanguy J-Y et al (2010) Autologous tumor cell vaccination plus infusion of GM-CSF by a programmable pump in the treatment of recurrent malignant gliomas. J Clin Neurosci 17:842–848

    Article  CAS  PubMed  Google Scholar 

  5. Sampson JH, Heimberger AB, Archer GE et al (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

    Article  PubMed Central  PubMed  Google Scholar 

  6. Sloan AE, Dansey R, Zamorano L et al (2000) Adoptive immunotherapy in patients with recurrent malignant glioma: preliminary results of using autologous whole-tumor vaccine plus granulocyte-macrophage colony-stimulating factor and adoptive transfer of anti-CD3-activated lymphocytes. Neurosurg Focus 9:1–8

    Article  Google Scholar 

  7. Muragaki Y, Maruyama T, Iseki H et al (2011) Phase I/IIa trial of autologous formalin-fixed tumor vaccine concomitant with fractionated radiotherapy for newly diagnosed glioblastoma: clinical article. J Neurosurg 115:248–255

    Article  PubMed  Google Scholar 

  8. Ishikawa E, Muragaki Y, Yamamoto T et al (2014) Phase I/IIa trial of fractionated radiotherapy, temozolomide, and autologous formalin-fixed tumor vaccine for newly diagnosed glioblastoma: clinical article. J Neurosurg 121:543–553

    Article  CAS  PubMed  Google Scholar 

  9. Steiner HH, Bonsanto MM, Beckhove P et al (2004) Antitumor vaccination of patients with glioblastoma multiforme: a pilot study to assess feasibility, safety, and clinical benefit. J Clin Oncol 22:4272–4281

    Article  PubMed  Google Scholar 

  10. Yamanaka R, Abe T, Yajima N et al (2003) Vaccination of recurrent glioma patients with tumour lysate-pulsed dendritic cells elicits immune responses: results of a clinical phase I/II trial. Br J Cancer 89:1172–1179

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Rutkowski S, De Vleeschouwer S, Kaempgen E et al (2004) Surgery and adjuvant dendritic cell-based tumour vaccination for patients with relapsed malignant glioma, a feasibility study. Br J Cancer 91:1656–1662

    PubMed Central  CAS  PubMed  Google Scholar 

  12. Vik-Mo EO, Nyakas M, Mikkelsen BV et al (2013) Therapeutic vaccination against autologous cancer stem cells with mRNA-transfected dendritic cells in patients with glioblastoma. Cancer Immunol Immunother 62:1499–1509

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  13. Ardon H, Van Gool S, Lopes IS et al (2010) Integration of autologous dendritic cell-based immunotherapy in the primary treatment for patients with newly diagnosed glioblastoma multiforme: a pilot study. J Neurooncol 99:261–272

    Article  CAS  PubMed  Google Scholar 

  14. Ishikawa E, Tsuboi K, Yamamoto T et al (2007) Clinical trial of autologous formalin-fixed tumor vaccine for glioblastoma multiforme patients. Cancer Sci 98:1226–1233

    Article  CAS  PubMed  Google Scholar 

  15. Fadul CE, Fisher JL, Hampton TH et al (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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  16. Yajima N, Yamanaka R, Mine T et al (2005) Immunologic evaluation of personalized peptide vaccination for patients with advanced malignant glioma. Clin Cancer Res 11:5900–5911

    Article  CAS  PubMed  Google Scholar 

  17. De Vleeschouwer S, Fieuws S, Rutkowski S et al (2008) Postoperative adjuvant dendritic cell-based immunotherapy in patients with relapsed glioblastoma multiforme. Clin Cancer Res 14:3098–3104

    Article  PubMed  Google Scholar 

  18. Wheeler CJ, Black KL, Liu G et al (2008) Vaccination elicits correlated immune and clinical responses in glioblastoma multiforme patients. Cancer Res 68:5955–5964

    Article  CAS  PubMed  Google Scholar 

  19. Akiyama Y, Oshita C, Kume A et al (2012) α-type-1 polarized dendritic cell-based vaccination in recurrent high-grade glioma: a phase I clinical trial. BMC Cancer 12:623

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  20. de Vries IJM, Bernsen MR, Lesterhuis WJ et al (2005) Immunomonitoring tumor-specific T cells in delayed-type hypersensitivity skin biopsies after dendritic cell vaccination correlates with clinical outcome. J Clin Oncol 23:5779–5787

    Article  PubMed  Google Scholar 

  21. Clay TM, Hobeika AC, Mosca PJ, Lyerly HK, Morse MA (2001) Assays for monitoring cellular immune responses to active immunotherapy of cancer. Clin Cancer Res 7:1127–1135

    CAS  PubMed  Google Scholar 

  22. Piguet PF, Vassalli P (1973) Study of the thymic-derived or-independent nature of mouse spleen cells induced to proliferate in culture by various mitogens and antigens. Eur J Immunol 3:477–483

    Article  CAS  PubMed  Google Scholar 

  23. Lyons AB, Parish CR (1994) Determination of lymphocyte division by flow cytometry. J Immunol Methods 171:131–137

    Article  CAS  PubMed  Google Scholar 

  24. Crane CA, Han SJ, Ahn B et al (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

    Article  CAS  PubMed  Google Scholar 

  25. Soares A, Govender L, Hughes J et al (2010) Novel application of Ki67 to quantify antigen-specific in vitro lymphoproliferation. J Immunol Methods 362:43–50

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. Rufer N, Dragowska W, Thornbury G, Roosnek E, Lansdorp PM (1998) Telomere length dynamics in human lymphocyte subpopulations measured by flow cytometry. Nat Biotechnol 16:743–747

    Article  CAS  PubMed  Google Scholar 

  27. Brunner K, Mauel J, Cerottini J-C, Chapuis B (1968) Quantitative assay of the lytic action of immune lymphoid cells of 51Cr-labelled allogeneic target cells in vitro; inhibition by isoantibody and by drugs. Immunology 14:181

    PubMed Central  CAS  PubMed  Google Scholar 

  28. Matzinger P (1991) The JAM test A simple assay for DNA fragmentation and cell death. J Immunol Methods 145:185–192

    Article  CAS  PubMed  Google Scholar 

  29. Kikuchi T, Akasaki Y, Abe T et al (2004) Vaccination of glioma patients with fusions of dendritic and glioma cells and recombinant human interleukin 12. J Immunother 27:452–459

    Article  CAS  PubMed  Google Scholar 

  30. Yu JS, Wheeler CJ, Zeltzer PM et al (2001) Vaccination of malignant glioma patients with peptide-pulsed dendritic cells elicits systemic cytotoxicity and intracranial T-cell infiltration. Cancer Res 61:842–847

    CAS  PubMed  Google Scholar 

  31. Yu JS, Liu G, Ying H, Yong WH, Black KL, Wheeler CJ (2004) Vaccination with tumor lysate-pulsed dendritic cells elicits antigen-specific, cytotoxic T-cells in patients with malignant glioma. Cancer Res 64:4973–4979

    Article  CAS  PubMed  Google Scholar 

  32. Nociari MM, Shalev A, Benias P, Russo C (1998) A novel one-step, highly sensitive fluorometric assay to evaluate cell-mediated cytotoxicity. J Immunol Methods 213:157–167

    Article  CAS  PubMed  Google Scholar 

  33. Liu L, Chahroudi A, Silvestri G et al (2002) Visualization and quantification of T cell-mediated cytotoxicity using cell-permeable fluorogenic caspase substrates. Nat Med 8:185–189

    Article  CAS  PubMed  Google Scholar 

  34. Vermes I, Haanen C, Steffens-Nakken H, Reutellingsperger C (1995) A novel assay for apoptosis flow cytometric detection of phosphatidylserine expression on early apoptotic cells using fluorescein labelled annexin V. J Immunol Methods 184:39–51

    Article  CAS  PubMed  Google Scholar 

  35. Schmid I, Krall WJ, Uittenbogaart CH, Braun J, Giorgi JV (1992) Dead cell discrimination with 7-amino-actinomcin D in combination with dual color immunofluorescence in single laser flow cytometry. Cytometry 13:204–208

    Article  CAS  PubMed  Google Scholar 

  36. Betts MR, Brenchley JM, Price DA et al (2003) Sensitive and viable identification of antigen-specific CD8+ T cells by a flow cytometric assay for degranulation. J Immunol Methods 281:65–78

    Article  CAS  PubMed  Google Scholar 

  37. Liau LM, Prins RM, Kiertscher SM et al (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

    Article  CAS  PubMed  Google Scholar 

  38. Phuphanich S, Wheeler CJ, Rudnick JD et al (2013) Phase I trial of a multi-epitope-pulsed dendritic cell vaccine for patients with newly diagnosed glioblastoma. Cancer Immunol Immunother 62:125–135

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  39. Engvall E, Perlmann P (1971) Enzyme-linked immunosorbent assay (ELISA) quantitative assay of immunoglobulin G. Immunochemistry 8:871–874

    Article  CAS  PubMed  Google Scholar 

  40. Czerkinsky CC, Nilsson L-Å, Nygren H, Ouchterlony Ö, Tarkowski A (1983) A solid-phase enzyme-linked immunospot (ELISPOT) assay for enumeration of specific antibody-secreting cells. J Immunol Methods 65:109–121

    Article  CAS  PubMed  Google Scholar 

  41. Jung T, Schauer U, Heusser C, Neumann C, Rieger C (1993) Detection of intracellular cytokines by flow cytometry. J Immunol Methods 159:197–207

    Article  CAS  PubMed  Google Scholar 

  42. Heid CA, Stevens J, Livak KJ, Williams PM (1996) Real time quantitative PCR. Genome Res 6:986–994

    Article  CAS  PubMed  Google Scholar 

  43. Pellegatta S, Eoli M, Frigerio S et al (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

    Article  PubMed Central  PubMed  Google Scholar 

  44. Olin MR, Low W, McKenna DH et al (2014) Vaccination with dendritic cells loaded with allogeneic brain tumor cells for recurrent malignant brain tumors induces a CD4+ IL17+ response. J Immunother Cancer 2:1–11

    Article  Google Scholar 

  45. Kikuchi T, Akasaki Y, Irie M, Homma S, Abe T, Ohno T (2001) Results of a phase I clinical trial of vaccination of glioma patients with fusions of dendritic and glioma cells. Cancer Immunol Immunother 50:337–344

    Article  CAS  PubMed  Google Scholar 

  46. Jie X, Hua L, Jiang W, Feng F, Feng G, Hua Z (2012) Clinical application of a dendritic cell vaccine raised against heat-shocked glioblastoma. Cell Biochem Biophys 62:91–99

    Article  CAS  PubMed  Google Scholar 

  47. Okada H, Lieberman FS, Walter KA et al (2007) Autologous glioma cell vaccine admixed with interleukin-4 gene transfected fibroblasts in the treatment of patients with malignant gliomas. J Transl Med 5:67

    Article  PubMed Central  PubMed  Google Scholar 

  48. Iwami K, Shimato S, Ohno M et al (2012) Peptide-pulsed dendritic cell vaccination targeting interleukin-13 receptor α2 chain in recurrent malignant glioma patients with HLA-A* 24/A* 02 allele. Cytotherapy 14:733–742

    Article  CAS  PubMed  Google Scholar 

  49. Schuster J, Lai RK, Recht LD, et al. (2015) A phase II, multicenter trial of rindopepimut (CDX-110) in newly diagnosed glioblastoma: the ACT III study. Neuro-oncology:nou348

  50. Bloch O, Crane CA, Fuks Y et al (2014) Heat-shock protein peptide complex–96 vaccination for recurrent glioblastoma: a phase II, single-arm trial. Neuro-oncology 16:274–279

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  51. Ardon H, Van Gool SW, Verschuere T et al (2012) Integration of autologous dendritic cell-based immunotherapy in the standard of care treatment for patients with newly diagnosed glioblastoma: results of the HGG-2006 phase I/II trial. Cancer Immunol Immunother 61:2033–2044

    Article  CAS  PubMed  Google Scholar 

  52. Prins RM, Wang X, Soto H et al (2013) Comparison of glioma-associated antigen peptide-loaded versus autologous tumor lysate-loaded dendritic cell vaccination in malignant glioma patients. J Immunother (Hagerstown, Md: 1997) 36:152

    CAS  Google Scholar 

  53. Fong B, Jin R, Wang X et al (2012) Monitoring of regulatory T cell frequencies and expression of CTLA-4 on T cells, before and after DC vaccination, can predict survival in GBM patients. PLoS ONE 7:e32614

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  54. Prins RM, Soto H, Konkankit V et al (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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  55. Perez OD, Nolan GP (2002) Simultaneous measurement of multiple active kinase states using polychromatic flow cytometry. Nat Biotechnol 20:155–162

    Article  CAS  PubMed  Google Scholar 

  56. Bendall SC, Simonds EF, Qiu P et al (2011) Single-cell mass cytometry of differential immune and drug responses across a human hematopoietic continuum. Science 332:687–696

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  57. Everson RG, Jin RM, Wang X et al (2014) Cytokine responsiveness of CD8 (+) T cells is a reproducible biomarker for the clinical efficacy of dendritic cell vaccination in glioblastoma patients. J Immunother Cancer 2:10

    Article  PubMed Central  PubMed  Google Scholar 

  58. Chang S, Kohrt H, Maecker HT (2014) Monitoring the immune competence of cancer patients to predict outcome. Cancer Immunol Immunother 63:713–719

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  59. Gustafson MP, Lin Y, LaPlant B et al (2013) Immune monitoring using the predictive power of immune profiles. J Immuno Ther Cancer 1:7–18

    Article  Google Scholar 

  60. Qiu P, Simonds EF, Bendall SC et al (2011) Extracting a cellular hierarchy from high-dimensional cytometry data with SPADE. Nat Biotechnol 29:886–891

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  61. E-aD Amir, Davis KL, Tadmor MD et al (2013) viSNE enables visualization of high dimensional single-cell data and reveals phenotypic heterogeneity of leukemia. Nat Biotechnol 31:545–552

    Article  Google Scholar 

  62. Lesokhin AM, Callahan MK, Postow MA, Wolchok JD (2015) On being less tolerant: Enhanced cancer immunosurveillance enabled by targeting checkpoints and agonists of T cell activation. Sci Transl Med 7:280sr281

    Article  Google Scholar 

  63. Ku GY, Yuan J, Page DB et al (2010) Single-institution experience with ipilimumab in advanced melanoma patients in the compassionate use setting: lymphocyte count after 2 doses correlates with survival. Cancer 116:1767–1775

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  64. Berman DM, Wolchok JD, Weber J, Hamid O, O’Day S, Chasalow SD (2009) Association of peripheral blood absolute lymphocyte count (ALC) and clinical activity in patients (pts) with advanced melanoma treated with ipilimumab. J Clin Oncol 27:abstract 3020

  65. Simeone E, Gentilcore G, Giannarelli D et al (2014) Immunological and biological changes during ipilimumab treatment and their potential correlation with clinical response and survival in patients with advanced melanoma. Cancer Immunol Immunother 63:675–683

    Article  CAS  PubMed  Google Scholar 

  66. Postow MA, Chasalow SD, Yuan J, et al (2013) Pharmacodynamic effect of ipilimumab on absolute lymphocyte count (ALC) and association with overall survival in patients with advanced melanoma. J Clin Oncol 31:abstract 9052

  67. Carthon BC, Wolchok JD, Yuan J et al (2010) Preoperative CTLA-4 blockade: tolerability and immune monitoring in the setting of a presurgical clinical trial. Clin Cancer Res 16:2861–2871

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  68. Nduom EK, Wei J, Yaghi NK, et al (2015) PD-L1 expression and prognostic impact in glioblastoma. Neuro Oncol

  69. Robert C, Long GV, Brady B et al (2015) Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med 372:320–330

    Article  CAS  PubMed  Google Scholar 

  70. Snyder A, Makarov V, Merghoub T et al (2014) Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med 371:2189–2199

    Article  PubMed Central  PubMed  Google Scholar 

  71. Le DT, Uram JN, Wang H et al (2015) PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med 372:2509–2520

    Article  CAS  PubMed  Google Scholar 

  72. Rizvi NA, Hellmann MD, Snyder A et al (2015) Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 348:124–128

    Article  CAS  PubMed  Google Scholar 

  73. Butterfield LH, Palucka AK, Britten CM et al (2011) Recommendations from the iSBTc-SITC/FDA/NCI Workshop on Immunotherapy Biomarkers. Clin Cancer Res 17:3064–3076

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  74. Janetzki S, Britten CM, Kalos M et al (2009) “MIATA”-minimal information about T cell assays. Immunity 31:527–528

    Article  PubMed Central  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

Support was derived from the Northwestern University Medical Scientist Training Program Training Grant T32 GM008152 (JBL) and the Howard Hughes Medical Institute (LA). Dr. Bloch is the Khatib Professor of Neurological surgery and supported by R00 NS078055 and R01 CA164714.

Author information

Authors and Affiliations

  1. Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, 676 N. Saint Clair Street, Suite 2210, Chicago, IL, 60611, USA

    Jonathan B. Lamano, Leonel Ampie, Winward Choy, Kartik Kesavabhotla, Joseph D. DiDomenico, Daniel E. Oyon, Andrew T. Parsa & Orin Bloch

Authors
  1. Jonathan B. Lamano
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Leonel Ampie
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Winward Choy
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kartik Kesavabhotla
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Joseph D. DiDomenico
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Daniel E. Oyon
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Andrew T. Parsa
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Orin Bloch
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Orin Bloch.

Ethics declarations

Conflicts of interest

The authors have no conflicts of interest to report.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lamano, J.B., Ampie, L., Choy, W. et al. Immunomonitoring in glioma immunotherapy: current status and future perspectives. J Neurooncol 127, 1–13 (2016). https://doi.org/10.1007/s11060-015-2018-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11060-015-2018-4

Keywords

Search

Navigation