A combination of E. coli DNA fragments and modified lipopolysaccharides as a cancer immunotherapy

Cho, Yang Je; Ahn, Bo Young; Lee, Na Gyong; Lee, Dong Hoon; Kim, Doo Sik

doi:10.1016/j.vaccine.2006.04.048

Cited by 27 publications

(50 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Maximal DNA uptake was reached at a length of 250 bp, which is in good agreement with our previous observation that E. coli DNA fragments ranging from 0.2 to 0.5 kb were the most effective for inducing cytokine secretion in vitro (9). When co-administered with an antigen to mice, in contrast, DNA fragments of 0.5-2.0 kb induced the highest antibody production, followed by intact DNA and 0.2-to 0.5-kb DNA (9). This difference between in vitro and in vivo activity of DNA fragments may attribute to higher chances of DNA fragments to be digested by nucleases in vivo.…”

Section: Discussionsupporting

confidence: 92%

“…In support of this notion, methylation of CpG motifs in bacterial DNA has been shown to significantly reduce the immunostimulatory effects (24,45). We previously showed that E. coli DNA fragments combined with LPS lacking lipid A had synergistic immunostimulatory activity; CIA07, a combination of the two components, induced IL-12 secretion from human peripheral blood mononuclear cells, stimulated antibody secretion when administered with an antigen, and reduced tumor formation in mice (9). In the present study, we investigated whether methylation of CpG motifs on E. coli DNA affected the immunostimulatory effects of CIA07.…”

Section: Discussionmentioning

confidence: 87%

“…CIA07 was prepared as previously described by Cho et al (9). Briefly, short carbohydrate chain-containing LPS was isolated from E. coli and alkaline-hydrolyzed for removal of lipid A moieties, followed by ethanol precipitation.…”

Section: Methodsmentioning

confidence: 99%

“…In a previous study, we examined the possibility of using a combination of bacterial DNA fragments and LPS as an anticancer agent (9). E. coli genomic DNA fragments of various sizes were tested for immunostimulatory activity, and the 0.5-2.0 kb fragment was found to have the highest adjuvant activity in mice.…”

mentioning

confidence: 99%

See 3 more Smart Citations

Bacterial DNA Containing Methylated CpG Motifs Retains Immunostimulatory Activity in Synergy with Modified Lipopolysaccharides

Cho

Ahn²,

Song

et al. 2007

Microbiology and Immunology

Self Cite

View full text Add to dashboard Cite

We previously described the immunostimulatory activity of CIA07, a combination of bacterial DNA fragments and modified LPS, and demonstrated that CIA07 has antitumor activity in a mouse bladder cancer model. In this study, we investigated whether methylation of the CpG motifs on the bacterial DNA fragments affects the immunostimulatory potential of CIA07. E. coli DNA fragments were methylated with CpG methylase, and then combined with modified LPS for experiments. Our results revealed that methylated CIA07 (mCIA07) and unmethylated CIA07 were equally active in inducing cytokine secretion from human whole blood cells. In addition, both methylated DNA fragments and mCIA07 retained the ability to activate expression and nuclear translocation of NF‐κB in RAW 264.7 cells. Finally, methylated DNA fragments and mCIA07 exhibited an antitumor activity comparable to those of their unmethylated counterparts in our mouse bladder cancer model. These data demonstrate that CpG methylation of E. coli DNA does not abrogate the immunostimulatory activity of DNA fragments or CIA07, suggesting that the synergistic activity by bacterial DNA in combination with LPS may be independent of the methylation status of CpG motifs.

show abstract

Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 87%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Bacterial DNA Containing Methylated CpG Motifs Retains Immunostimulatory Activity in Synergy with Modified Lipopolysaccharides

Cho

Ahn²,

Song

et al. 2007

Microbiology and Immunology

Self Cite

View full text Add to dashboard Cite

show abstract

“…Other studies have showed the importance of using a TLR4 agonist to achieve tumor regression [14,[31][32][33]. However, most of these studies used other immune-stimulatory molecules associated with TLR ligands [17], or rather used more than one dose of the agonist [15].…”

Section: Discussionmentioning

confidence: 99%

Intratumoral TLR-4 Agonist Injection Is Critical for Modulation of Tumor Microenvironment and Tumor Rejection

et al. 2012

View full text Add to dashboard Cite

The tumor microenvironment shelters a complex network of mechanisms that enables local Immunosuppression to support tumor growth. In this study we found that, B16F10 melanoma growth is inversely correlated with peritumoral infiltrate cell number and with cell numbers in draining lymph nodes. Tumor growth ensued even when a foreign antigen was expressed by B16F10 cells in the presence of naïve specific CD8 + T cells. Treatment with TLR agonists has shown to sometimes result in tumor regression, however, not always with long-lasting effects. We compared the relevance of different injection regimens of lipopolysaccharide (LPS). Tumor growth was arrested only by intratumoral LPS injection after the tumor was already established. This result was accompanied by a dramatic change in DC activation inside the tumor. Intratumoral LPS also enhanced antigen presentation and tumor-specific CD4 + T cell production of IFN-γ. Injection of LPS before tumor challenge or codelivery of tumor cells and LPS did not have any effect on tumor progression. Our results suggest that an efficient antitumor immune response leading to tumor regression can be achieved with proper TLR4 activation inside the tumor tissue, impacting the tumor microenvironment. These findings are relevant for the design of treatment for patients with malignant melanomas.

show abstract

Cancer Immunotherapy of TLR4 Agonist–Antigen Constructs Enhanced with Pathogen‐Mimicking Magnetite Nanoparticles and Checkpoint Blockade of PD‐L1

Traini

Ruiz‐de‐Angulo

Blanco‐Canosa

et al. 2018

Small

View full text Add to dashboard Cite

Despite the tremendous potential of Toll‐like receptor 4 (TLR4) agonists in vaccines, their efficacy as monotherapy to treat cancer has been limited. Only some lipopolysaccharides (LPS) isolated from particular bacterial strains or structures like monophosphoryl lipid A (MPLA) derived from lipooligosaccharide (LOS), avoid toxic overactivation of innate immune responses while retaining adequate immunogenicity to act as adjuvants. Here, different LOS structures are incorporated into nanoparticle‐filled phospholipid micelles for efficient vaccine delivery and more potent cancer immunotherapy. The structurally unique LOS of the plant pathogen Xcc is incorporated into phospholipid micelles encapsulating iron oxide nanoparticles, producing stable pathogen‐mimicking nanostructures suitable for targeting antigen presenting cells in the lymph nodes. The antigen is conjugated via a hydrazone bond, enabling rapid, easy‐to‐monitor and high‐yield antigen ligation at low concentrations. The protective effect of these constructs is investigated against a highly aggressive model for tumor immunotherapy. The results show that the nanovaccines lead to a higher‐level antigen‐specific cytotoxic T lymphocyte (CTL) effector and memory responses, which when combined with abrogation of the immunosuppressive programmed death‐ligand 1 (PD‐L1), provide 100% long‐term protection against repeated tumor challenge. This nanovaccine platform in combination with checkpoint inhibition of PD‐L1 represents a promising approach to improve the cancer immunotherapy of TLR4 agonists.

show abstract

A combination of E. coli DNA fragments and modified lipopolysaccharides as a cancer immunotherapy

Cited by 27 publications

References 41 publications

Bacterial DNA Containing Methylated CpG Motifs Retains Immunostimulatory Activity in Synergy with Modified Lipopolysaccharides

Bacterial DNA Containing Methylated CpG Motifs Retains Immunostimulatory Activity in Synergy with Modified Lipopolysaccharides

Intratumoral TLR-4 Agonist Injection Is Critical for Modulation of Tumor Microenvironment and Tumor Rejection

Cancer Immunotherapy of TLR4 Agonist–Antigen Constructs Enhanced with Pathogen‐Mimicking Magnetite Nanoparticles and Checkpoint Blockade of PD‐L1

Contact Info

Product

Resources

About