Expert Rev Vaccines. 2016 Aug 10:1-10.
Advances and challenges: dendritic cell vaccination strategies for glioblastoma.
1a Department of Neurosurgery , Duke University Medical Center , Durham , NC , USA.
Glioblastoma is the most common primary brain tumor in adults and prognosis remains poor with a median survival of approximately 15-17 months. This review provides an overview of recent advances in the field of glioblastoma immunotherapy.
Recent advances in dendritic cell vaccination immunotherapy are showing encouraging results in clinical trials and promise to extend patient survival. In this report we discuss current scientific knowledge regarding dendritic cell (DC) vaccines, including approaches to differentiating, priming, and injecting dendritic cells to achieve maximal anti-tumor efficacy in glioblastoma. These findings are compared to recently completed and currently ongoing glioblastoma clinical trials. Novel methods such as ‘fastDCs’ and vaccines targeting DCs in-vivo may offer more effective treatment when compared to traditional DC vaccines and have already entered the clinic. Expert commentary: Finally, we discuss the challenges of T-cell dysfunctions caused by glioblastoma immunosuppression and how they affect dendritic cell vaccinations approaches.
KEYWORDS: Glioblastoma; T-cell dysfunction; cancer vaccine; clinical trials; dendritic cell; fastDCs; immunosuppression; immunotherapy; in-vivo DC vaccine; recall antigens
Expert Opin Biol Ther. 2015 Jan;15(1):79-94. doi: 10.1517/14712598.2015.972361. Epub 2014 Oct 18.
Enhancing dendritic cell-based vaccination for highly aggressive glioblastoma.
1Duke Brain Tumor Immunotherapy Program, Division of Neurosurgery, Department of Surgery ; Durham, NC 27710 , USA.
Patients with primary glioblastoma (GBM) have a dismal prognosis despite standard therapy, which can induce potentially deleterious side effects. Arming the immune system is an alternative therapeutic approach, as its cellular effectors and inherent capacity for memory can be utilized to specifically target invasive tumor cells, while sparing collateral damage to otherwise healthy brain parenchyma.
Active immunotherapy is aimed at eliciting a specific immune response against tumor antigens. Dendritic cells (DCs) are one of the most potent activators of de novo and recall immune responses and are thus a vehicle for successful immunotherapy. Currently, investigators are optimizing DC vaccines by enhancing maturation status and migratory potential to induce more potent antitumor responses. An update on the most recent DC immunotherapy trials is provided.
Targeting of unique antigens restricted to the tumor itself is the most important parameter in advancing DC vaccines. In order to overcome intrinsic mechanisms of immune evasion observed in GBM, the future of DC-based therapy lies in a multi-antigenic vaccine approach. Successful targeting of multiple antigens will require a comprehensive understanding of all immunologically relevant oncological epitopes present in each tumor, thereby permitting a rational vaccine design.
EGFR variant III; antigen escape; dendritic cell; glioblastoma; immunotherapy; tumor-specific antigen
Cytotherapy. 2016 Sep;18(9):1146-61. doi: 10.1016/j.jcyt.2016.05.014. Epub 2016 Jul 14.
Tumor antigen-specific T cells for immune monitoring of dendritic cell-treated glioblastoma patients.
1Institute of Clinical Hemostaseology and Transfusion Medicine, Saarland University Medical Center, Homburg, Germany. Electronic address: firstname.lastname@example.org.
2Institute of Clinical Hemostaseology and Transfusion Medicine, Saarland University Medical Center, Homburg, Germany.
3Stem Cell Laboratory, University Children’s Hospital, University of Würzburg, Würzburg, Germany.
4Immungenetic/HLA, German Red Cross Blood Service, Bad Kreuznach, Germany.
5Biophysics, Center for Integrative Physiology and Molecular Medicine, Saarland University School of Medicine, Homburg, Germany.
6Department of Neurosurgery, Saarland University Medical Center, Homburg, Germany.
CD8(+) T cells are part of the adaptive immune system and, as such, are responsible for the elimination of tumor cells.Dendritic cells (DC) are professional antigen-presenting cells (APC) that activate CD8(+) T cells. Effector CD8(+) T cells in turn mediate the active immunotherapeutic response of DC vaccination against the aggressive glioblastoma (GBM). The lack of tumor response assays complicates the assessment of treatment success in GBM patients.
A novel assay to identify specific cytotoxicity of activated T cells by APC was evaluated. Tumor antigen-pulsed DCs from HLA-A*02-positive GBM patients were cultivated to stimulate autologous cytotoxic T lymphocytes (CTL) over a 12-day culture period. To directly correlate antigen specificity and cytotoxic capacity, intracellular interferon (IFN)-γ fluorescence flow cytometry-based measurements were combined with anti-GBM tumor peptide dextramer staining. IFN-γ response was quantified by real-time polymerase chain reaction (PCR), and selected GBM genes were compared with healthy human brain cDNA by single specific primer PCR characterization.
Using CTL of GBM patients stimulated with GBM lysate-pulsed DCs increased IFN-γ messenger RNA levels, and intracellular IFN-γ protein expression was positively correlated with specificity against GBM antigens. Moreover, the GBM peptide-specific CD8(+) T-cell response correlated with specific GBM gene expression. Following DC vaccination, GBM patients showed 10-fold higher tumor-specific signals compared with unvaccinated GBM patients.
These data indicate that GBM tumor peptide-dextramer staining of CTL in combination with intracellular IFN-γ staining may be a useful tool to acquire information on whether a specific tumor antigen has the potential to induce an immune response in vivo.
CD8(+) T cells; GBM peptides; IFN-γ; cancer immunotherapy; dextramer staining; immune monitoring