Generation of an optimized polyvalent monocyte-derived dendritic cell vaccine by transfecting defined RNAs after rather than before maturation

Schaft, Niels; Dörrie, Jan; Thumann, Peter; Beck, Verena; Müller, Ina; Schultz, E. S.; Kämpgen, Eckhart; Dieckmann, Detlef

doi:10.4049/jimmunol.174.9.5884

Cited by 34 publications

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“…HLA-A201/Melan-A/MART-1 [26][27][28][29][30][31][32][33][34][35] (EAAGIGILTV) -specific CD8 1 T cells after stimulation with matured, uninfected DCs were 0.7 or 0.8% of total CD8 1 T cells in A or B, respectively. These percentages were 8.5 or 6.1%, respectively, if matured, uninfected DCs loaded with peptide Melan-A/MART-1 [26][27][28][29][30][31][32][33][34][35] A27L analogue (ELAGI-GILTV) were used. oncolytic adenoviruses show strongly attenuated replication potential in human monocyte-derived DCs and no toxicity for iDCs after high titer infection; minimal loss of viability was observed for mDCs at high titers and long incubation times.…”

Section: Discussionmentioning

confidence: 99%

“…Immature DCs were infected with indicated adenoviruses at 10,000 vp/cell, or were mock-infected and incubated without (2MC) or with MC (1MC). After 3 days, DCs were pulsed with HLA-A2-binding peptide Melan-A/MART-1 [26][27][28][29][30][31][32][33][34][35] (EAAGIGILTV). Autologous CD8 1 cells were then cocultivated with DC at final concentrations of 1 3 10 6 and 1 3 10 5 ml 21 , respectively.…”

Section: Discussionmentioning

confidence: 99%

“…Monocyte-derived dendritic cells (moDC) were generated from leukapheresis products of healthy donors in a standardized procedure as described previously. 32 The generated, immature DCs (iDC) were used for further experiments after analyzing maturation and purity status. Mature DCs (mDCs) were generated by adding a maturation cocktail (MC) consisting of 10 ng/ml tumor necrosis factor alpha (TNFa, Strathmann, Hamburg, Germany), 1 lg/ml prostaglandin E2 (PGE2, Sigma-Aldrich, Deisenhofen, Germany), 200 U/ml Interleukin-1b (IL-1b, Strathmann) and 1,000 U/ml Interleukin6 (IL6, Strathmann) for 2 days.…”

Section: Cell Culture and Generation Of Dcs And T Cellsmentioning

confidence: 99%

“…Immature DCs of HLA-A201-typed donors were infected with Ad5.2xTyr or Ad5/ 3.2xTyr at 10,000 vp/cell or were mock-infected and subsequently cultured for 3 days with or without MC. DCs were then loaded with peptide Melan-A/MART-1 [26][27][28][29][30][31][32][33][34][35] (EAAGIGILTV) and were incubated for 7 days with autologous CD8 1 T cells in a ratio of 1 to 10. The quantity and quality of HLA-A2/MelanA-specific CD8 1 T cells after stimulation was determined by FACS analysis of cells stained with the corresponding tetramer and with antibodies for CCR7 and CD45RA.…”

Section: T Cell Stimulation By Dcs After Infection With Oncolytic Adementioning

confidence: 99%

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Modulation of viability and maturation of human monocyte‐derived dendritic cells by oncolytic adenoviruses

Schierer

Hesse

Müller

et al. 2007

Intl Journal of Cancer

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Adenoviral oncolysis is a promising new modality for treatment of cancer based on selective viral replication in tumor cells. However, tumor cell killing by adenoviral oncolysis needs to be improved to achieve therapeutic benefit in the clinic. Towards this end, the activation of anti-tumor immunity by adenoviral oncolysis might constitute a potent mechanism for systemic killing of uninfected tumor cells, thereby effectively complementing direct tumor cell killing by the virus. Knowledge of anti-tumor immune induction by adenoviral oncolysis, however, is lacking mostly due to species-specificity of adenovirus replication, which has hampered studies of human oncolytic adenoviruses in animals. We suggest the analysis of interactions of oncolytic adenoviruses with human immune cells as rational basis for the implementation of adenoviral oncolysis-induced anti-tumor immune activation. The goal of our study was to investigate how oncolytic adenoviruses affect human dendritic cells (DCs), key regulators of innate and adoptive immunity that are widely investigated as tumor vaccines. We report that melanoma-directed oncolytic adenoviruses, like replication-deficient adenoviruses but unlike adenoviruses with unrestricted replication potential, are not toxic to monocytederived immature DCs and do not block DC maturation by external stimuli. Of note, this is in contrast to reports for other viruses/ viral vectors and represents a prerequisite for anti-tumor immune activation by adenoviral oncolysis. Furthermore, we show that these oncolytic adenoviruses alone do not or only partially induce DC maturation. Thus additional signals are required for optimal immune activation. These could be delivered, for example, by inserting immunoregulatory transgenes into the oncolytic adenovirus genome. ' 2007 Wiley-Liss, Inc.Key words: oncolytic adenovirus; dendritic cell; DC maturation; virotherapy; tumor vaccination Oncolytic adenoviruses are emerging agents for the treatment of cancer based on tumor cell killing by virus infection, replication, cell lysis and spread. 1,2 Tumor-selectivity of virus replication is pivotal for this therapeutic strategy and has been achieved for oncolytic adenoviruses by (i) the mutation of adenoviral genes that are required for viral replication in normal cells, but which are dispensable in tumor cells, and (ii) the expression of essential viral genes, mostly of E1A, from heterologous, tumor-selective promoters. 1 Importantly, the advanced knowledge of the adenovirus structure, genome and replication cycle facilitates molecular modifications to the virus that are required or beneficial for therapeutic applications: besides the introduction of tumor-selective replication and cell killing potential, these are the modification of the virus tropism, or the expression of therapeutic genes. 3,4 Oncolytic adenoviruses have shown promise in clinical trials, which demonstrated proof-of-concept for tumor-selective virus replication and a favorable safety profile. 5,6 However, therapeutic efficacy of the investigat...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Cell Culture and Generation Of Dcs And T Cellsmentioning

confidence: 99%

Section: T Cell Stimulation By Dcs After Infection With Oncolytic Adementioning

confidence: 99%

See 2 more Smart Citations

Modulation of viability and maturation of human monocyte‐derived dendritic cells by oncolytic adenoviruses

Schierer

Hesse

Müller

et al. 2007

Intl Journal of Cancer

Self Cite

View full text Add to dashboard Cite

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“…Likewise, DCs electroporated with mRNA encoding full-length TAA are currently being optimized for clinical testing. 24 Vaccination strategies aiming to raise immunity to a full-length antigen have the advantage that the HLA haplotype of the individual patient does not need to be considered. On the other hand, and apart from the problems related to each mode of delivery (virus, DNA, mRNA, protein; reviewed in van der Bruggen and Van den Eynde 9 and Berzofsky et al 10 ), vaccination with single-whole antigens has the important drawback that vaccine-induced immune pressure may induce escape through antigen loss variants of the tumor.…”

Section: Vaccination Strategies With Defined Full-length Taamentioning

confidence: 99%

Identification of T-cell epitopes for cancer immunotherapy

2007

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The effectiveness of T-cell-mediated immunotherapy of cancer depends on both an optimal immunostimulatory context of the therapy and the proper selection with respect to quality and quantity of the targeted tumor-associated antigens (TAA), and, more precisely, the T-cell epitopes contained in these tumor proteins. Our progressing insight in human leukocyte antigen (HLA) class I and class II antigen processing and presentation mechanisms has improved the prediction by reverse immunology of novel cytotoxic T lymphocyte and T-helper cell epitopes within known antigens. Computer algorithms that in silico predict HLA class I and class II binding, proteasome cleavage patterns and transporter associated with antigen processing translocation are now available to expedite epitope identification. The advent of genomics allows a high-throughput screening for tumor-specific transcripts and mutations, with that identifying novel shared and unique TAA. The increasing power of mass spectrometry and proteomics will lead to the direct identification from the tumor cell surface of numerous novel tumor-specific HLA class I and class II presented ligands. Together, the expanded repertoire of tumor-specific T-cell epitopes will enable more precise immunomonitoring and the development of effective epitope-defined adoptive T-cell transfer and multi-epitope-based vaccination strategies targeting epitopes derived from a wider diversity of TAA presented in a broader array of HLA molecules.

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The clinical significance of MAGEA3 expression in pancreatic cancer

Kim

Reber

Hines

et al. 2005

Intl Journal of Cancer

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The MAGEA gene family that encodes cancer testis antigens is differentially expressed in many cancers. Though MAGEA3 expression has been detected in gastrointestinal malignancies, its role in pancreatic ductal adenocarcinoma (PDAC) has not been well established. We assessed 57 patients who underwent intentto-cure surgery for PDAC. Total RNA from paraffin-embedded pancreatic tumors was extracted and assessed for MAGEA3 gene expression by an optimized probe-based quantitative real-time RT-PCR (qRT) assay. MAGEA3 gene expression was detected by qRT in 25 (44%) patients. For the entire cohort, detection of MAGEA3 expression was associated with significantly decreased overall survival (median, 16 vs 33 months; log-rank, p 5 0.032). When clinicopathologic factors, including age, gender, stage, tumor extent, lymph node metastasis, tumor grade, perineural invasion and lymphovascular invasion were assessed by univariate analysis, MAGEA3 gene expression and tumor grade were significant prognostic factors for poor survival (HR 2.1, 95% CI: 1.0-4.4, p 5 0.041; and HR 3.7, 95% CI: 1.8-7.6, p 5 0.0004, respectively). Immunohistochemistry (IHC) was performed and confirmed MAGEA3 protein in PDAC specimens. In conclusion, MAGEA3 is differentially expressed in patients with PDAC; its expression correlates with significantly worse survival. Molecular assessment for MAGEA3 should be considered to improve prognostic evaluation and to identify eligible patients for potential immune-based therapy. ' 2005 Wiley-Liss, Inc.

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Generation of an optimized polyvalent monocyte-derived dendritic cell vaccine by transfecting defined RNAs after rather than before maturation

Abstract: This information is current as before maturation transfecting defined RNAs after rather than monocyte-derived dendritic cell vaccine by Generation of an optimized polyvalent

Cited by 34 publications

References 0 publications

Modulation of viability and maturation of human monocyte‐derived dendritic cells by oncolytic adenoviruses

Modulation of viability and maturation of human monocyte‐derived dendritic cells by oncolytic adenoviruses

Identification of T-cell epitopes for cancer immunotherapy

The clinical significance of MAGEA3 expression in pancreatic cancer

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