Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Cancer Immunology, Immunotherapy
Published in: Cancer Immunology, Immunotherapy 9/2013

Open Access 01-09-2013 | Original Article

Therapeutic vaccination against autologous cancer stem cells with mRNA-transfected dendritic cells in patients with glioblastoma

Authors: Einar Osland Vik-Mo, Marta Nyakas, Birthe Viftrup Mikkelsen, Morten Carstens Moe, Paulina Due-Tønnesen, Else Marit Inderberg Suso, Stein Sæbøe-Larssen, Cecilie Sandberg, Jan E. Brinchmann, Eirik Helseth, Anne-Marie Rasmussen, Knut Lote, Steinar Aamdal, Gustav Gaudernack, Gunnar Kvalheim, Iver A. Langmoen

Published in: Cancer Immunology, Immunotherapy | Issue 9/2013

Login to get access

Abstract

Background

The growth and recurrence of several cancers appear to be driven by a population of cancer stem cells (CSCs). Glioblastoma, the most common primary brain tumor, is invariably fatal, with a median survival of approximately 1 year. Although experimental data have suggested the importance of CSCs, few data exist regarding the potential relevance and importance of these cells in a clinical setting.

Methods

We here present the first seven patients treated with a dendritic cell (DC)-based vaccine targeting CSCs in a solid tumor. Brain tumor biopsies were dissociated into single-cell suspensions, and autologous CSCs were expanded in vitro as tumorspheres. From these, CSC-mRNA was amplified and transfected into monocyte-derived autologous DCs. The DCs were aliquoted to 9–18 vaccines containing 107 cells each. These vaccines were injected intradermally at specified intervals after the patients had received a standard 6-week course of post-operative radio-chemotherapy. The study was registered with the ClinicalTrials.​gov identifier NCT00846456.

Results

Autologous CSC cultures were established from ten out of eleven tumors. High-quality RNA was isolated, and mRNA was amplified in all cases. Seven patients were able to be weaned from corticosteroids to receive DC immunotherapy. An immune response induced by vaccination was identified in all seven patients. No patients developed adverse autoimmune events or other side effects. Compared to matched controls, progression-free survival was 2.9 times longer in vaccinated patients (median 694 vs. 236 days, p = 0.0018, log-rank test).

Conclusion

These findings suggest that vaccination against glioblastoma stem cells is safe, well-tolerated, and may prolong progression-free survival.
Appendix
Available only for authorised users
Literature
1.
Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC et al (2009) 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 10:459–466PubMedCrossRef
2.
Reya T, Morrison SJ, Clarke MF, Weissman IL (2001) Stem cells, cancer, and cancer stem cells. Nature 414:105–111PubMedCrossRef
3.
Vermeulen L, de Sousa e Melo F, Richel DJ, Medema JP (2012) The developing cancer stem-cell model: clinical challenges and opportunities. Lancet Oncol 13:e83–e89PubMedCrossRef
4.
Ignatova TN, Kukekov VG, Laywell ED, Suslov ON, Vrionis FD, Steindler DA (2002) Human cortical glial tumors contain neural stem-like cells expressing astroglial and neuronal markers in vitro. Glia 39:193–206PubMedCrossRef
5.
Reynolds BA, Weiss S (1992) Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system. Science 255:1707–1710PubMedCrossRef
6.
Chen R, Nishimura MC, Bumbaca SM, Kharbanda S, Forrest WF, Kasman IM et al (2010) A hierarchy of self-renewing tumor-initiating cell types in glioblastoma. Cancer Cell 17:362–375PubMedCrossRef
7.
Deleyrolle LP, Ericksson G, Morrison BJ, Lopez JA, Burrage K, Burrage P et al (2011) Determination of somatic and cancer stem cell self-renewing symmetric division rate using sphere assays. PLoS ONE 6:e15844PubMedCrossRef
8.
Moe MC, Varghese M, Danilov AI, Westerlund U, Ramm-Pettersen J, Brundin L et al (2005) Multipotent progenitor cells from the adult human brain: neurophysiological differentiation to mature neurons. Brain 128:2189–2199PubMedCrossRef
9.
Galli R, Binda E, Orfanelli U, Cipelletti B, Gritti A, De Vitis S et al (2004) Isolation and characterization of tumorigenic, stem-like neural precursors from human glioblastoma. Cancer Res 64:7011–7021PubMedCrossRef
10.
Singh SK, Clarke ID, Terasaki M, Bonn VE, Hawkins C, Squire J et al (2003) Identification of a cancer stem cell in human brain tumors. Cancer Res 63:5821–5828PubMed
11.
Varghese M, Olstorn H, Sandberg C, Vik-Mo EO, Noordhuis P, Nistér M et al (2008) A comparison between stem cells from the adult human brain and from brain tumors. Neurosurgery 63:1022–1033PubMedCrossRef
12.
Bao S, Wu Q, McLendon RE, Hao Y, Shi Q, Hjelmeland AB et al (2006) Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 444:756–760PubMedCrossRef
13.
Salmaggi A, Boiardi A, Gelati M, Russo A, Calatozzolo C, Ciusani E et al (2006) Glioblastoma-derived tumorspheres identify a population of tumor stem-like cells with angiogenic potential and enhanced multidrug resistance phenotype. Glia 54:850–860PubMedCrossRef
14.
Quintana E, Shackleton M, Sabel MS, Fullen DR, Johnson TM, Morrison SJ (2008) Efficient tumour formation by single human melanoma cells. Nature 456:593–598PubMedCrossRef
15.
Eppert K, Takenaka K, Lechman ER, Waldron L, Nilsson B, van Galen P et al (2011) Stem cell gene expression programs influence clinical outcome in human leukemia. Nat Med 17:1086–1093PubMedCrossRef
16.
Gentles AJ, Plevritis SK, Majeti R, Alizadeh AA (2010) Association of a leukemic stem cell gene expression signature with clinical outcomes in acute myeloid leukemia. JAMA 304:2706–2715PubMedCrossRef
17.
Herrera MB, Bruno S, Buttiglieri S, Tetta C, Gatti S, Dereqibus MC et al (2006) Isolation and characterization of a stem cell population from adult human liver. Stem Cells 24:2840–2850PubMedCrossRef
18.
Takamiya M, Haider KH, Ashraf M (2011) Identification and characterization of a novel multipotent sub-population of Sca-1(+) cardiac progenitor cells for myocardial regeneration. PLoS ONE 6:e25265PubMedCrossRef
19.
Wu Y, Wu PY (2009) CD133 as a marker for cancer stem cells: progresses and concerns. Stem Cells Dev 18:1127–1134PubMedCrossRef
20.
Kyte JA, Mu L, Aamdal S, Kvalheim G, Dueland S, Hauser M et al (2006) Phase I/II trial of melanoma therapy with dendritic cells transfected with autologous tumor-mRNA. Cancer Gene Ther 13:905–918PubMedCrossRef
21.
Mu LJ, Kyte JA, Kvalheim G, Aamdal S, Dueland S, Hauser M et al (2005) Immunotherapy with allotumour mRNA-transfected dendritic cells in androgen-resistant prostate cancer patients. Br J Cancer 93:749–756PubMedCrossRef
22.
Brown CE, Starr R, Martinez C, Aquilar B, D’Apuzzo M, Todorov I et al (2009) Recognition and killing of brain tumor stem-like initiating cells by CD8+ cytolytic T cells. Cancer Res 69:8886–8893PubMedCrossRef
23.
Pellegatta S, Poliani PL, Corno D, Menghi F, Ghielmetti F, Suarez-Merino B et al (2006) Neurospheres enriched in cancer stem-like cells are highly effective in eliciting a dendritic cell-mediated immune response against malignant gliomas. Cancer Res 66:10247–10252PubMedCrossRef
24.
Saeboe-Larssen S, Fossberg E, Gaudernack G (2002) mRNA-based electrotransfection of human dendritic cells and induction of cytotoxic T lymphocyte responses against the telomerase catalytic subunit (hTERT). J Immunol Methods 259:191–203PubMedCrossRef
25.
Suso EM, Dueland S, Rasmussen AM, Vetrhus T, Aamdal S, Kvalheim G et al (2011) hTERT mRNA dendritic cell vaccination: complete response in a pancreatic cancer patient associated with response against several hTERT epitopes. Cancer Immunol Immunother 60:809–818PubMedCrossRef
26.
Helseth R, Helseth E, Johannesen TB, Langberg CW, Lote K, Rønning P et al (2010) Overall survival, prognostic factors, and repeated surgery in a consecutive series of 516 patients with glioblastoma multiforme. Acta Neurol Scand 122:159–167PubMedCrossRef
27.
Vik-Mo EO, Sandberg C, Olstorn H, Varghese M, Brandal P, Ramm-Pettersen J et al (2010) Brain tumor stem cells maintain overall phenotype and tumorigenicity after in vitro culturing in serum-free conditions. Neuro Oncol 12:1220–1230PubMed
28.
Vik-Mo EO, Sandberg C, Joel M, Stangeland B, Watanabe Y, Mackay-Sim A et al (2011) A comparative study of the structural organization of spheres derived from the adult human subventricular zone and glioblastoma biopsies. Exp Cell Res 317:1049–1059PubMedCrossRef
29.
Boczkowski D, Nair SK, Nam JH, Lyerly HK, Gilboa E (2000) Induction of tumor immunity and cytotoxic T lymphocyte responses using dendritic cells transfected with messenger RNA amplified from tumor cells. Cancer Res 60:1028–1034PubMed
30.
Kyte JA, Kvalheim G, Aamdal S, Saeboe-Larssen S, Gaudernack G (2005) Preclinical full-scale evaluation of dendritic cells transfected with autologous tumor-mRNA for melanoma vaccination. Cancer Gene Ther 12:579–591PubMedCrossRef
31.
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent R, Ford R et al (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45:228–247PubMedCrossRef
32.
Wakimoto H, Mohapatra G, Kanai R, Curry WT Jr, Yip S, Nitta M et al (2012) Maintenance of primary tumor phenotype and genotype in glioblastoma stem cells. Neuro Oncol 14:132–144PubMedCrossRef
33.
deCarvalho AC, Nelson K, Lemke N, Lehman NL, Arbab AS, Kalkanis S et al (2010) Gliosarcoma stem cells undergo glial and mesenchymal differentiation in vivo. Stem Cells 28:181–190PubMed
34.
Singh SK, Clarke ID, Hide T, Dirks PB (2004) Cancer stem cells in nervous system tumors. Oncogene 23:7267–7273PubMedCrossRef
35.
Laks DR, Masterman-Smith M, Visnyei K, Angenieux B, Orozco NM, Foran I et al (2009) Neurosphere formation is an independent predictor of clinical outcome in malignant glioma. Stem Cell 27:980–987CrossRef
36.
Pallini R, Ricci-Vitiani L, Banna GL, Signore M, Lombardi D, Todaro M et al (2008) Cancer stem cell analysis and clinical outcome in patients with glioblastoma multiforme. Clin Cancer Res 14:8205–8212PubMedCrossRef
37.
Wu A, Wiesner S, Xiao J, Ericson K, Chen W, Hall WA et al (2007) Expression of MHC I and NK ligands on human CD 133+ glioma cells: possible targets of immunotherapy. J Neurooncol 83:121–131PubMedCrossRef
38.
Cancer Research Genome Atlas Network (2008) Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455:1061–1068CrossRef
39.
Lottaz C, Beier D, Meyer K, Kumar P, Hermann A, Schwarz J et al (2010) Transcriptional profiles of CD133+ and CD133− glioblastoma-derived cancer stem cell lines suggest different cells of origin. Cancer Res 70:2030–2040PubMedCrossRef
40.
Johnson RS, Walker AI, Ward SJ (2009) Cancer vaccines: will we ever learn? Expert Rev Anticancer Ther 9:67–74PubMedCrossRef
41.
Iversen TZ, Brimnes MK, Nikolaisen K, Andersen RS, Hadrup SR, Andersen MH et al (2013) Depletion of T lymphocytes is correlated with response to temozolomide in melanoma patients. Oncoimmunology 2:e23288PubMedCrossRef
42.
Kyte JA, Gaudernack G, Dueland S, Trachsel S, Julsrud L, Aamdal S (2011) Telomerase peptide vaccination combined with temozolomide: a clinical trial in stage IV melanoma patients. Clin Cancer Res 17:4568–4580PubMedCrossRef
43.
Ardon H, Van Gool S, Verschuere T, Maes W, Fieuws S, Sciot R 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 61:2033–2044PubMedCrossRef
44.
Grossman Z, Min B, Meier-Schellersheim M, Paul WE (2004) Concomitant regulation of T-cell activation and homeostasis. Nat Rev Immunol 4:387–395PubMedCrossRef
45.
Parajuli P, Mathupala S, Sloan AE (2004) Systematic comparison of dendritic cell-based immunotherapeutic strategies for malignant gliomas: in vitro induction of cytolytic and natural killer-like T cells. Neurosurgery 55:1194–1204PubMedCrossRef
46.
Moe MC, Kolberg RS, Sandberg C, Vik-Mo E, Olstorn H, Varghese M et al (2009) A comparison of epithelial and neural properties in progenitor cells derived from the adult human ciliary body and brain. Exp Eye Res 88:30–38PubMedCrossRef
47.
Xu Q, Liu G, Yuan X, Xu M, Wang H, Ji J et al (2009) Antigen-specific T-cell response from dendritic cell vaccination using cancer stem-like cell-associated antigens. Stem Cells 27:1734–1740PubMedCrossRef
48.
Puphanich S, Wheeler CJ, Rudnick J, Mazer M, Wang HQ, Nuno M et al (2013) Phase I trial of a multi-epitope-pulsed dendritic cell vaccine for patients with newly diagnosed glioblastoma. Cancer Immunol Immunother 62:125–135CrossRef
Metadata
Title
Therapeutic vaccination against autologous cancer stem cells with mRNA-transfected dendritic cells in patients with glioblastoma
Authors
Einar Osland Vik-Mo
Marta Nyakas
Birthe Viftrup Mikkelsen
Morten Carstens Moe
Paulina Due-Tønnesen
Else Marit Inderberg Suso
Stein Sæbøe-Larssen
Cecilie Sandberg
Jan E. Brinchmann
Eirik Helseth
Anne-Marie Rasmussen
Knut Lote
Steinar Aamdal
Gustav Gaudernack
Gunnar Kvalheim
Iver A. Langmoen
Publication date
01-09-2013
Publisher
Springer Berlin Heidelberg
Published in
Cancer Immunology, Immunotherapy / Issue 9/2013
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI
https://doi.org/10.1007/s00262-013-1453-3

Other articles of this Issue 9/2013

Cancer Immunology, Immunotherapy 9/2013 Go to the issue

Original Article

Identification of HLA ligands and T-cell epitopes for immunotherapy of lung cancer

Original Article

Phase I study of intraprostatic vaccine administration in men with locally recurrent or progressive prostate cancer

Original Article

Vaccination of castration-resistant prostate cancer patients with TroVax (MVA–5T4) in combination with docetaxel: a randomized phase II trial

Original Article

Increased CD14+HLA-DR-/low myeloid-derived suppressor cells correlate with extrathoracic metastasis and poor response to chemotherapy in non-small cell lung cancer patients

Original Article

Synergy between chemotherapeutic agents and CTLA-4 blockade in preclinical tumor models

Original Article

CXCR5 polymorphisms in non-Hodgkin lymphoma risk and prognosis
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits