13 results on '"Bretaudeau L"'
Search Results
2. Induction of antigen presentation by macrophages after phagocytosis of tumour apoptotic cells
- Author
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Henry, F., primary, Bretaudeau, L., additional, Barbieux, I., additional, Meflah, K., additional, and Gregoire, M., additional
- Published
- 1998
- Full Text
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3. Adenosine Methylation Level of miR-125a-5p Promotes Anti-PD-1 Therapy Escape through the Regulation of IGSF11/VSIG3 Expression.
- Author
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Bougras-Cartron G, Nadaradjane A, Joalland MP, Lalier-Bretaudeau L, Raimbourg J, and Cartron PF
- Abstract
Background: Despite encouraging anti-tumour activity in lung cancer, anti-PD-1 therapy has encountered increasing resistance to treatment. Several companion diagnostic assays have been performed to identify patients who may benefit from this immunotherapy and to adapt this therapy in case of acquired resistance., Methods: A large panel of methods was used for the analysis of expression and methylation levels of miRNAs (qPCR, MemiRIP, …), protein/miRNA interactions (CLIP, oligo pull-down, …), and protein-protein interactions (CoIP) in cells and/or blood samples., Results: Our work highlights that the saturation of PD-1 by anti-PD1 therapies induces an immune escape phenomenon due to the overexpression of IGSF11 following adenosine methylation of miR-125a-5p. Mechanistically, we identify METTL3/KHDRBS3 and HuR as two crucial players in the methylation and the loss of the repressive function of this miRNA. Finally, our work shows that the adenosine methylation of miR-125a-5p is analyzable from EVs/exosomes from longitudinal blood samples and that such EVs/exosomes modulate the IGSF11/VSIG3 expression in lung cancer cells to promote an immune escape phenomenon., Conclusions: Our data provide a biomarker (m6A-miR-125a-5p level) and two therapeutic solutions (anti-IGSF11 antibody and METTL3 inhibitor) that could potentially address the anti-PD1 therapy failure in the context of precision and personalized medicine., Competing Interests: The authors declare no conflict of interest.
- Published
- 2023
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4. Good Manufacturing Practice (GMP) Compliance for Phage Therapy Medicinal Products.
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Bretaudeau L, Tremblais K, Aubrit F, Meichenin M, and Arnaud I
- Abstract
Facing the emergence of difficult-to-treat bacterial infections, the perspective of using bacteriophages has re-gained interest in many countries. In terms of pharmaceutical classification in EU and United States, phages are considered as anti-infectious medicinal products and biological products, given the intended use and their live nature. During the production steps, the compliance with the Good Manufacturing Practice (GMP) represents the gold-standard to ensure the quality, safety and efficacy of medicinal products, either investigational or approved. In practice, the implementation of GMP rules for phage therapy medicinal products benefits from the long history of vaccine development. Accordingly, a well-structured strategy can be defined for each medicinal product, taking into account the specified indication (i.e., the target bacteria species, the infected site, the route of administration, the product composition). Based on the experience of different phage therapy medicinal products from the recent years, the most important requirements to achieve and claim GMP grade are reviewed here, including for genetically modified phages. Like all new medicinal products, the manufacturing of investigational phages incorporates significant challenges. However, the use of GMP-certified phages provides the best guarantee for the rigorous assessment of quality, safety and efficacy during the clinical development of phage medicinal products, thus appears as a key component for the successful development of phage therapy approaches., (Copyright © 2020 Bretaudeau, Tremblais, Aubrit, Meichenin and Arnaud.)
- Published
- 2020
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5. Epigenetic protein complexes: the adequate candidates for the use of a new generation of epidrugs in personalized and precision medicine in cancer.
- Author
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Cartron PF, Cheray M, and Bretaudeau L
- Subjects
- Antineoplastic Agents pharmacology, DNA Methylation drug effects, Humans, Multiprotein Complexes antagonists & inhibitors, Neoplasms genetics, Antineoplastic Agents therapeutic use, Epigenesis, Genetic drug effects, Neoplasms drug therapy, Precision Medicine
- Abstract
Until recently, drug development in oncology was focused on treating most patients for a specific cancer type without taking in account the heterogeneity between these patients in term of response to treatment. Therefore, this type of broad treatment approach excludes the treatment of patient not responding to disease-specific common drugs. In this review, we focus on the different types of epigenetic drugs currently used as DNA methylation inhibitor agents and their limits in patient care due to their lack of specificity. We also highlight the emergence of a new type of epidrug with higher target specificity due to their original mechanism of action: the disruption of protein complexes involved in the epigenetic modifications.
- Published
- 2020
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6. Efficacy and tolerability of a cocktail of bacteriophages to treat burn wounds infected by Pseudomonas aeruginosa (PhagoBurn): a randomised, controlled, double-blind phase 1/2 trial.
- Author
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Jault P, Leclerc T, Jennes S, Pirnay JP, Que YA, Resch G, Rousseau AF, Ravat F, Carsin H, Le Floch R, Schaal JV, Soler C, Fevre C, Arnaud I, Bretaudeau L, and Gabard J
- Subjects
- Adult, Aged, Anti-Bacterial Agents therapeutic use, Belgium, Double-Blind Method, Female, France, Humans, Male, Middle Aged, Pseudomonas Infections microbiology, Pseudomonas aeruginosa virology, Treatment Outcome, Burns microbiology, Burns therapy, Drug Tolerance, Phage Therapy methods, Pseudomonas Infections therapy, Pseudomonas Phages
- Abstract
Background: Wound infections are the main cause of sepsis in patients with burns and increase burn-related morbidity and mortality. Bacteriophages, natural bacterial viruses, are being considered as an alternative therapy to treat infections caused by multidrug-resistant bacteria. We aimed to compare the efficacy and tolerability of a cocktail of lytic anti-Pseudomonas aeruginosa bacteriophages with standard of care for patients with burns., Methods: In this randomised phase 1/2 trial, patients with a confirmed burn wound infection were recruited from nine burn centres in hospitals in France and Belgium. Patients were eligible if they were aged 18 years or older and had a burn wound clinically infected with P aeruginosa. Eligible participants were randomly assigned (1:1) by use of an interactive web response system to a cocktail of 12 natural lytic anti-P aeruginosa bacteriophages (PP1131; 1 × 10
6 plaque-forming units [PFU] per mL) or standard of care (1% sulfadiazine silver emulsion cream), both given as a daily topical treatment for 7 days, with 14 days of follow-up. Masking of treatment from clinicians was not possible because of the appearance of the two treatments (standard of care a thick cream, PP1131 a clear liquid applied via a dressing), but assignments were masked from microbiologists who analysed the samples and patients (treatment applied while patients were under general anaesthetic). The primary endpoint was median time to sustained reduction in bacterial burden by at least two quadrants via a four-quadrant method, assessed by use of daily swabs in all participants with a microbiologically documented infection at day 0 who were given at least one sulfadiazine silver or phage dressing (modified intention-to-treat population). Safety was assessed in all participants who received at least one dressing according to protocol. Ancillary studies were done in the per-protocol population (all PP1131 participants who completed 7 days of treatment) to assess the reasons for success or failure of phage therapy. This trial is registered with the European Clinical Trials database, number 2014-000714-65, and ClinicalTrials.gov, number NCT02116010, and is now closed., Findings: Between July 22, 2015, and Jan 2, 2017, across two recruitment periods spanning 13 months, 27 patients were recruited and randomly assigned to receive phage therapy (n=13) or standard of care (n=14). One patient in the standard of care group was not exposed to treatment, giving a safety population of 26 patients (PP1131 n=13, standard of care n=13), and one patient in the PP1131 group did not have an infection at day 0, giving an efficacy population of 25 patients (PP1131 n=12, standard of care n=13). The trial was stopped on Jan 2, 2017, because of the insufficient efficacy of PP1131. The primary endpoint was reached in a median of 144 h (95% CI 48-not reached) in the PP1131 group versus a median of 47 h (23-122) in the standard of care group (hazard ratio 0·29, 95% CI 0·10-0·79; p=0·018). In the PP1131 group, six (50%) of 12 analysable participants had a maximal bacterial burden versus two (15%) of 13 in the standard of care group. PP1131 titre decreased after manufacturing and participants were given a lower concentration of phages than expected (1 × 102 PFU/mL per daily dose). In the PP1131 group, three (23%) of 13 analysable participants had adverse events versus seven (54%) of 13 in the standard of care group. One participant in each group died after follow-up and the deaths were determined to not be related to treatment. The ancillary study showed that the bacteria isolated from patients with failed PP1131 treatment were resistant to low phage doses., Interpretation: At very low concentrations, PP1131 decreased bacterial burden in burn wounds at a slower pace than standard of care. Further studies using increased phage concentrations and phagograms in a larger sample of participants are warranted., Funding: European Commission: Framework Programme 7., (Copyright © 2019 Elsevier Ltd. All rights reserved.)- Published
- 2019
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7. A high-performance, non-radioactive potency assay for measuring cytotoxicity: A full substitute of the chromium-release assay targeting the regulatory-compliance objective.
- Author
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Rossignol A, Bonnaudet V, Clémenceau B, Vié H, and Bretaudeau L
- Subjects
- Animals, Humans, Antibody-Dependent Cell Cytotoxicity, Cytotoxicity Tests, Immunologic methods, Luciferases, Luminescent Measurements methods
- Abstract
Standardized and biologically relevant potency assays are required by the regulatory authorities for the characterization and quality control of therapeutic antibodies. As critical mechanisms of action (MoA) of antibodies, the antibody-dependent cell-meditated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) must be characterized by appropriate potency assays. The current reference method for measuring cytotoxicity is the
51 Cr-release method. However, radioactivity handling is difficult to implement in an industrial context because of environmental and operator protection constraints. Alternative non-radioactive methods suffer from poor validation performances and surrogate assays that measure FcγR-dependent functions do not comply with the regulatory requirement of biological relevance. Starting from these observations, we developed a non-radioactive luminescent method that is specific for target cell cytolysis. In adherent and non-adherent target cell models, the ADCC (using standardized effector cells) or CDC activities of rituximab, trastuzumab and adalimumab were compared in parallel using the51 Cr or luminescent methods. We demonstrated that the latter method is highly sensitive, with validation performances similar or better than the51 Cr method. This method also detected apoptosis following induction by a chemical agent or exposure to ultraviolet light. Moreover, it is more accurate, precise and specific than the concurrent non-radioactive calcein- and TR-FRET-based methods. The method is easy to use, versatile, standardized, biologically relevant and cost effective for measuring cytotoxicity. It is an ideal candidate for developing regulatory-compliant cytotoxicity assays for the characterization of the ADCC, CDC or apoptosis activities from the early stages of development to lot release.- Published
- 2017
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8. Quality and safety requirements for sustainable phage therapy products.
- Author
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Pirnay JP, Blasdel BG, Bretaudeau L, Buckling A, Chanishvili N, Clark JR, Corte-Real S, Debarbieux L, Dublanchet A, De Vos D, Gabard J, Garcia M, Goderdzishvili M, Górski A, Hardcastle J, Huys I, Kutter E, Lavigne R, Merabishvili M, Olchawa E, Parikka KJ, Patey O, Pouilot F, Resch G, Rohde C, Scheres J, Skurnik M, Vaneechoutte M, Van Parys L, Verbeken G, Zizi M, and Van den Eede G
- Subjects
- Bacteriophages isolation & purification, Humans, Bacterial Infections microbiology, Bacterial Infections therapy, Bacteriophages growth & development, Biological Therapy adverse effects, Biological Therapy standards, Biological Therapy trends, Drug Resistance, Multiple, Bacterial
- Abstract
The worldwide antibiotic crisis has led to a renewed interest in phage therapy. Since time immemorial phages control bacterial populations on Earth. Potent lytic phages against bacterial pathogens can be isolated from the environment or selected from a collection in a matter of days. In addition, phages have the capacity to rapidly overcome bacterial resistances, which will inevitably emerge. To maximally exploit these advantage phages have over conventional drugs such as antibiotics, it is important that sustainable phage products are not submitted to the conventional long medicinal product development and licensing pathway. There is a need for an adapted framework, including realistic production and quality and safety requirements, that allows a timely supplying of phage therapy products for 'personalized therapy' or for public health or medical emergencies. This paper enumerates all phage therapy product related quality and safety risks known to the authors, as well as the tests that can be performed to minimize these risks, only to the extent needed to protect the patients and to allow and advance responsible phage therapy and research.
- Published
- 2015
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9. ADCC potency assay: increased standardization with modified lymphocytes.
- Author
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Bretaudeau L and Bonnaudet V
- Published
- 2011
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10. Inducible Hsp70 as target of anticancer immunotherapy: Identification of HLA-A*0201-restricted epitopes.
- Author
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Faure O, Graff-Dubois S, Bretaudeau L, Derré L, Gross DA, Alves PM, Cornet S, Duffour MT, Chouaib S, Miconnet I, Grégoire M, Jotereau F, Lemonnier FA, Abastado JP, and Kosmatopoulos K
- Subjects
- Animals, Antigens, Neoplasm chemistry, Blotting, Western, CD8-Positive T-Lymphocytes metabolism, COS Cells, Cell Line, Tumor, Dose-Response Relationship, Drug, Epitopes chemistry, HLA Antigens chemistry, HLA-A2 Antigen, Humans, Interferon-gamma metabolism, Mice, Mice, Transgenic, Peptides chemistry, Plasmids metabolism, T-Lymphocytes, Cytotoxic metabolism, Tumor Necrosis Factor-alpha metabolism, HLA-A Antigens chemistry, HSP70 Heat-Shock Proteins metabolism, Immunotherapy methods
- Abstract
The design of a broad application tumor vaccine requires the identification of tumor antigens expressed in a majority of tumors of various origins. We questioned whether the major stress-inducible heat shock protein Hsp70 (also known as Hsp72), a protein frequently overexpressed in human tumors of various histological origins, but not in most physiological normal tissues, constitutes a tumor antigen. We selected the p391 and p393 peptides from the sequence of the human inducible Hsp70 that had a high affinity for HLA-A*0201. These peptides were able to trigger a CTL response in vivo in HLA-A*0201-transgenic HHD mice and in vitro in HLA-A*0201+ healthy donors. p391- and p393-specific human and murine CTL recognized human tumor cells overexpressing Hsp70 in a HLA-A*0201-restricted manner. Tetramer analysis of TILs showed that these Hsp70 epitopes are targets of an immune response in many HLA-A*0201+ breast cancer patients. Hsp70 is a tumor antigen and the Hsp70-derived peptides p391 and p393 could be used to raise a cytotoxic response against tumors of various origins., (Copyright 2003 Wiley-Liss, Inc.)
- Published
- 2004
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11. Apoptotic body-loaded dendritic cells efficiently cross-prime cytotoxic T lymphocytes specific for NA17-A antigen but not for Melan-A/MART-1 antigen.
- Author
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Labarrière N, Bretaudeau L, Gervois N, Bodinier M, Bougras G, Diez E, Lang F, Gregoire M, and Jotereau F
- Subjects
- Antigen Presentation immunology, Antigens, Neoplasm metabolism, Flow Cytometry, Humans, Immunomagnetic Separation, MART-1 Antigen, Phagocytosis, Tumor Cells, Cultured, Antigens, Neoplasm immunology, Apoptosis, Dendritic Cells immunology, Neoplasm Proteins immunology, Peptide Fragments immunology, T-Lymphocytes, Cytotoxic immunology
- Abstract
DCs hold promise for cancer immunotherapy due to their functional ambivalence: iDCs internalize antigens, then mDCs trigger naive T-cell activation. However, no consensus has been reached concerning the optimal mode of antigen acquisition for efficient cross-priming of TAA-specific CTLs, and this remains a field of investigation. Here, we used highly purified apobodies derived from an HLA-A*0201-negative melanoma line as a source of tumor antigens for HLA-A*0201 DCs. We compared in vitro mDCs loaded with apobodies to DCs loaded with antigenic peptides, NA17-A(1-9) and Melan-A/MART-1(26-35) A27L analogue, for their capacity to stimulate melanoma antigen-specific T cells from autologous PBLs. Apobody phagocytosis did not induce spontaneous DC maturation, but phagocytic DCs were still responsive to maturation signals, resulting in a functional ability to activate antigen-specific lymphocytes. NA17-A-specific T lymphocytes were activated by both types of stimulation, whereas only peptide-pulsed DCs stimulated the growth of Melan-A/MART-1-specific lymphocytes. We also observed a lack of staining of melanoma-derived apobodies with a Melan-A-specific MAb, suggesting protein alteration during apoptosis induction. After HLA-A*0201/NA17-A multimer sorting, antigen-specific lymphocytes induced by mature DCs loaded with either peptide or apobodies displayed similar functional capacity against peptide-pulsed T2 cells and melanoma cells. Therefore, apobody-loaded DCs can achieve T-cell priming similar to that induced by peptide-pulsed DCs, provided that the apoptotic process allows the preservation of antigen expression., (Copyright 2002 Wiley-Liss, Inc.)
- Published
- 2002
- Full Text
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12. Standardized generation of fully mature p70 IL-12 secreting monocyte-derived dendritic cells for clinical use.
- Author
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Spisek R, Bretaudeau L, Barbieux I, Meflah K, and Gregoire M
- Subjects
- Apoptosis, Cell Differentiation, Cell Division, Cell Survival, Cells, Cultured cytology, Cells, Cultured drug effects, Cells, Cultured metabolism, Dendritic Cells drug effects, Dendritic Cells metabolism, Dinoprostone pharmacology, Flow Cytometry, Granulocyte-Macrophage Colony-Stimulating Factor pharmacology, Hemocyanins immunology, Humans, Immunophenotyping, Interleukin-1 pharmacology, Interleukin-12 chemistry, Interleukin-13 pharmacology, Interleukin-6 pharmacology, Lymphocyte Culture Test, Mixed, Melanoma pathology, Phagocytosis, Poly I-C pharmacology, Protein Structure, Tertiary, Recombinant Proteins pharmacology, Reproducibility of Results, Tumor Cells, Cultured, Tumor Necrosis Factor-alpha pharmacology, Cell Culture Techniques methods, Dendritic Cells cytology, Interleukin-12 metabolism
- Abstract
Dendritic cells (DC) have been shown to be efficient antigen-presenting cells (APC) and, as such, could be considered ideal candidates for cancer immunotherapy. Immature DC (iDC) efficiently capture surrounding antigens; however, only mature DC (mDC) prime naive T lymphocytes. Clinical trials using DC-based tumor vaccines have achieved encouraging, but limited, success, possibly due to the use of immature or incompletely mature DC. Thus, it was apparent that a method capable of generating large numbers of fully functional iDC, their pulsing with desired form of tumor antigens and the subsequent complete and reproducible maturation of iDC is needed. Therefore, we compared two different methods of producing large numbers of iDC. Both protocols yielded comparable numbers of cells with an iDC phenotype with phagocytic function. We next determined which of the clinically applicable activators could induce the complete and reproducible maturation of DC, in order to define the most suitable combination for future clinical trials. Only a combination of TNFalpha + Poly (I:C), or a previously described cytokine cocktail of TNFalpha + IL-1beta + IL-6 + prostaglandin E2, induced the complete activation of the whole DC population, as assessed by the cell surface expression of CD83 and costimulatory molecules. The matured DC were functionally superior to iDC in their ability to stimulate the proliferation of allogeneic lymphocytes and autologous keyhole limpet hemocyanin (KLH)-specific T lymphocytes. Furthermore, only the combination of TNFalpha + Poly (L:C) activated DC to produce large amounts of biologically active p70 IL-12. Thus DC maturation by TNFalpha + Poly (I:C) could efficiently bias T cell response towards Th1 response. Implementation of our results into clinical protocols used for DC generation could be beneficial for future immunotherapy trials.
- Published
- 2001
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13. Antigen-presenting cells that phagocytose apoptotic tumor-derived cells are potent tumor vaccines.
- Author
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Henry F, Boisteau O, Bretaudeau L, Lieubeau B, Meflah K, and Grégoire M
- Subjects
- Animals, Antibodies, Monoclonal immunology, Antigen-Presenting Cells physiology, Antigens, Neoplasm immunology, Colonic Neoplasms immunology, Colonic Neoplasms pathology, Lymphocyte Activation, Monocytes physiology, Monocytes transplantation, Rats, T-Lymphocytes, Cytotoxic immunology, Antigen-Presenting Cells transplantation, Apoptosis, Cancer Vaccines therapeutic use, Colonic Neoplasms therapy, Immunotherapy, Active, Phagocytosis
- Abstract
We have reported recently that treatments combining injections of apoptotic bodies from tumor cells and interleukin 2 led to tumor regression and induced specific protection. In the present study, we show that tumor-bearing rats were cured with an 80% success rate by injection of antigen-presenting cells (APCs) that had phagocytosed apoptotic bodies derived from poorly immunogenic tumor cells, whereas phagocytic cells exposed to nonapoptotic tumor cell extracts were essentially without effect. In addition, curative vaccination using APCs that had phagocytosed apoptotic bodies generated a tumor-specific cytotoxic T-cell response and long-term protection from parental tumor challenge. Thus, systems using the processing and presentation of antigenic molecules by professional APCs after phagocytosis of apoptotic bodies appear to offer new possibilities for anticancer treatment.
- Published
- 1999
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