Generation of clinical grade dendritic cells with capacity to produce biologically active IL-12p70

Zobywalski, Anke; Javorovic, Miran; Frankenberger, Bernhard; Pohla, Heike; Kremmer, Elisabeth; Bigalke, Iris; Schendel, Dolores J.

doi:10.1186/1479-5876-5-18

Cited by 119 publications

(128 citation statements)

References 45 publications

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“…The simultaneous activation of multiple PRR pathways has been employed to facilitate IL-12 secretion and enhance CD4 C Th1-cell polarization, 15,23 and has been assessed for antitumor activity. [24][25][26] Here, we show that the sequential triggering first of a MyD88-independent pathway, and then of a MyD88-dependent pathway, leads to even higher Th1 responses than synergy relying on simultaneous stimulation, but with a different mechanism: We have demonstrated earlier that the viral activation of RLR reprograms the TLR7 receptor pathway and renders this pathway more sensitive to subsequent stimuli in a type I IFN-dependent manner.…”

Section: Discussionmentioning

confidence: 99%

Reprogramming of TLR7 signaling enhances antitumor NK and cytotoxic T cell responses

et al. 2016

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Toll-like receptor (TLR) 7 agonists are effective in topical application for the immunotherapy of skin cancers, but their performance for the systemic treatment of solid tumors is limited by the development of TLR tolerance. In this study, we describe a novel strategy to overcome TLR tolerance and enhance TLR7-dependent antitumor immune responses through reprogramming of TLR signaling pathways. The sensitivity of TLR7 signaling in dendritic cells (DC) was increased by prior stimulation with the dsRNA poly (I:C) that mimics virally induced immune activation. Timing of the stimulations was important, as sequential stimulation with poly(I:C) and the TLR7 agonist R848 interspaced by 24 h induced higher MAPK and NFkB signaling in DC than the simultaneous application of the same ligands. DC activated by sequential poly(I:C)/R848 stimulation efficiently induced Th1 differentiation and primed NK-cell and cytotoxic T-cell responses. We have developed a treatment regimen taking advantage of TLR7 reprogramming that cured over 80% of large immunogenic tumors in mice by the action of NK cells and cytotoxic T cells. These results have direct implications for the use of these clinically established ligands in the immunotherapy of cancer.

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Section: Discussionmentioning

confidence: 99%

Reprogramming of TLR7 signaling enhances antitumor NK and cytotoxic T cell responses

et al. 2016

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“…Despite the advantages of DCs as APCs, the development of cellular immunotherapeutic agents using DCs remain limited because DCs are present in blood and lymphoid tissues in only small numbers and are difficult to isolate. In addition, several days are required for ex vivo generation of DCs from precursors with the addition of cytokines (6,7). Therefore, an alternative cellular immunotherapeutic agent is needed.…”

Section: Ell-based Vaccines Using Apcs Have Been Shown To Activate Cd8mentioning

confidence: 99%

Immunosuppressive Myeloid-Derived Suppressor Cells Can Be Converted into Immunogenic APCs with the Help of Activated NKT Cells: An Alternative Cell-Based Antitumor Vaccine

Lee

Kim

et al. 2009

The Journal of Immunology

124

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Myeloid-derived suppressor cells (MDSCs), which are known to be accumulated in the blood, spleen, and bone marrow of tumor-bearing mice and cancer patients, were tested as APCs for a cellular vaccine because they have phenotypical similarity with inflammatory monocytes and may be differentiated from the same precursors as monocytes. Although MDSCs have immunosuppressive properties, in vivo transferred MDSCs, which present tumor Ag and NKT cell ligand (α-galactosylceramide), significantly prolonged survival time in metastatic tumor-bearing mice in a CD8+ cell-, NK cell-, and NKT cell-dependent manner vs a CD4+ T cell- and host dendritic cell-independent manner. Major concerns about using MDSCs as APCs in a vaccine are their suppression of CTLs and their induction of Foxp3+ regulatory T cells. However, α-galactosylceramide-loaded MDSCs did not suppress CD4+ and CD8+ T cells and allowed for the generation of Ag-specific CTL immunity without increasing the generation of regulatory T cells. Furthermore, stimulation with activated NKT cells induced changes on MDSCs in phenotypical or maturation markers, including CD11b, CD11c, and CD86. Taken together, these findings suggest that NKT cells facilitate the conversion of immunosuppressive MDSCs into immunogenic APCs, eliciting successful antitumor immunity and providing the basis for alternative cell-based vaccines.

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“…As described above, TLR7/8 agonists induce efficient maturation and activation of DCs, and these cells can be used in DC-based cancer vaccines. Therefore, R-848 has been included in maturation cocktails to generate mature clinical-grade DCs [149,150]. Furthermore, DCs have been shown to exhibit a higher Th1-polarizing potential if TLR7/8 agonists are combined with other factors, like TLR3 or TLR4 agonists and CD40 ligand [151][152][153][154][155].…”

Section: How Can Cancer Vaccine Approaches Benefit From Tlr7/8 Ligands?mentioning

confidence: 99%

The Use of TLR7 and TLR8 Ligands for the Enhancement of Cancer Immunotherapy

et al. 2008

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After completing this course, the reader should be able to:1. Describe the subtypes of Toll-like receptor 7 and 8 agonists and their effect on the different components of the antitumor immune response.2. Argue why they are used as stand-alone immunotherapeutic agents.3. Evaluate their potential to improve current approaches of active and passive immunotherapy.This article is available for continuing medical education credit at CME.TheOncologist.com. CME CME ABSTRACT

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Generation of clinical grade dendritic cells with capacity to produce biologically active IL-12p70

Cited by 119 publications

References 45 publications

Reprogramming of TLR7 signaling enhances antitumor NK and cytotoxic T cell responses

Reprogramming of TLR7 signaling enhances antitumor NK and cytotoxic T cell responses

Immunosuppressive Myeloid-Derived Suppressor Cells Can Be Converted into Immunogenic APCs with the Help of Activated NKT Cells: An Alternative Cell-Based Antitumor Vaccine

The Use of TLR7 and TLR8 Ligands for the Enhancement of Cancer Immunotherapy

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