Oncolysate-loaded Escherichia coli bacterial ghosts enhance the stimulatory capacity of human dendritic cells

Michálek, Jaroslav; Héžová, Renata; Turanek-Knotigova, Pavlina; Gabková, Jana; Strioga, Marius; Lubitz, Werner; Kudela, Pavol

doi:10.1007/s00262-016-1932-4

Cited by 28 publications

(15 citation statements)

References 48 publications

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“…Consequently, these armed DCs were able to stimulate and activate T-cells -which are specific for the native cancer cells used for the oncolysate-in co-culture. 59 Similar properties were found for OK-432. 60 Accordingly, there is already clinical evidence that by stimulating dendritic cells (and also NK cells) via in vitro cytokine treatment, the anti-CRC activity of the FOLFOX scheme can be improved.…”

Section: Discussionsupporting

confidence: 64%

Bacterial ghosts as adjuvant to oxaliplatin chemotherapy in colorectal carcinomatosis

Groza

Gehrig

Kudela³

et al. 2018

OncoImmunology

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Colorectal cancer (CRC) is one of the most commonly diagnosed cancers and a major cause of cancer mortality worldwide. At late stage of the disease CRC often shows (multiple) metastatic lesions in the peritoneal cavity which cannot be efficiently targeted by systemic chemotherapy. This is one major factor contributing to poor prognosis. Oxaliplatin is one of the most commonly used systemic treatment options for advanced CRC. However, drug resistanceoften due to insufficient drug deliveryis still hampering successful treatment. The anticancer activity of oxaliplatin includes besides DNA damage also a strong immunogenic component. Consequently, the aim of this study was to investigate the effect of bacterial ghosts (BGs) as adjuvant immunostimulant on oxaliplatin efficacy. BGs are empty envelopes of gramnegative bacteria with a distinct immune-stimulatory potential. Indeed, we were able to show that the combination of BGs with oxaliplatin treatment had strong synergistic anticancer activity against the CT26 allograft, resulting in prolonged survival and even a complete remission in this murine model of CRC carcinomatosis. This synergistic effect was based on an enhanced induction of immunogenic cell death and activation of an efficient T-cell response leading to long-term anti-tumor memory effects. Taken together, co-application of BGs strengthens the immunogenic component of the oxaliplatin anticancer response and thus represents a promising natural immune-adjuvant to chemotherapy in advanced CRC.

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Section: Discussionsupporting

confidence: 64%

Bacterial ghosts as adjuvant to oxaliplatin chemotherapy in colorectal carcinomatosis

Groza

Gehrig

Kudela³

et al. 2018

OncoImmunology

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“…We also propose that BG may increase the migratory potential of DC through upregulation of CCR7, essential for activation of naïve T cells in the draining lymph nodes. Furthermore, in line with previous studies (45, 59, 61) our MLR experiments showed that BG-treated DC resulted in enhanced CD4 T cell proliferation and differentiation. Unlike previous studies however (38, 41, 45), we failed to observe a significant impact of BG treatment on CD8 T cell proliferation both in vitro and in vivo .…”

Section: Discussionsupporting

confidence: 92%

“…Furthermore, in line with previous studies (45, 59, 61) our MLR experiments showed that BG-treated DC resulted in enhanced CD4 T cell proliferation and differentiation. Unlike previous studies however (38, 41, 45), we failed to observe a significant impact of BG treatment on CD8 T cell proliferation both in vitro and in vivo . Nevertheless, an increased proportion of activated CD8 T cells supports that BG treatment does potentiate CD8 T cells in their effector functions.…”

Section: Discussionsupporting

confidence: 92%

“…The presence of various pathogen associated molecular patterns (PAMPs) in the cell wall of BG—lipopolysaccharide (LPS), peptidoglycan, glycolipids, flagellin, and lipoproteins—makes them potent activators of innate immune cells, which leads to the production of pro-inflammatory cytokines and bactericidal elements, such as reactive oxygen and nitrogen intermediates (ROIs and RNIs) (37, 42, 43). Furthermore, through their ability to activate DC, BG have also been shown to promote greater pathogen-specific antibody responses (40), increased T lymphocytes recruitment and proliferation with their associated cytokine production (39, 41, 44, 45).…”

Section: Introductionmentioning

confidence: 99%

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Harnessing the Immunomodulatory Properties of Bacterial Ghosts to Boost the Anti-mycobacterial Protective Immunity

et al. 2019

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Tuberculosis (TB) pathogenesis is characterized by inadequate immune cell activation and delayed T cell response in the host. Recent immunotherapeutic efforts have been directed at stimulating innate immunity and enhancing interactions between antigen presenting cells and T cells subsets to improve the protective immunity against TB. In this study, we investigated the immunostimulatory properties of bacterial ghosts (BG) as a novel approach to potentiate the host immunity against mycobacterial infection. BG are intact cytoplasm-free Escherichia coli envelopes and have been developed as bacterial vaccines and adjuvant/delivery system in cancer immunotherapy. However, BG have yet to be exploited as immunopotentiators in the context of infectious diseases. Here, we showed that BG are potent inducers of dendritic cells (DC), which led to enhanced T cell proliferation and differentiation into effector cells. BG also induced macrophage activation, which was associated with enhanced nitric oxide production, a key anti-mycobacterial weapon. We further demonstrated that the immunostimulatory capability of BG far exceeds that of LPS and involves both TLR4-dependent and independent pathways. Consistently, BG treatment, but not LPS treatment, reduced the bacterial burden in infected mice, which correlated with increased influx of innate and adaptive effector immune cells and increased production of key cytokines in the lungs. Finally and importantly, enhanced bacilli killing was seen in mice co-administered with BG and second-line TB drugs bedaquiline and delamanid. Overall, this work paves the way for BG as potent immunostimulators that may be harnessed to improve mycobacteria killing at the site of infection.

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“…The BGs can also carry recombinant antigen within its inner lumen. Finally BGs and recombinant antigens can be simply mixed together, to utilize the intrinsic adjuvant effect of BGs (40–42). Production of BGs is an efficient, stable and safe process resulting in freeze dried vaccine preparations which are stable at ambient temperatures for many months (43); and for the first time as shown in this communication, BGs are stable in liquid formulation for several months.…”

Section: Introductionmentioning

confidence: 99%

Subcutaneous Immunization of Dogs With Bordetella bronchiseptica Bacterial Ghost Vaccine

Muhammad¹,

Kassmannhuber

Rauscher

et al. 2019

Front. Immunol.

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The Bordetella species are Gram-negative bacterial pathogens that colonizes mammalian respiratory tract causing respiratory diseases in humans and animals. B. bronchiseptica causes clinical conditions in many mammals including immunocompromised humans. Using the dog model of respiratory infection, it has been shown in this study that a newly developed B. bronchiseptica Bacterial Ghost (BbBG) vaccine exhibited significant protection in the face of a severe pathogenic bacterial challenge in seronegative dogs. The protein E -specific lysis mechanism was used to produce BbBGs. Bacterial Ghosts (BGs) are the empty cell envelope of Gram-negative bacterium. They are genetically processed to form a microscopic hole in their membrane, through which all the cytoplasmic contents are expelled leaving behind intact empty bacterial shells. Due to the intact surface structures of BGs, they offer the safety of inactivated but efficacy of live attenuated vaccines. In this study, seronegative dogs were vaccinated subcutaneously (s/c) with two different doses of a newly developed BbBG vaccine [lower 10 ∧ 5 (BbBG – 5) and higher 10 ∧ 7 (BbBG – 7)] on day 0 and 21. The animals were challenged (by aerosol) with virulent live B. bronchiseptica strains 41 days after first vaccination. The dogs vaccinated s/c with BbBG – 7 vaccine had significantly lower spontaneous coughing scores ( P = 0.0001) than dogs in negative control group. Furthermore, the tested BbBG – 7 vaccine was equivalent to the positive control vaccine Bronchicine CAe in terms of safety and efficacy. For the first time, we report the successful use of liquid formulated BGs vaccines in animal studies. Earlier reported studies using BGs vaccines were performed with resuspended freeze-dried BGs preparations.

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Oncolysate-loaded Escherichia coli bacterial ghosts enhance the stimulatory capacity of human dendritic cells

Cited by 28 publications

References 48 publications

Bacterial ghosts as adjuvant to oxaliplatin chemotherapy in colorectal carcinomatosis

Bacterial ghosts as adjuvant to oxaliplatin chemotherapy in colorectal carcinomatosis

Harnessing the Immunomodulatory Properties of Bacterial Ghosts to Boost the Anti-mycobacterial Protective Immunity

Subcutaneous Immunization of Dogs With Bordetella bronchiseptica Bacterial Ghost Vaccine

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