Combined dendritic cell- and CpG oligonucleotide-based immune therapy cures large murine tumors that resist chemotherapy

Heckelsmiller, Klaus; Beck, Sebastian; Rall, Katharina; Sipos, Bence; Schlamp, Angelika; Tuma, Evelyn; Rothenfußer, Simon; Endres, Stefan; Hartmann, Gunther

doi:10.1002/1521-4141(200211)32:11<3235::aid-immu3235>3.0.co;2-j

Cited by 100 publications

(65 citation statements)

References 42 publications

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“…Further studies have shown that peritumoral treatment resulted in complete rejection or strong inhibition of a variety of established mouse tumours, including B16 melanoma and 3LL lung carcinoma, whereas systemic administration only had partial effects (Kawarada et al, 2001). Heckelsmiller et al (2002) reported the combined use of CpG and antigen-pulsed DCs to cure large murine tumours that were resistant to chemotherapy.…”

Section: Discussionmentioning

confidence: 99%

Polarisation of a T-helper cell immune response by activation of dendritic cells with CpG-containing oligonucleotides: a potential therapeutic regime for bladder cancer immunotherapy

et al. 2003

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Intravesical bacillus Calmette -Guerin (BCG) is a treatment for transitional cell carcinoma (TCC) and carcinoma in situ (cis) of the urinary bladder, but some patients remain refractory. The mechanism of cancer clearance is not known, but T cells are thought to play a contributory role. Tissue dendritic cells (DCs) are known to initiate antigen-specific immune responses following activation of receptors, which recognise molecular patterns on the surface of microorganisms. A family of these receptors, the toll-like receptors (TLRs), are also crucial for activating DC to produce cytokines that polarise the T-cell response towards a T helper (Th)1 or Th2 phenotype. This study compared the potential of intact BCG to activate DC with that of the defined TLR4 ligand lipopolysaccharide (LPS) and the TLR9 ligand CpG-oligonucleotide. It was found that all three stimuli efficiently activated normal DC, but cells expressing a mutant TLR4 responded poorly to stimulation with LPS. Importantly, stimulation with BCG induced both IL-12 and IL-10, suggesting subsequent development of a poorly focused T-cell immune response containing both Th1 and Th2 immune function. By contrast, LPS-and CpG-oligonucleotides induced only IL-12, indicating the potential to produce a Th1 response, which is likely to clear cancer most efficiently. Given the toxicity of LPS, our data suggest that CpG-oligonucleotides may be beneficial for intravesical therapy of bladder cancer.

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Section: Discussionmentioning

confidence: 99%

Polarisation of a T-helper cell immune response by activation of dendritic cells with CpG-containing oligonucleotides: a potential therapeutic regime for bladder cancer immunotherapy

et al. 2003

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“…The treatment was started on day 3 after tumor inoculation and performed every second day for a total of seven injections. A dose of 50 lg for each reagent was selected since in most publications where repeated injections of CpG DNA oligonucleotides have been used, the amount applied was between 10 and 100 lg/injection [10,12,[23][24][25]. In these studies, the schedule for CpG DNA treatments varied between daily to weekly injections.…”

Section: Protamine-stabilized Mrna As An Anti-tumor Treatmentmentioning

confidence: 99%

Therapeutic anti‐tumor immunity triggered by injections of immunostimulating single‐stranded RNA

et al. 2006

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Stabilized synthetic RNA oligonucleotides (ORN) and protected messenger RNA (mRNA) were recently discovered to possess an immunostimulatory capacity through their recognition by TLR 7 and 8. We wanted to find out whether this danger signal is capable of triggering anti-tumor immunity when injected locally into an established tumor. Using the mouse glioma tumor cell line SMA-560 in syngenic VM/Dk mice, we were able to show that intra-tumor injections of protamine-stabilized mRNA do indeed induce tumor regression and long-term anti-tumor immunity. Residual RNA-injected tumors show CD8 infiltration. Distant injections of protamine-protected mRNA and intra-tumor injection of naked mRNA also result in anti-tumor immunity. Although they are strong danger signals, RNA are labile molecules with a short half-life: they do not trigger side effects such as long-term, uncontrolled immunostimulation evidenced by splenomegaly in CpG DNA-treated mice. In conclusion, RNA molecules are potent and safe danger signals that are relevant for active immunotherapy strategies aimed at the eradication of solid tumors.

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“…As a consequence, bacterial CpG motifs trigger pleiotropic effects in immune cells such as proliferation, activation and cytokine/ chemokine secretion (5). An intratumoral injection of CpG oligonucleotides (CpG-ODN), which mimic bacterial DNA, was shown to exert antitumoral effects in various experimental tumor models (8)(9)(10)(11). This therapeutic effect involving CD8 + T cells or natural killer (NK) cell activation can also induce the recruitment of macrophages or dendritic cells (DCs) within the tumor (9,10) or in draining lymph nodes (11).…”

Section: Introductionmentioning

confidence: 99%

Plasmidic CpG sequences induce tumor microenvironment modifications in a rat liver metastasis model

Bertin

Anjuère²,

Gavelli³

et al. 2008

Int J Mol Med

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Abstract. Bacterial DNA contains unmethylated cytosinephosphate-guanine (CpG) motifs which are recognized by mammalian immune cells as a danger signal indicating an infection. These immunostimulatory properties led to the use of oligodeoxynucleotides bearing CpG motifs (CpG-ODN) for cancer treatment in preclinical and clinical studies. Although naked DNA administration presently represents 18% of the gene therapy clinical trials worldwide, most of the work regarding the effects of unmethylated CpG sequences was performed using CpG-ODN. In the present study, we analyzed early induced tumor microenvironment modifications in a rat liver metastasis model after intratumoral injection of a plasmid used in suicide gene therapy. We first showed that plasmidic CpG motifs were active, i.e. able to induce IFN-γ secretion by rat splenocytes. Then, we compared tumorinfiltrating immune cells 24 h after injection of native or SssI-treated plasmid, in which immunostimulatory CpG motifs have been inactivated by methylation. The presence of active plasmidic CpG sequences within the tumor was associated with a decrease in the number of tumor-infiltrating conventional dendritic cells and an upregulation of the CCR7 chemokine receptor responsible for lymph node homing. We also observed an increase in plasmacytoid dendritic cells and natural killer cell infiltration within the tumors as well as an increased mRNA expression of three cytokines/chemokines . These data suggest that, although suicide plasmid injection without prodrug treatment is not sufficient to observe a therapeutic effect, the presence of plasmidic CpG motifs within the tumor induces the recruitment and activation of the immune cells involved in antitumor response. These early cellular and molecular events should facilitate the induction of the immune response against tumor antigens released after in situ drug production.

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Combined dendritic cell- and CpG oligonucleotide-based immune therapy cures large murine tumors that resist chemotherapy

Cited by 100 publications

References 42 publications

Polarisation of a T-helper cell immune response by activation of dendritic cells with CpG-containing oligonucleotides: a potential therapeutic regime for bladder cancer immunotherapy

Polarisation of a T-helper cell immune response by activation of dendritic cells with CpG-containing oligonucleotides: a potential therapeutic regime for bladder cancer immunotherapy

Therapeutic anti‐tumor immunity triggered by injections of immunostimulating single‐stranded RNA

Plasmidic CpG sequences induce tumor microenvironment modifications in a rat liver metastasis model

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