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

Vik-Mo EO, Nyakas M, Mikkelsen BV, Moe MC, Due-Tønnesen P, Suso EM, Sæbøe-Larssen S, Sandberg C, Brinchmann JE, Helseth E, Rasmussen AM, Lote K, Aamdal S, Gaudernack G, Kvalheim G, Langmoen IA - Cancer Immunol. Immunother. (2013)

Bottom Line: 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).These findings suggest that vaccination against glioblastoma stem cells is safe, well-tolerated, and may prolong progression-free survival.

View Article: PubMed Central - PubMed

Affiliation: Vilhelm Magnus Laboratory for Neurosurgical Research, Institute for Surgical Research, University of Oslo, Oslo, Norway. e.o.vik-mo@medisin.uio.no

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 10(7) 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.

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Related in: MedlinePlus

Changes in size of contrast-enhancing tumor over time. a Brain MRI axial T1 images after intravenous gadolinium contrast in patient #5. Days before (negative) and after surgery are noted on the MRI scans. No residual tumor was observed post-operatively (day 2), but at the end of the 6 weeks course of combined chemo/radiotherapy, a small contrast-enhancing lesion could be detected at the anterior margin of the resection cavity, as indicated with the white arrow (day 64). b Maximal area of contrast enhancement plotted against days since surgery (abscissa). Lower part of the figure indicates the timing of concomitant chemo-radiotherapy (blue box), DC vaccinations (blue arrows), and immune response (red arrow)
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Fig2: Changes in size of contrast-enhancing tumor over time. a Brain MRI axial T1 images after intravenous gadolinium contrast in patient #5. Days before (negative) and after surgery are noted on the MRI scans. No residual tumor was observed post-operatively (day 2), but at the end of the 6 weeks course of combined chemo/radiotherapy, a small contrast-enhancing lesion could be detected at the anterior margin of the resection cavity, as indicated with the white arrow (day 64). b Maximal area of contrast enhancement plotted against days since surgery (abscissa). Lower part of the figure indicates the timing of concomitant chemo-radiotherapy (blue box), DC vaccinations (blue arrows), and immune response (red arrow)

Mentions: Tumor volume was monitored by serial brain MRIs (Fig. 2). A contrast-enhancing lesion had recurred or grown in five of the seven patients at the conclusion of radiotherapy, prior to the initiation of immunotherapy. These lesions all increased in size during the first phase of vaccination and reached a maximum mean volume of 805 mm3 (363–1,526 mm3) during ongoing vaccination. Subsequently, the contrast-enhancing lesions decreased to a minimum of 209 mm3 (9–452 mm3) after 448 days (342–568 days) (Fig. 2).Fig. 2


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

Vik-Mo EO, Nyakas M, Mikkelsen BV, Moe MC, Due-Tønnesen P, Suso EM, Sæbøe-Larssen S, Sandberg C, Brinchmann JE, Helseth E, Rasmussen AM, Lote K, Aamdal S, Gaudernack G, Kvalheim G, Langmoen IA - Cancer Immunol. Immunother. (2013)

Changes in size of contrast-enhancing tumor over time. a Brain MRI axial T1 images after intravenous gadolinium contrast in patient #5. Days before (negative) and after surgery are noted on the MRI scans. No residual tumor was observed post-operatively (day 2), but at the end of the 6 weeks course of combined chemo/radiotherapy, a small contrast-enhancing lesion could be detected at the anterior margin of the resection cavity, as indicated with the white arrow (day 64). b Maximal area of contrast enhancement plotted against days since surgery (abscissa). Lower part of the figure indicates the timing of concomitant chemo-radiotherapy (blue box), DC vaccinations (blue arrows), and immune response (red arrow)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3755221&req=5

Fig2: Changes in size of contrast-enhancing tumor over time. a Brain MRI axial T1 images after intravenous gadolinium contrast in patient #5. Days before (negative) and after surgery are noted on the MRI scans. No residual tumor was observed post-operatively (day 2), but at the end of the 6 weeks course of combined chemo/radiotherapy, a small contrast-enhancing lesion could be detected at the anterior margin of the resection cavity, as indicated with the white arrow (day 64). b Maximal area of contrast enhancement plotted against days since surgery (abscissa). Lower part of the figure indicates the timing of concomitant chemo-radiotherapy (blue box), DC vaccinations (blue arrows), and immune response (red arrow)
Mentions: Tumor volume was monitored by serial brain MRIs (Fig. 2). A contrast-enhancing lesion had recurred or grown in five of the seven patients at the conclusion of radiotherapy, prior to the initiation of immunotherapy. These lesions all increased in size during the first phase of vaccination and reached a maximum mean volume of 805 mm3 (363–1,526 mm3) during ongoing vaccination. Subsequently, the contrast-enhancing lesions decreased to a minimum of 209 mm3 (9–452 mm3) after 448 days (342–568 days) (Fig. 2).Fig. 2

Bottom Line: 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).These findings suggest that vaccination against glioblastoma stem cells is safe, well-tolerated, and may prolong progression-free survival.

View Article: PubMed Central - PubMed

Affiliation: Vilhelm Magnus Laboratory for Neurosurgical Research, Institute for Surgical Research, University of Oslo, Oslo, Norway. e.o.vik-mo@medisin.uio.no

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 10(7) 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.

Show MeSH
Related in: MedlinePlus