47 results on '"Irena Adkins"'
Search Results
2. 1087 SOT201 is a novel cis-acting immunocytokine targeting IL-15Rβγ to reinvigorate PD-1+tumor infiltrating lymphocytes and potentiate anti-tumor efficacy
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Ulrich Moebius, Radek Špíšek, David Béchard, Zuzana Antosova, Nada Podzimkova, Irena Adkins, Klara Danova, Lenka Palova Jelinkova, Katerina Behalova, Petr Danek, Matej Fabisik, Kamila Hladikova, Nataliia Kalynovska, Lucie Kosinova, Pavel Marasek, Vladyslav Mazhara, Jan Praslicka, Katerina Sajnerova, Milada Sirova, Marek Kovar, and Martin Steegmaier
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Published
- 2023
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3. 713 Nanrilkefusp alfa, a high-affinity IL-15Rβγ agonist, promotes an innate and adaptive anti-tumour inflammatory environment as single agent or combined with anti-PD-1 in patients with advanced cancers
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Ulrich Moebius, Radek Špíšek, David Béchard, Nada Podzimkova, Irena Adkins, Richard Sachse, Joachim Kiemle-Kallee, Ekaterina Simonova, Lenka Palova Jelinkova, Petr Danek, and Martin Steegmaier
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Published
- 2023
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4. SOT101 induces NK cell cytotoxicity and potentiates antibody-dependent cell cytotoxicity and anti-tumor activity
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Zuzana Antosova, Nada Podzimkova, Jakub Tomala, Katerina Augustynkova, Katerina Sajnerova, Eva Nedvedova, Milada Sirova, Guy de Martynoff, David Bechard, Ulrich Moebius, Marek Kovar, Radek Spisek, and Irena Adkins
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NK cells ,antibody-dependent cytotoxicity ,interleukin-15 ,immunotherapy ,therapeutic antibodies ,RLI-15 ,Immunologic diseases. Allergy ,RC581-607 - Abstract
SOT101 is a superagonist fusion protein of interleukin (IL)-15 and the IL-15 receptor α (IL-15Rα) sushi+ domain, representing a promising clinical candidate for the treatment of cancer. SOT101 among other immune cells specifically stimulates natural killer (NK) cells and memory CD8+ T cells with no significant expansion or activation of the regulatory T cell compartment. In this study, we showed that SOT101 induced expression of cytotoxic receptors NKp30, DNAM-1 and NKG2D on human NK cells. SOT101 stimulated dose-dependent proliferation and the relative expansion of both major subsets of human NK cells, CD56brightCD16- and CD56dimCD16+, and these displayed an enhanced cytotoxicity in vitro. Using human PBMCs and isolated NK cells, we showed that SOT101 added concomitantly or used for immune cell pre-stimulation potentiated clinically approved monoclonal antibodies Cetuximab, Daratumumab and Obinutuzumab in killing of tumor cells in vitro. The anti-tumor efficacy of SOT101 in combination with Daratumumab was assessed in a solid multiple myeloma xenograft in CB17 SCID mouse model testing several combination schedules of administration in the early and late therapeutic setting of established tumors in vivo. SOT101 and Daratumumab monotherapies decreased with various efficacy tumor growth in vivo in dependence on the advancement of the tumor development. The combination of both drugs showed the strongest anti-tumor efficacy. Specifically, the sequencing of both drugs did not matter in the early therapeutic setting where a complete tumor regression was observed in all animals. In the late therapeutic treatment of established tumors Daratumumab followed by SOT101 administration or a concomitant administration of both drugs showed a significant anti-tumor efficacy over the respective monotherapies. These results suggest that SOT101 might significantly augment the anti-tumor activity of therapeutic antibodies by increasing NK cell-mediated activity in patients. These results support the evaluation of SOT101 in combination with Daratumumab in clinical studies and present a rationale for an optimal clinical dosing schedule selection.
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- 2022
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5. 563 Pharmacodynamics and pharmacokinetics of SO-C101 in cynomolgus monkeys
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Ulrich Moebius, Radek Špíšek, David Béchard, Nada Podzimkova, Guy de Martynoff, and Irena Adkins
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Published
- 2020
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6. Myeloid - derived suppressor cells in Type 1 diabetes are an expanded population exhibiting diverse T-cell suppressor mechanisms.
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Anna Grohová, Klára Dáňová, Irena Adkins, Zdeněk Šumník, Lenka Petruželková, Barbora Obermannová, Stanislava Koloušková, Radek Špíšek, and Lenka Palová-Jelínková
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Medicine ,Science - Abstract
Myeloid-derived suppressor cells (MDSC) represent a heterogeneous group of immature myeloid cells with immunoregulatory function in cancer and autoimmune diseases. In humans, two subsets of MDSC were determined based on the characteristic surface markers, monocytic MDSC (M-MDSC) and granulocytic MDSC (G-MDSC). Expansion of MDSC has been reported in some murine models and patients with autoimmune diseases and their immune-suppressive properties were characterized. However, the exact role of MDSC in the pathogenesis of autoimmune diseases is more complex and/or controversial. In type 1 diabetes mellitus (T1D), the increased frequency of MDSC was found in the blood of T1D patients but their suppressor capacity was diminished. In our study, we assessed the role of M-MDSC in the pathogenesis of T1D and showed for the first time the increased frequency of M-MDSC not only in the blood of T1D patients but also in their at-risk relatives compared to healthy donors. T1D patients with inadequate long term metabolic control showed an elevation of M-MDSC compared to patients with better disease control. Furthermore, we described the positive correlation between the percentage of M-MDSC and Th17 cells and IFN-γ producing T cells in T1D patients and their at-risk relatives. Finally, we found that the ability of M-MDSC to suppress autologous T cells is efficient only at the high MDSC: T cells ratio and dependent on cell-cell-contact and TGF-β production. Our data show that the engagement of MDSC in the pathogenesis of T1D is evident, yet not entirely explored and more experiments are required to clarify whether MDSC are beneficial or harmful in T1D.
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- 2020
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7. Radiotherapy in Combination With Cytokine Treatment
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Ondrej Palata, Nada Hradilova Podzimkova, Eva Nedvedova, Alexandra Umprecht, Lenka Sadilkova, Lenka Palova Jelinkova, Radek Spisek, and Irena Adkins
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radiotherapy ,cytokine ,immunocytokine ,immunotherapy ,immunogenic cell death ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Radiotherapy (RT) plays an important role in the management of cancer patients. RT is used in more than 50% of patients during the course of their disease in a curative or palliative setting. In the past decades it became apparent that the abscopal effect induced by RT might be dependent on the activation of immune system, and that the induction of immunogenic cancer cell death and production of danger-associated molecular patterns from dying cells play a major role in the radiotherapy-mediated anti-tumor efficacy. Therefore, the combination of RT and immunotherapy is of a particular interest that is reflected in designing clinical trials to treat patients with various malignancies. The use of cytokines as immunoadjuvants in combination with RT has been explored over the last decades as one of the immunotherapeutic combinations to enhance the clinical response to anti-cancer treatment. Here we review mainly the data on the efficacy of IFN-α, IL-2, IL-2-based immunocytokines, GM-CSF, and TNF-α used in combinations with various radiotherapeutic techniques in clinical trials. Moreover, we discuss the potential of IL-15 and its analogs and IL-12 cytokines in combination with RT based on the efficacy in preclinical mouse tumor models.
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- 2019
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8. Severe, but not mild heat-shock treatment induces immunogenic cell death in cancer cells
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Irena Adkins, Lenka Sadilkova, Nada Hradilova, Jakub Tomala, Marek Kovar, and Radek Spisek
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antitumor immunity ,calreticulin ,cancer immunotherapy ,dendritic cells ,heat-shock treatment ,hyperthermia ,immunogenic cell death ,Immunologic diseases. Allergy ,RC581-607 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
The mechanisms of immunogenicity underlying mild heat-shock (mHS) treatment < 42°C of tumor cells are largely attributed to the action of heat-shock proteins; however, little is known about the immunogenicity of tumor cells undergoing severe cytotoxic heat-shock treatment (sHS > 43°C). Here, we found that sHS, but not mHS (42°C), induces immunogenic cell death in human cancer cell lines as defined by the induction of ER stress response and ROS generation, cell surface exposure of calreticulin, HSP70 and HSP90, decrease of cell surface CD47, release of ATP and HMGB1. Only sHS-treated tumor cells were efficiently killed and phagocytosed by dendritic cells (DCs), which was partially dependent on cell surface calreticulin. DCs loaded with mHS or sHS-treated tumor cells displayed similar level of maturation and stimulated IFNγ-producing CD8+ T cells without any additional adjuvants in vitro. However, only DCs loaded with sHS-treated tumor cells stimulated antigen-specific CD4+ T cells and induced higher CD8+ T-cell activation and proliferation. sHS-treated murine cells also exposed calreticulin, HSP70 and HSP90 and activated higher DC maturation than mHS treated cells. Vaccination with sHS-treated tumor cells elicited protective immunity in mice. In this study, we defined specific conditions for the sHS treatment of human lung and ovarian tumor cells to arrive at optimal ratio between effective cell death, immunogenicity and content of tumor antigens for immunotherapeutic vaccine generation.
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- 2017
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9. Generation of dendritic cell-based vaccine using high hydrostatic pressure for non-small cell lung cancer immunotherapy.
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Nada Hradilova, Lenka Sadilkova, Ondrej Palata, Dagmar Mysikova, Hana Mrazkova, Robert Lischke, Radek Spisek, and Irena Adkins
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Medicine ,Science - Abstract
High hydrostatic pressure (HHP) induces immunogenic death of tumor cells which confer protective anti-tumor immunity in vivo. Moreover, DC pulsed with HHP-treated tumor cells induced therapeutic effect in mouse cancer model. In this study, we tested the immunogenicity, stability and T cell stimulatory activity of human monocyte-derived dendritic cell (DC)-based HHP lung cancer vaccine generated in GMP compliant serum free medium using HHP 250 MPa. DC pulsed with HHP-killed lung cancer cells and poly(I:C) enhanced DC maturation, chemotactic migration and production of pro-inflammatory cytokines after 24h. Moreover, DC-based HHP lung cancer vaccine showed functional plasticity after transfer into serum-containing media and stimulation with LPS or CD40L after additional 24h. LPS and CD40L stimulation further differentially enhanced the expression of costimulatory molecules and production of IL-12p70. DC-based HHP lung cancer vaccine decreased the number of CD4+CD25+Foxp3+ T regulatory cells and stimulated IFN-γ-producing tumor antigen-specific CD4+ and CD8+ T cells from non-small cell lung cancer (NSCLC) patients. Tumor antigen specific CD8+ and CD4+ T cell responses were detected in NSCLC patient's against a selected tumor antigens expressed by lung cancer cell lines used for the vaccine generation. We also showed for the first time that protein antigen from HHP-killed lung cancer cells is processed and presented by DC to CD8+ T cells. Our results represent important preclinical data for ongoing NSCLC Phase I/II clinical trial using DC-based active cellular immunotherapy (DCVAC/LuCa) in combination with chemotherapy and immune enhancers.
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- 2017
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10. Invasion of Dendritic Cells, Macrophages and Neutrophils by the Bordetella Adenylate Cyclase Toxin: A Subversive Move to Fool Host Immunity
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Giorgio Fedele, Ilaria Schiavoni, Irena Adkins, Nela Klimova, and Peter Sebo
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immune response ,intracellular pathways ,phagocytosis ,T-helper cells ,Medicine - Abstract
Adenylate cyclase toxin (CyaA) is released in the course of B. pertussis infection in the host’s respiratory tract in order to suppress its early innate and subsequent adaptive immune defense. CD11b-expressing dendritic cells (DC), macrophages and neutrophils are professional phagocytes and key players of the innate immune system that provide a first line of defense against invading pathogens. Recent findings revealed the capacity of B. pertussis CyaA to intoxicate DC with high concentrations of 3′,5′-cyclic adenosine monophosphate (cAMP), which ultimately skews the host immune response towards the expansion of Th17 cells and regulatory T cells. CyaA-induced cAMP signaling swiftly incapacitates opsonophagocytosis, oxidative burst and NO-mediated killing of bacteria by neutrophils and macrophages. The subversion of host immune responses by CyaA after delivery into DC, macrophages and neutrophils is the subject of this review.
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- 2017
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11. Bordetella adenylate cyclase toxin differentially modulates toll-like receptor-stimulated activation, migration and T cell stimulatory capacity of dendritic cells.
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Irena Adkins, Jana Kamanova, Aneta Kocourkova, Martina Svedova, Jakub Tomala, Hana Janova, Jiri Masin, Barbora Chladkova, Ladislav Bumba, Marek Kovar, Padraig J Ross, Ludmila Tuckova, Radek Spisek, Kingston H G Mills, and Peter Sebo
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Medicine ,Science - Abstract
Adenylate cyclase toxin (CyaA) is a key virulence factor of the whooping cough agent Bordetella pertussis. The toxin targets CD11b-expressing phagocytes and delivers into their cytosol an adenylyl cyclase (AC) enzyme that subverts cellular signaling by increasing cAMP levels. In the present study, we analyzed the modulatory effects of CyaA on adhesive, migratory and antigen presenting properties of Toll-like receptor (TLR)-activated murine and human dendritic cells (DCs). cAMP signaling of CyaA enhanced TLR-induced dissolution of cell adhesive contacts and migration of DCs towards the lymph node-homing chemokines CCL19 and CCL21 in vitro. Moreover, we examined in detail the capacity of toxin-treated DCs to induce CD4(+) and CD8(+) T cell responses. Exposure to CyaA decreased the capacity of LPS-stimulated DCs to present soluble protein antigen to CD4+ T cells independently of modulation of co-stimulatory molecules and cytokine production, and enhanced their capacity to promote CD4(+)CD25(+)Foxp3(+) T regulatory cells in vitro. In addition, CyaA decreased the capacity of LPS-stimulated DCs to induce CD8(+) T cell proliferation and limited the induction of IFN-γ producing CD8(+) T cells while enhancing IL-10 and IL-17-production. These results indicate that through activation of cAMP signaling, the CyaA may be mobilizing DCs impaired in T cell stimulatory capacity and arrival of such DCs into draining lymph nodes may than contribute to delay and subversion of host immune responses during B. pertussis infection.
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- 2014
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12. Calcium influx rescues adenylate cyclase-hemolysin from rapid cell membrane removal and enables phagocyte permeabilization by toxin pores.
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Radovan Fiser, Jiri Masin, Ladislav Bumba, Eva Pospisilova, Catherine Fayolle, Marek Basler, Lenka Sadilkova, Irena Adkins, Jana Kamanova, Jan Cerny, Ivo Konopasek, Radim Osicka, Claude Leclerc, and Peter Sebo
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Immunologic diseases. Allergy ,RC581-607 ,Biology (General) ,QH301-705.5 - Abstract
Bordetella adenylate cyclase toxin-hemolysin (CyaA) penetrates the cytoplasmic membrane of phagocytes and employs two distinct conformers to exert its multiple activities. One conformer forms cation-selective pores that permeabilize phagocyte membrane for efflux of cytosolic potassium. The other conformer conducts extracellular calcium ions across cytoplasmic membrane of cells, relocates into lipid rafts, translocates the adenylate cyclase enzyme (AC) domain into cells and converts cytosolic ATP to cAMP. We show that the calcium-conducting activity of CyaA controls the path and kinetics of endocytic removal of toxin pores from phagocyte membrane. The enzymatically inactive but calcium-conducting CyaA-AC⁻ toxoid was endocytosed via a clathrin-dependent pathway. In contrast, a doubly mutated (E570K+E581P) toxoid, unable to conduct Ca²⁺ into cells, was rapidly internalized by membrane macropinocytosis, unless rescued by Ca²⁺ influx promoted in trans by ionomycin or intact toxoid. Moreover, a fully pore-forming CyaA-ΔAC hemolysin failed to permeabilize phagocytes, unless endocytic removal of its pores from cell membrane was decelerated through Ca²⁺ influx promoted by molecules locked in a Ca²⁺-conducting conformation by the 3D1 antibody. Inhibition of endocytosis also enabled the native B. pertussis-produced CyaA to induce lysis of J774A.1 macrophages at concentrations starting from 100 ng/ml. Hence, by mediating calcium influx into cells, the translocating conformer of CyaA controls the removal of bystander toxin pores from phagocyte membrane. This triggers a positive feedback loop of exacerbated cell permeabilization, where the efflux of cellular potassium yields further decreased toxin pore removal from cell membrane and this further enhances cell permeabilization and potassium efflux.
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- 2012
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13. 716 AURELIO-04: a phase 2, open-label, single-arm, multicenter study to determine the efficacy and safety of SOT101 in combination with pembrolizumab in patients with selected advanced solid tumors
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Stephane Champiat, Aurelien Marabelle, Diwakar Davar, Peter Grell, Kaissa Ouali, Anna Patrikidou, Andreu Schoenenberger, Lenka Palova Jelinkova, Irena Adkins, Sascha Tillmanns, Joachim Kiemle-Kallee, Richard Sachse, and Elena Garralda
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- 2022
14. Detection of tumor antigens and tumor-antigen specific T cells in NSCLC patients: Correlation of the quality of T cell responses with NSCLC subtype
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Beata Kutna, Nada Hradilova, Radek Spisek, Irena Adkins, Robert Lischke, D. Myšíková, Ondrej Palata, and Hana Mrazkova
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Male ,0301 basic medicine ,Lung Neoplasms ,T-Lymphocytes ,medicine.medical_treatment ,T cell ,Immunology ,T-Cell Antigen Receptor Specificity ,Cancer Vaccines ,03 medical and health sciences ,0302 clinical medicine ,Antigens, Neoplasm ,Carcinoma, Non-Small-Cell Lung ,Cell Line, Tumor ,medicine ,Humans ,Immunology and Allergy ,Lung cancer ,neoplasms ,Aged ,Neoplasm Staging ,PRAME ,business.industry ,Cancer ,Dendritic Cells ,Immunotherapy ,Middle Aged ,medicine.disease ,Tumor antigen ,respiratory tract diseases ,030104 developmental biology ,medicine.anatomical_structure ,Cancer cell ,Cancer research ,Female ,business ,CD8 ,T-Lymphocytes, Cytotoxic ,030215 immunology - Abstract
Allogeneic cancer cell lines serve as universal source of tumor-associated antigens in cancer vaccines. Immunogenic high hydrostatic pressure-killed cancer cells derived from cell lines can be used for the generation of dendritic cell (DC)-based active cellular immunotherapy of non-small cell lung cancer (NSCLC). We investigated the expression of 12 known NSCLC tumor-associated antigens (TAA) (CEA, MAGE-A1, MAGE-A3, MAGE-A4, PRAME, hTERT, HER2, MUC1, Survivin, STEAP1, SOX2 and NY-ESO-1) in 6 NSCLC cell lines as candidates for the generation of DC-based lung cancer vaccine. We showed that the selected antigenic profile of these cell lines overlaps to various degrees with that of primary NSCLC tumors (n = 52), indicating that 4 out of 6 NSCLC cell lines would be suitable for DC-based vaccine generation. We further investigated the presence of TAA-specific T cells in blood of NSCLC patients (n = 32) using commercially available peptide mixes in an in vitro stimulation assay. IFN-γ+CD8+ and IFN-γ+CD4+ T cell responses to all antigens were detected in NSCLC patients. Interestingly, despite higher TAA expression in squamous cell carcinoma (SCC) the responsiveness of patients' T cells to stimulation was significantly lower in SCC patients than in adenocarcinoma (AC) patients. This suggests qualitative differences in T cell functionality between NSCLC subtypes. Based on this study, and in order to maximize the amount of treatable patients, we selected a mix of H520 and H522 NSCLC cell lines for DC-based vaccine preparation. We also established a minimal panel of antigenic peptide mixes (CEA, hTERT, PRAME, HER2) for immunomonitoring of T cell responses during the DC-based lung cancer immunotherapy in Phase I lung cancer clinical trial (NCT02470468).
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- 2020
15. Abstract 3510: SOT201 is a novel targeted IL-15Rbg agonist to alleviate PD-1-mediated immune cell suppression and potentiate anti-tumor efficacy
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Irena Adkins, Zuzana Antosova, Klara Danova, Kamila Hladikova, Katerina Augustynkova, Katerina Sajnerova, Nada Podzimkova, Pavel Marasek, Guy de Martynoff, David Bechard, Ulrich Moebius, and Radek Spisek
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Cancer Research ,Oncology - Abstract
SOT201 is a novel immunocytokine consisting of a monoclonal humanized, Fc silenced antibody against PD-1 fused to a covalent RLI-15 complex of a human IL-15 mutein linked to the high-affinity binding site of the IL-15Rα, the sushi+ domain. SOT201 is developed for immunotherapeutic treatment of various types of cancers. The activity of SOT201 is based on spatiotemporal reinvigorating of anti-tumor immune responses by disrupting co-inhibitory T-cell signaling by blocking PD-1 and synergistically activating adaptive as well as innate immunity by IL-15-mediated signaling via the IL-2/IL-15βγ receptor on T cells, NK, NKT, and γδ T cells. SOT201 showed a superior potentiation of T cell stimulation over pembrolizumab in mixed lymphocyte reaction in vitro. Studies in cynomolgus monkeys showed that decreased affinity of IL-15 mutein in SOT201 for its IL-15Rβγ is well optimized to ensure favorable pharmacokinetic properties while inducing strong CD8+ T cell and NK cell activation and expansion. Synergistic action on CD8+ T cell activation of both anti-PD-1 and RLI-15 moieties was confirmed using mouse surrogate SOT201 molecules in vivo. Strong anti-tumor efficacy after SOT201 treatment was achieved in a human PD-1 transgenic mouse model implanted with the MC38-hPD-L1 cell line. These data represent a promising therapeutic candidate molecule leveraging the synergistic concerted action of anti-PD-1 blockage and simultaneous immune cell activation directed preferentially to the high PD-1+ T cell tumor environment. The therapeutic potential of SOT201 is currently being prepared for evaluation in a Phase I clinical study in metastatic advanced cancer patients as well as for PD-1 resistant/refractory patients as our clinical stage IL-2/IL-15Rβγ agonist SOT101 already showed a clinical benefit in these patients in its ongoing Phase I study. Citation Format: Irena Adkins, Zuzana Antosova, Klara Danova, Kamila Hladikova, Katerina Augustynkova, Katerina Sajnerova, Nada Podzimkova, Pavel Marasek, Guy de Martynoff, David Bechard, Ulrich Moebius, Radek Spisek. SOT201 is a novel targeted IL-15Rbg agonist to alleviate PD-1-mediated immune cell suppression and potentiate anti-tumor efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3510.
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- 2022
16. Abstract CT040: SOT101, an IL-2/IL-15 Rβγ superagonist, in combination with pembrolizumab in patients with advanced solid tumors: Interim safety and efficacy results from the AURELIO-03 dose escalation trial
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Stephane Champiat, Aurelien Marabelle, Vladimir Galvao, Patricia LoRusso, Peter Grell, Philippe Cassier, Carlos Gomez-Roca, Iphigenie Korakis, Aung Naing, Lenka Palova Jelinkova, Irena Adkins, Ulrich Moebius, Richard Sachse, Sascha Tillmanns, David Bechard, Joachim Kiemle-Kallee, and Elena Garralda
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Cancer Research ,Oncology - Abstract
Introduction: SOT101 (previously SO-C101), a fusion protein of IL-15 and the IL-15 receptor α sushi+ domain, was investigated in an open-label, multicenter, dose-escalation study as monotherapy and in combination with pembrolizumab in patients with selected advanced tumors (NCT04234113). Here we report an update on the safety and efficacy of the combination treatment. Methods Dose escalation followed a standard 3+3 design. Objectives were to determine the maximum tolerated dose (MTD) and the recommended phase 2 dose (RP2D). The evaluation period for dose-limiting toxicities in each dose step was 21 days. The RP2D was defined as the MTD or a dose below, considering pharmacokinetic and pharmacodynamic parameters. The study is ongoing (data cut-off 26 January 2022). Results: Twenty-one patients with a median of 2 (range 1-6) lines of previous systemic therapies were treated with 1.5, 3.0, 6.0, 9.0, and 12.0 μg/kg of SOT101 subcutaneously in combination with pembrolizumab. The MTD was not yet reached at the ongoing dose level 12.0 µg/kg, which is the RP2D in SOT101 monotherapy. The most common treatment-emergent adverse events were transient and included pyrexia, chills, injection site reaction, anemia, transaminase elevation, vomiting, and lymphopenia. One dose-limiting toxicity with rash, hypotension, and oliguria was reported at 6.0 µg/kg. The event resolved within 2 days and the patient continued with SOT101 at a lower dose. No treatment-related death was reported. One patient achieved a confirmed complete response (CR): mesothelioma at 9.0 µg/kg, on treatment 20 weeks with CR. This patient was immune checkpoint blocker (ICB)-naïve. Four patients achieved a partial response (PR): thyroid gland carcinoma at 3.0 µg/kg, ICB-naïve, on treatment 61 weeks with PR; skin squamous cell carcinoma at 6.0 µg/kg, ICB-relapsed, with PR and disappearance of target lesions, then fluctuating lesions, and on treatment 46 weeks with significant clinical benefit; skin melanoma at 6.0 µg/kg, ICB-relapsed, on treatment 41 weeks with PR; cervical melanoma at 9.0 µg/kg, ICB-pretreated, discontinued treatment after 8 weeks while still on PR. Five patients had confirmed stable disease (SD): anal squamous cell carcinoma (anal SCC) at 1.5 µg/kg, gastric cancer at 3.0 µg/kg, cervical cancer at 6.0 µg/kg, liver cancer at 6.0 µg/kg, and colorectal cancer at 9.0 µg/kg, with 1 patient (anal SCC) having a long-lasting SD over 40 weeks. In this heavily pretreated population, the observed preliminary clinical benefit rate was 63%. Conclusions: SOT101 in combination with pembrolizumab showed a favorable safety profile. Highly promising efficacy signals were reported in ICB-naïve and ICB pre-treated patients, including ICB-resistant tumors. Citation Format: Stephane Champiat, Aurelien Marabelle, Vladimir Galvao, Patricia LoRusso, Peter Grell, Philippe Cassier, Carlos Gomez-Roca, Iphigenie Korakis, Aung Naing, Lenka Palova Jelinkova, Irena Adkins, Ulrich Moebius, Richard Sachse, Sascha Tillmanns, David Bechard, Joachim Kiemle-Kallee, Elena Garralda. SOT101, an IL-2/IL-15 Rβγ superagonist, in combination with pembrolizumab in patients with advanced solid tumors: Interim safety and efficacy results from the AURELIO-03 dose escalation trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT040.
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- 2022
17. Interim safety and efficacy results from AURELIO-03: A phase 1 dose escalation study of the IL-2/IL-15 receptor βγ superagonist SOT101 as a single agent and in combination with pembrolizumab in patients with advanced solid tumors
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Elena Garralda, Aung Naing, Vladimir Galvao, Patricia LoRusso, Peter Grell, Philippe Alexandre Cassier, Carlos A. Gomez-Roca, Iphigenie Korakis, David Bechard, Lenka Palova Jelinkova, Irena Adkins, Sascha Tillmanns, Joachim Kiemle-Kallee, Aurelien Marabelle, and Stephane Champiat
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Cancer Research ,Oncology - Abstract
2502 Background: SOT101 (previously SO-C101) is a fusion protein of IL-15 and the IL-15 receptor α sushi+ domain. Synergistic effects of SOT101 and an anti-programmed cell death protein 1 antibody have been validated in various tumor mouse models inducing a protective memory response. Methods: In this phase 1 study, safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of increasing doses of SOT101 administered subcutaneously were investigated in patients (pts) with advanced solid tumors as monotherapy (Part A) and in combination with pembrolizumab every 3-week cycle (Part B). Dose escalation followed a standard 3+3 design. Data cut-off was 26 January 2022. Results: Overall, 51 pts were treated: 30 in Part A monotherapy at 0.25 to 15 μg/kg SOT101 and 21 in Part B combination therapy (Tx) at 1.5 to 12 μg/kg SOT101. The median (range) number of previous lines of Tx was 3 (1-9) in Part A and 2 (1-6) in Part B. In Part A, 19 (63.3%) pts had previous check-point inhibitor (CPI) Tx, of whom 9 (30 %) were refractory, 5 (16.7%) relapsed. In Part B, 11 pts (52.4%) had previous CPI Tx, and the outcome was 9 (42.9%) pts relapsed, 1 (4.8%) refractory. The most common treatment-emergent adverse events (TEAEs) were transient, and included pyrexia, chills, lymphopenia, anemia, transaminase elevation and vomiting. Most TEAEs were ≤ Grade 2. No treatment-related death was reported. For both monotherapy and combination Tx, the recommended phase 2 dose of SOT101 was determined to be 12 μg/kg. In Part A, in 13 pts at 6 to 12 μg/kg SOT101, the observed clinical benefit rate was 38%. A partial response (PR) was confirmed in 1 pt with skin squamous cell carcinoma, CPI refractory, PR duration 46 days (d), on treatment 154 d. Four pts (all CPI pretreated) had stable disease (SD), range 33-183 d. Final median duration on treatment was 84 d, range 43-183 d. The median duration of clinical benefit was 190 d. In Part B, the observed clinical benefit rate across all SOT101 doses was 63%. A complete response (CR) was confirmed in 1 pt with mesothelioma, CPI naïve, starting at the first tumor assessment, and the pt is ongoing in cycle 5. Three pts, 2 CPI pretreated, had a PR, range 51-232 d, 2 ongoing with PR, and 1 Tx discontinuation while still on PR. Five pts, 3 CPI pretreated, had SD, range 92-340 d, 2 ongoing with SD. The 3 CPI pretreated pts had SD range 41-340 d, 1 pt ongoing. The preliminary median duration on combination Tx was 113 d, range 7-429 d. The preliminary median duration of clinical benefit was 131 d. Conclusions: SOT101 as monotherapy and in combination with pembrolizumab showed a favorable safety profile. Highly promising efficacy signals with one ongoing CR and several long-lasting PRs were reported in CPI-naïve and CPI pretreated pts, including CPI-resistant tumors. Clinical trial information: NCT04234113.
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- 2022
18. 562 SO-C101 induces NK cell cytotoxicity and potentiates antibody-dependent cell cytotoxicity and anti-tumor activity
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David Bechard, Radek Spisek, Ulrich Moebius, Guy de Martynoff, Zuzana Antosova, Irena Adkins, Eva Nedvedova, Nada Podzimkova, and Marketa Jiratova
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Antibody-dependent cell-mediated cytotoxicity ,Chemistry ,medicine.drug_class ,Daratumumab ,Monoclonal antibody ,NKG2D ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,lcsh:RC254-282 ,Monoclonal ,Cancer cell ,Cancer research ,medicine ,Cytotoxic T cell ,CD8 - Abstract
Background SO-C101 is a superagonist fusion protein of interleukin (IL)-15 and the IL-15 receptor α (IL-15Rα) sushi+ domain, representing a promising clinical candidate for the treatment of cancer. SO-C101 specifically stimulates natural killer (NK) cells and memory CD8+ T cells with no significant expansion and activation of regulatory T cell compartment. Methods Human NK cell proliferation, the expression of NK cell receptors and ADCC activity of human PBMC after stimulation with SO-C101 in vitro in combination with monoclonal antibodies were detected by flow cytometry. The anti-tumor efficacy of SO-C101 in combination with Daratumumab was assessed in a multiple myeloma SCID xenograft mouse model in vivo. Results In this study, we show that SO-C101 induced proliferation and expansion of both major subsets of human NK cells, CD56brightCD16- and CD56dimCD16+. Furthermore, SO-C101 induced expression of the cytotoxic receptors NKp30 and NKG2D whereas no upregulation of the inhibitory receptors CD158a, CD158b and NKG2A was detected. Both NK cell subsets activated by SO-C101 exhibited cytotoxicity towards cancer cells in vitro. Using human PBMCs, we show that SO-C101 potentiated killing of tumor cells induced by several clinically approved therapeutic monoclonal antibodies such as Cetuximab, Daratumumab and Obinutuzumab in vitro. SO-C101 and Daratumumab monotherapy treatment inhibited tumor growth in vivo, however, their combination showed the strongest anti-tumor efficacy. Specifically, sequential administration of Daratumumab, followed by SO-C101 promoted complete tumor regression, compared to partial anti-tumor responses induced by the respective monotherapies. Conclusions SO-C101 augments the anti-tumor activity of therapeutic antibodies by increasing NK cells mediated antibody-dependent cell cytotoxicity. These results support the evaluation of SO-C101 in combination with monoclonal therapeutic antibodies in clinical studies. Ethics Approval The anti-tumor efficacy studies in mice were approved by the internal ethics board of the respective contract research organization (CRO).
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- 2020
19. Myeloid - derived suppressor cells in Type 1 diabetes are an expanded population exhibiting diverse T-cell suppressor mechanisms
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Radek Spisek, Zdeněk Šumník, Lenka Palová-Jelínková, Irena Adkins, Barbora Obermannova, Anna Grohová, Stanislava Kolouskova, Lenka Petruželková, and Klára Dáňová
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Male ,endocrine system diseases ,Physiology ,Biochemistry ,T-Lymphocytes, Regulatory ,law.invention ,Pathogenesis ,White Blood Cells ,Endocrinology ,Medical Conditions ,Animal Cells ,law ,Immune Physiology ,Medicine and Health Sciences ,Diabetes diagnosis and management ,Cytotoxic T cell ,Medicine ,Child ,Innate Immune System ,education.field_of_study ,Multidisciplinary ,T Cells ,Body Fluids ,Blood ,Cytokines ,Female ,Cellular Types ,Anatomy ,Research Article ,HbA1c ,Adolescent ,Endocrine Disorders ,Immune Cells ,Science ,Immunology ,Population ,Cytotoxic T cells ,Immune Suppression ,Autoimmune Diseases ,Interferon-gamma ,Signs and Symptoms ,Diabetes mellitus ,Diabetes Mellitus ,Humans ,Hemoglobin ,education ,Type 1 diabetes ,Blood Cells ,business.industry ,Myeloid-Derived Suppressor Cells ,Biology and Life Sciences ,Proteins ,Cancer ,Cell Biology ,Molecular Development ,medicine.disease ,Diagnostic medicine ,CD4 Lymphocyte Count ,Diabetes Mellitus, Type 1 ,Metabolic Disorders ,Immune System ,Myeloid-derived Suppressor Cell ,Th17 Cells ,Suppressor ,Clinical Immunology ,Clinical Medicine ,business ,Developmental Biology - Abstract
Myeloid-derived suppressor cells (MDSC) represent a heterogeneous group of immature myeloid cells with immunoregulatory function in cancer and autoimmune diseases. In humans, two subsets of MDSC were determined based on the characteristic surface markers, monocytic MDSC (M-MDSC) and granulocytic MDSC (G-MDSC). Expansion of MDSC has been reported in some murine models and patients with autoimmune diseases and their immune-suppressive properties were characterized. However, the exact role of MDSC in the pathogenesis of autoimmune diseases is more complex and/or controversial. In type 1 diabetes mellitus (T1D), the increased frequency of MDSC was found in the blood of T1D patients but their suppressor capacity was diminished. In our study, we assessed the role of M-MDSC in the pathogenesis of T1D and showed for the first time the increased frequency of M-MDSC not only in the blood of T1D patients but also in their at-risk relatives compared to healthy donors. T1D patients with inadequate long term metabolic control showed an elevation of M-MDSC compared to patients with better disease control. Furthermore, we described the positive correlation between the percentage of M-MDSC and Th17 cells and IFN-γ producing T cells in T1D patients and their at-risk relatives. Finally, we found that the ability of M-MDSC to suppress autologous T cells is efficient only at the high MDSC: T cells ratio and dependent on cell-cell-contact and TGF-β production. Our data show that the engagement of MDSC in the pathogenesis of T1D is evident, yet not entirely explored and more experiments are required to clarify whether MDSC are beneficial or harmful in T1D.
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- 2020
20. Case-Control Study: Smoking History Affects the Production of Tumor Antigen–Specific Antibodies NY-ESO-1 in Patients with Lung Cancer in Comparison with Cancer Disease–Free Group
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Anna Skallová-Fialová, Robert Lischke, D. Myšíková, Nada Hradilova, O. Palata, Irena Adkins, Simonek J, Jan Kolařík, J Pozniak, and Radek Spisek
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Adult ,Male ,0301 basic medicine ,Pulmonary and Respiratory Medicine ,Oncology ,medicine.medical_specialty ,Lung Neoplasms ,Receptor, ErbB-2 ,Adenocarcinoma ,03 medical and health sciences ,0302 clinical medicine ,Antigen ,Antigens, Neoplasm ,Carcinoma, Non-Small-Cell Lung ,Internal medicine ,Biomarkers, Tumor ,medicine ,Humans ,Prospective Studies ,Lung cancer ,Aged ,Neoplasm Staging ,Aged, 80 and over ,biology ,business.industry ,Smoking ,Case-control study ,Membrane Proteins ,Cancer ,Middle Aged ,Prognosis ,medicine.disease ,Tumor antigen ,Neoplasm Proteins ,030104 developmental biology ,Case-Control Studies ,030220 oncology & carcinogenesis ,Carcinoma, Squamous Cell ,biology.protein ,Female ,NY-ESO-1 ,Antibody ,business ,Follow-Up Studies - Abstract
Introduction Lung cancer is the leading cause of cancer mortality worldwide; therefore, understanding the biological or clinical role of tumor-associated antigens and autoantibodies is of eminent interest for designing antitumor immunotherapeutic strategies. Methods Here we prospectively analyzed the serum frequencies of New York esophageal squamous cell carcinoma 1 (NY-ESO-1), human epidermal growth factor 2/neu, and melanoma-associated antigen A4 (MAGE-A4) antibodies and expression of the corresponding antigens in tumors of 121 patients with NSCLC undergoing an operation without prior neoadjuvant chemotherapy and compared them with those in 57 control age-matched patients with no history of a malignant disease. Results We found that only antibodies specific for NY-ESO-1 (19.8% [n = 24 of 121]) were significantly increased in the group of patients with NSCLC compared with in the controls. NY-ESO-1 seropositivity was significantly positively associated with an active smoking history in patients with NSCLC but not in smokers from the control group. In tumors, the frequency of NY-ESO-1 mRNA expression was 6.3% (in four of 64 patients), the frequency of human epidermal growth factor 2/neu (HER 2/neu) expression was 11.9% (five of 42), and the frequency of MAGE-A4 expression was 35.1% (20 of 57). MAGE-A4 expression in tumors correlated with smoking status and male sex in patients with NSCLC. Patients with squamous cell carcinoma displayed higher expression of NY-ESO-1 and MAGE-A4 in tumors than did patients with adenocarcinoma. On the other hand, 94.7% of nonsmoking patients in our study had adenocarcinoma (of whom 73.7% were women). Conclusion These results confirm the reported high immunogenicity of NY-ESO-1 and suggest that a smoking-induced chronic inflammatory state might potentiate the development of NY-ESO-1–specific immune responses. Moreover, smoking might contribute to the expression of other cancer/testis antigens such as MAGE-A4 at early stages of NSCLC development.
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- 2017
21. Pore‐formation by adenylate cyclase toxoid activates dendritic cells to prime CD8+and CD4+T cells
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Marek Kovar, Jiri Masin, Peter Sebo, Irena Adkins, Martina Svedova, Ludmila Tučková, Marina A. Freudenberg, Jakub Tomala, Radovan Fišer, Gilles Dadaglio, Ondrej Cerny, Institute of Microbiology of the ASCR, v. v. i. [Prague, Czech Republic], Charles University [Prague] (CU), Albert-Ludwigs-Universität Freiburg, Régulation Immunitaire et Vaccinologie, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), This work was supported by grants No. GA13‐14547 S (P. S.) and GAP302/12/0460 (J. M.) of the Czech Science Foundation and the RVO61388971 of the Institute of Microbiology. We thank to Prof. Stefan F. Martin, University Medical Center, Freiburg, Germany, for providing the P2X7, ASC and NLRP3 knockout mice. Martina Svedova and Ondrej Cerny are doctoral students of the Charles University in Prague, Czech Republic. Martina Svedova was a recipient of a stipend from the Ministry of Education of the Czech Republic and of the support from the Specific Research Project No. 33779266 of Charles University in Prague, Czech Republic., The authors wish to thank Sona Kozubova and Hana Lukeova for excellent technical help., and Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)
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CD4-Positive T-Lymphocytes ,0301 basic medicine ,Cell Membrane Permeability ,[SDV]Life Sciences [q-bio] ,MESH: Adjuvants, Immunologic ,CD8-Positive T-Lymphocytes ,Lymphocyte Activation ,p38 Mitogen-Activated Protein Kinases ,MESH: Cancer Vaccines ,Mice ,Immunology and Allergy ,MESH: Animals ,MESH: Cell Membrane Permeability ,Cells, Cultured ,MESH: Cytokines ,MESH: Pore Forming Cytotoxic Proteins ,MESH: Dendritic Cells ,Chemistry ,Toxoid ,MESH: CD4-Positive T-Lymphocytes ,Cell Differentiation ,Inflammasome ,MESH: CD8-Positive T-Lymphocytes ,Cell biology ,Adenylate Cyclase Toxin ,Cytokines ,MESH: Protein Domains ,[SDV.IMM]Life Sciences [q-bio]/Immunology ,MESH: Cells, Cultured ,medicine.drug ,Pore Forming Cytotoxic Proteins ,MESH: Cell Differentiation ,Immunology ,Adenylate kinase ,Cancer Vaccines ,Cyclase ,03 medical and health sciences ,Adjuvants, Immunologic ,Protein Domains ,MESH: Mice, Inbred C57BL ,medicine ,Animals ,Secretion ,MESH: Lymphocyte Activation ,MESH: Mice ,Ion Transport ,Chemotaxis ,Dendritic Cells ,Cell Biology ,cyaA ,MESH: Adenylate Cyclase Toxin ,Mice, Inbred C57BL ,MESH: Ion Transport ,MESH: p38 Mitogen-Activated Protein Kinases ,030104 developmental biology ,[SDV.IMM.VAC]Life Sciences [q-bio]/Immunology/Vaccinology - Abstract
International audience; The adenylate cyclase toxin-hemolysin (CyaA) of Bordetella pertussis is a bi-functional leukotoxin. It penetrates myeloid phagocytes expressing the complement receptor 3 and delivers into their cytosol its N-terminal adenylate cyclase enzyme domain (~400 residues). In parallel, ~1300 residue-long RTX hemolysin moiety of CyaA forms cation-selective pores and permeabilizes target cell membrane for efflux of cytosolic potassium ions. The non-enzymatic CyaA-AC(-) toxoid, has repeatedly been successfully exploited as an antigen delivery tool for stimulation of adaptive T-cell immune responses. We show that the pore-forming activity confers on the CyaA-AC(-) toxoid a capacity to trigger Toll-like receptor and inflammasome signaling-independent maturation of CD11b-expressing dendritic cells (DC). The DC maturation-inducing potency of mutant toxoid variants in vitro reflected their specifically enhanced or reduced pore-forming activity and K(+) efflux. The toxoid-induced in vitro phenotypic maturation of DC involved the activity of mitogen activated protein kinases p38 and JNK and comprised increased expression of maturation markers, interleukin 6, chemokines KC and LIX and granulocyte-colony-stimulating factor secretion, prostaglandin E2 production and enhancement of chemotactic migration of DC. Moreover, i.v. injected toxoids induced maturation of splenic DC in function of their cell-permeabilizing capacity. Similarly, the capacity of DC to stimulate CD8(+) and CD4(+) T-cell responses in vitro and in vivo was dependent on the pore-forming activity of CyaA-AC(-). This reveals a novel self-adjuvanting capacity of the CyaA-AC(-) toxoid that is currently under clinical evaluation as a tool for delivery of immunotherapeutic anti-cancer CD8(+) T-cell vaccines into DC.
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- 2015
22. Abstract 6686: SO-C101 displays strong anti-tumor effect in TC-1 and TRAMP-C2 tumor mice and in combination with PD-1 blockade prevents tumor development in a NK and CD8+ T cells dependent manner
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Guy de Martynoff, Nada Hradilova, David Bechard, Romana Mikyšková, Ulrich Moebius, Milan Reiniš, Radek Spisek, and Irena Adkins
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Cancer Research ,biology ,Chemistry ,T cell ,Cell ,Interleukin ,Immune system ,medicine.anatomical_structure ,Oncology ,Cancer research ,medicine ,biology.protein ,Cytotoxic T cell ,Antibody ,Receptor ,CD8 - Abstract
SO-C101 (RLI-15) is a superagonist fusion protein of interleukin (IL)-15 and the IL-15 receptor α (IL-15Rα) sushi+ domain designed to bypass the need of endogenous IL-15Rα, thereby leveraging the activity of IL-15 in vivo on target immune cells and reducing the toxicity of IL-15 as such. SO-C101 was previously shown to exhibit a potent anti-metastatic activity in Renca, B16F10 melanoma and delayed tumor growth in T cell-based mouse tumor models (CT26, MC38). Here we investigated the anti-tumor efficacy in predominantly natural killer (NK)-cell based mouse tumor models TC-1 and TRAMP-C2. We showed that SO-C101 monotherapy was effective in the treatment of established TC-1 tumors, which was dependent on the presence of both NK and CD8+ T cells, but not CD4+ T cells. In an early treatment setting SO-C101 significantly decreased the rate of tumor development also in dependence on NK and CD8+ T cells. SO-C101 effectively reduced tumor growth in TRAMP-C2 mice in early and advanced treatment settings. However, only in combination with anti-PD-1 antibody treatment the tumor development was prevented in majority of mice. This effect was durable, and the new tumor development was further significantly delayed after a tumor cell re-challenge, which suggests the involvement of memory T cells despite an important NK cell role in anti-tumor efficacy in these models. The efficacy of SO-C101 and anti-PD-1 treatment was not dependent on CD4+ T cells, but mainly on NK and CD8+ T cells. Interestingly, SO-C101 and anti-PD-1 treatment in double NK/CD8+ T cell-depleted mice decreased tumor growth which suggests an involvement of other immune cell populations in the anti-tumor efficacy. SO-C101 stimulated the proliferation and the cytotoxic activity of NK cells and memory CD8+ T cells without significant expansion of regulatory T cells. These data show the importance of various immune cell populations during SO-C101 monotherapy and the treatment in combination with anti-PD-1 antibodies, and set a base for further complex analysis of SO-C101 behavior. The therapeutic potential of SO-C101 is currently being tested in an ongoing Phase I clinical study in cancer patients. Citation Format: Irena Adkins, Romana Mikyskova, Nada Hradilova, Guy de Martynoff, David Bechard, Ulrich Moebius, Milan Reinis, Radek Spisek. SO-C101 displays strong anti-tumor effect in TC-1 and TRAMP-C2 tumor mice and in combination with PD-1 blockade prevents tumor development in a NK and CD8+ T cells dependent manner [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6686.
- Published
- 2020
23. Abstract B82: Distinct immune status in patients with adenocarcinoma and squamous cell carcinoma: Implication for immunotherapy of non-small cell lung cancer
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Ondrej Palata, Hana Mrazkova, Robert Lischke, Irena Adkins, Nada Hradilova, Radek Spisek, D. Myšíková, and Lenka Sadilkova
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Cancer Research ,Tumor microenvironment ,business.industry ,medicine.medical_treatment ,Immunology ,FOXP3 ,Immunotherapy ,medicine.disease ,Immune system ,Cancer research ,Medicine ,Adenocarcinoma ,IL-2 receptor ,business ,Lung cancer ,CD8 - Abstract
Lung cancer is the leading cause of cancer mortality worldwide; therefore, understanding the biologic role of immune cell infiltrates in the tumor microenvironment is of eminent interest. In this study we compared immune cell populations, T-cell responses and secreted cytokines in primary tumors and nontumoral lung tissue from more than 40 adenocarcinomas (AC) and 40 squamous cell carcinomas (SCC) of non-small cell lung cancer (NSCLC) patients undergoing neoadjuvant surgery. Moreover, we compared immune-suppressive populations such as CD4+CD25+Foxp3+ T regulatory cells and myeloid-derived suppressor cells (MDSC) and the expression of immune checkpoint molecules PD-1, TIM3, LAG-3 and CTLA-4 in the blood of these patients. In both tumor subtypes we observed similarly higher infiltration of B cells, memory T cells, dendritic cells, NK cells, monocytes/macrophages, mast cells and CD4+CD25+Foxp3+ T regulatory cells compared to nontumoral tissue. However, immune cells seemed to be suppressed functionally more in SCC than AC as we detected significantly lower IFN-γ-positive T cells and production of proinflammatory cytokines after stimulation. PD-1, TIM3 and LAG-3 expression on T cells in blood and PD-1 on intratumoral CD8+ T cells of SSC patients were significantly elevated compared to AC patients. Similarly, the high number of MDSC, which correlated with Arginase 1 mRNA levels and downregulation of CD3zeta in T cells, was detected only in SCC. These results suggest that immune system of SSC patients might be subjected to a higher systemic and tumor-associated immune suppression than in AC patients. This should be taken into consideration in designing lung cancer immunotherapeutic approaches. Citation Format: Nada Hradilova, Ondrej Palata, Lenka Sadilkova, Dagmar Mysikova, Hana Mrazkova, Robert Lischke, Radek Spisek, Irena Adkins. Distinct immune status in patients with adenocarcinoma and squamous cell carcinoma: Implication for immunotherapy of non-small cell lung cancer [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr B82.
- Published
- 2020
24. Radiotherapy in Combination With Cytokine Treatment
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Ondrej Palata, Nada Hradilova Podzimkova, Eva Nedvedova, Alexandra Umprecht, Lenka Sadilkova, Lenka Palova Jelinkova, Radek Spisek, and Irena Adkins
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0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,immunocytokine ,medicine.medical_treatment ,Review ,lcsh:RC254-282 ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Internal medicine ,immunogenic cell death ,cytokine ,Medicine ,radiotherapy ,business.industry ,Abscopal effect ,Cancer ,Immunotherapy ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.disease ,Clinical trial ,Radiation therapy ,030104 developmental biology ,Cytokine ,030220 oncology & carcinogenesis ,Immunogenic cell death ,immunotherapy ,business - Abstract
Radiotherapy (RT) plays an important role in the management of cancer patients. RT is used in more than 50% of patients during the course of their disease in a curative or palliative setting. In the past decades it became apparent that the abscopal effect induced by RT might be dependent on the activation of immune system, and that the induction of immunogenic cancer cell death and production of danger-associated molecular patterns from dying cells play a major role in the radiotherapy-mediated anti-tumor efficacy. Therefore, the combination of RT and immunotherapy is of a particular interest that is reflected in designing clinical trials to treat patients with various malignancies. The use of cytokines as immunoadjuvants in combination with RT has been explored over the last decades as one of the immunotherapeutic combinations to enhance the clinical response to anti-cancer treatment. Here we review mainly the data on the efficacy of IFN-α, IL-2, IL-2-based immunocytokines, GM-CSF, and TNF-α used in combinations with various radiotherapeutic techniques in clinical trials. Moreover, we discuss the potential of IL-15 and its analogs and IL-12 cytokines in combination with RT based on the efficacy in preclinical mouse tumor models.
- Published
- 2018
25. High hydrostatic pressure in cancer immunotherapy and biomedicine
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Lenka Palová-Jelínková, Lenka Sadilkova, Ondrej Palata, Radek Spisek, Nada Hradilova, and Irena Adkins
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0301 basic medicine ,medicine.medical_treatment ,Hydrostatic pressure ,Bioengineering ,Tumor cells ,Applied Microbiology and Biotechnology ,03 medical and health sciences ,0302 clinical medicine ,Cancer immunotherapy ,Neoplasms ,medicine ,Hydrostatic Pressure ,Humans ,Orthopedic Procedures ,Biomedicine ,Vaccines ,business.industry ,Cancer ,Immunotherapy ,Dendritic cell ,Dendritic Cells ,medicine.disease ,030104 developmental biology ,Eukaryotic Cells ,030220 oncology & carcinogenesis ,Cancer research ,Virus Inactivation ,Whole cell ,business ,Biotechnology - Abstract
High hydrostatic pressure (HHP) has been known to affect biological systems for >100 years. In this review, we describe the technology of HHP and its effect macromolecules and physiology of eukaryotic cells. We discuss the use of HHP in cancer immunotherapy to kill tumor cells for generation of whole cell and dendritic cell-based vaccines. We further summarize the current use and perspectives of HHP application in biomedicine, specifically in orthopedic surgery and for the viral, microbial and protozoan inactivation to develop vaccines against infectious diseases.
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- 2017
26. Cyclic AMP-Elevating Capacity of Adenylate Cyclase Toxin-Hemolysin Is Sufficient for Lung Infection but Not for Full Virulence of Bordetella pertussis
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Radim Osicka, Peter Sebo, Ivan Kanchev, Jakub Tomala, Barbora Tomalova, Pavel Rossmann, Ilona Bibova, Marek Kovar, Jiri Masin, Karolina Skopova, Radislav Sedlacek, Martina Svedova, Nicole Guiso, and Irena Adkins
- Subjects
0301 basic medicine ,Bordetella pertussis ,Whooping Cough ,T-Lymphocytes ,Immunology ,Macrophage-1 Antigen ,Adenylate kinase ,Hemolysin Proteins ,Microbiology ,Cyclase ,Adenylyl cyclase ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,Cyclic AMP ,Animals ,Lung ,Mice, Inbred BALB C ,Phagocytes ,Cellular Microbiology: Pathogen-Host Cell Molecular Interactions ,CD11b Antigen ,Virulence ,030102 biochemistry & molecular biology ,biology ,Cell Membrane ,Dendritic Cells ,cyaA ,biology.organism_classification ,Mice, Inbred C57BL ,030104 developmental biology ,Infectious Diseases ,chemistry ,Adenylate Cyclase Toxin ,Female ,Parasitology ,Pertactin - Abstract
The adenylate cyclase toxin-hemolysin (CyaA, ACT, or AC-Hly) of Bordetella pertussis targets phagocytic cells expressing the complement receptor 3 (CR3, Mac-1, α M β 2 integrin, or CD11b/CD18). CyaA delivers into cells an N-terminal adenylyl cyclase (AC) enzyme domain that is activated by cytosolic calmodulin and catalyzes unregulated conversion of cellular ATP into cyclic AMP (cAMP), a key second messenger subverting bactericidal activities of phagocytes. In parallel, the hemolysin (Hly) moiety of CyaA forms cation-selective hemolytic pores that permeabilize target cell membranes. We constructed the first B. pertussis mutant secreting a CyaA toxin having an intact capacity to deliver the AC enzyme into CD11b-expressing (CD11b + ) host phagocytes but impaired in formation of cell-permeabilizing pores and defective in cAMP elevation in CD11b − cells. The nonhemolytic AC + Hly − bacteria inhibited the antigen-presenting capacities of coincubated mouse dendritic cells in vitro and skewed their Toll-like receptor (TLR)-triggered maturation toward a tolerogenic phenotype. The AC + Hly − mutant also infected mouse lungs as efficiently as the parental AC + Hly + strain. Hence, elevation of cAMP in CD11b − cells and/or the pore-forming capacity of CyaA were not required for infection of mouse airways. The latter activities were, however, involved in bacterial penetration across the epithelial layer, enhanced neutrophil influx into lung parenchyma during sublethal infections, and the exacerbated lung pathology and lethality of B. pertussis infections at higher inoculation doses (>10 7 CFU/mouse). The pore-forming activity of CyaA further synergized with the cAMP-elevating activity in downregulation of major histocompatibility complex class II (MHC-II) molecules on infiltrating myeloid cells, likely contributing to immune subversion of host defenses by the whooping cough agent.
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- 2017
27. Severe, but not mild heat-shock treatment induces immunogenic cell death in cancer cells
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Marek Kovar, Radek Spisek, Lenka Sadilkova, Nada Hradilova, Irena Adkins, and Jakub Tomala
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0301 basic medicine ,lcsh:Immunologic diseases. Allergy ,heat-shock treatment ,medicine.medical_treatment ,antitumor immunity ,Immunology ,Cell ,Biology ,complex mixtures ,lcsh:RC254-282 ,calreticulin ,03 medical and health sciences ,Cancer immunotherapy ,Antigen ,immunogenic cell death ,medicine ,Immunology and Allergy ,dendritic cells ,Original Research ,cancer immunotherapy ,CD47 ,hyperthermia ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,Cell culture ,Cancer cell ,Cancer research ,Immunogenic cell death ,lcsh:RC581-607 ,CD8 - Abstract
The mechanisms of immunogenicity underlying mild heat-shock (mHS) treatment < 42°C of tumor cells are largely attributed to the action of heat-shock proteins; however, little is known about the immunogenicity of tumor cells undergoing severe cytotoxic heat-shock treatment (sHS > 43°C). Here, we found that sHS, but not mHS (42°C), induces immunogenic cell death in human cancer cell lines as defined by the induction of ER stress response and ROS generation, cell surface exposure of calreticulin, HSP70 and HSP90, decrease of cell surface CD47, release of ATP and HMGB1. Only sHS-treated tumor cells were efficiently killed and phagocytosed by dendritic cells (DCs), which was partially dependent on cell surface calreticulin. DCs loaded with mHS or sHS-treated tumor cells displayed similar level of maturation and stimulated IFNγ-producing CD8+ T cells without any additional adjuvants in vitro. However, only DCs loaded with sHS-treated tumor cells stimulated antigen-specific CD4+ T cells and induced higher CD8+ T-cell activation and proliferation. sHS-treated murine cells also exposed calreticulin, HSP70 and HSP90 and activated higher DC maturation than mHS treated cells. Vaccination with sHS-treated tumor cells elicited protective immunity in mice. In this study, we defined specific conditions for the sHS treatment of human lung and ovarian tumor cells to arrive at optimal ratio between effective cell death, immunogenicity and content of tumor antigens for immunotherapeutic vaccine generation.
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- 2017
28. High hydrostatic pressure affects antigenic pool in tumor cells: Implication for dendritic cell-based cancer immunotherapy
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Lenka Sadilkova, Linda Urbanova, Nada Hradilova, Irena Adkins, Radek Spisek, Sarka Vosahlikova, Irena Moserova, and Michal Hensler
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0301 basic medicine ,medicine.medical_treatment ,Immunology ,Hydrostatic pressure ,Active immunotherapy ,Biology ,Cell therapy ,03 medical and health sciences ,0302 clinical medicine ,Cancer immunotherapy ,Antigens, Neoplasm ,Neoplasms ,medicine ,Hydrostatic Pressure ,Immunology and Allergy ,Cytotoxic T cell ,Humans ,Dendritic cell ,Dendritic Cells ,medicine.disease ,030104 developmental biology ,A549 Cells ,030220 oncology & carcinogenesis ,Cancer research ,Immunogenic cell death ,Immunotherapy ,Ovarian cancer - Abstract
High hydrostatic pressure (HHP) can be used to generate dendritic cell (DC)-based active immunotherapy for prostate, lung and ovarian cancer. We showed here that HHP treatment of selected human cancer cell lines leads to a degradation of tumor antigens which depends on the magnitude of HHP applied and on the cancer cell line origin. Whereas prostate or ovarian cell lines displayed little protein antigen degradation with HHP treatment up to 300MPa after 2h, tumor antigens are hardly detected in lung cancer cell line after treatment with HHP 250MPa at the same time. On the other hand, quick reduction of tumor antigen-coding mRNA was observed at HHP 200MPa immediately after treatment in all cell lines tested. To optimize the DC-based active cellular therapy protocol for HHP-sensitive cell lines the immunogenicity of HHP-treated lung cancer cells at 150, 200 and 250MPa was compared. Lung cancer cells treated with HHP 150MPa display characteristics of immunogenic cell death, however cells are not efficiently phagocytosed by DC. Despite induction of the highest number of antigen-specific CD8+ T cells, 150 MPa-treated lung cancer cells survive in high numbers. This excludes their use in DC vaccine manufacturing. HHP of 200MPa treatment of lung cancer cells ensures the optimal ratio of efficient immunogenic killing and delivery of protein antigens in DC. These results represent an important pre-clinical data for generation of immunogenic killed lung cancer cells in ongoing NSCLC Phase I/II clinical trial using DC-based active cellular immunotherapy (DCVAC/LuCa).
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- 2017
29. PUB056 Smoking History Affects the Production of Tumor Antigen Specific Antibodies NY-ESO-1 in Patients with Lung Cancer
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Nada Hradilova, Simonek J, O. Palata, A. Fialová, J Pozniak, Robert Lischke, D. Myšíková, Radek Spisek, J. Kolařík, and Irena Adkins
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Pulmonary and Respiratory Medicine ,Oncology ,medicine.medical_specialty ,business.industry ,medicine.disease ,Smoking history ,Tumor antigen ,Specific antibody ,Internal medicine ,Immunology ,medicine ,In patient ,NY-ESO-1 ,Lung cancer ,business - Published
- 2017
30. Bacterial Toxins in Cancer Immunotherapy
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Lenka Palová-Jelínková, Lenka Sadilkova, and Irena Adkins
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Microbial toxins ,Antigen delivery ,business.industry ,medicine.medical_treatment ,Toxoid ,Biochemistry ,Cancer immunotherapy ,Immunotoxin ,Immunology ,Genetics ,Molecular Medicine ,Medicine ,business ,Biotechnology - Published
- 2013
31. Heterosubtypic protection against influenza A induced by adenylate cyclase toxoids delivering conserved HA2 subunit of hemagglutinin
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Martina Kosova, E. Varečková, Zuzana Staneková, Jana Janulíková, Irena Adkins, and Peter Sebo
- Subjects
Cross Protection ,Hemagglutinin (influenza) ,Hemagglutinin Glycoproteins, Influenza Virus ,Antibodies, Viral ,medicine.disease_cause ,Antigenic drift ,Virus ,Microbiology ,Mice ,Orthomyxoviridae Infections ,Antigen ,Virology ,Influenza A virus ,medicine ,Animals ,Pharmacology ,Mice, Inbred BALB C ,Vaccines, Synthetic ,biology ,Immunogenicity ,Toxoid ,Dendritic Cells ,Th1 Cells ,Toxoids ,Survival Analysis ,Recombinant Proteins ,Vaccination ,Disease Models, Animal ,Protein Subunits ,Influenza Vaccines ,biology.protein ,Female ,Adenylyl Cyclases - Abstract
The protective efficacy of currently available influenza vaccines is restricted to vaccine strains and their close antigenic variants. A new strategy to obtain cross-protection against influenza is based on conserved antigens of influenza A viruses (IAV), which are able to elicit a protective immune response. Here we describe a vaccination approach involving the conserved stem part of hemagglutinin, the HA2 subunit, shared by different HA subtypes of IAV. To increase its immunogenicity, a novel strategy of antigen delivery to antigen presenting cells (APCs) has been used. The HA2 segment (residues 23-185) was inserted into a genetically detoxified adenylate cyclase toxoid (CyaA-E5) which specifically targets and penetrates CD11b-expressing dendritic cells. The CyaA-E5-HA2 toxoid induced HA2(93-102), HA2(96-104) and HA2(170-178)-specific and Th1 polarized T-cell responses, and also elicited strong broadly cross-reactive HA2-specific antibody response. BALB/c mice immunized with three doses of purified CyaA-E5-HA2 without any adjuvant recovered from influenza infection 2days earlier than the control mock-immunized mice. More importantly, immunized mice were protected against a lethal challenge with 2LD(50) dose of a homologous virus (H3 subtype), as well as against the infection with a heterologous (H7 subtype) influenza A virus. This is the first report on heterosubtypic protection against influenza A infection mediated by an HA2-based vaccine that can induce both humoral and cellular immune responses without the need of adjuvant.
- Published
- 2013
32. Abstract 3775: Use of RLI-15 a clinical grade fusion protein with IL-15 superagonistic activity for the activation of anti-tumor immune response
- Author
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Guy de Martynoff, Ulrich Moebius, Romana Mikyšková, David Bechard, Marek Kovar, Nada Hradilova, Milan Reiniš, Irena Adkins, Jakub Tomala, Lenka Sadilkova, Barbora Tomalova, and Radek Spisek
- Subjects
Cancer Research ,biology ,business.industry ,Regulatory T cell ,T cell ,Cancer ,medicine.disease ,Immune system ,medicine.anatomical_structure ,Oncology ,Interleukin 15 ,Cancer research ,biology.protein ,Medicine ,Cytotoxic T cell ,Antibody ,business ,CD8 - Abstract
RLI-15, a superagonist fusion protein of interleukin (IL)-15 and the IL-15 receptor α (IL-15Rα) sushi+ domain represents a promising candidate for the induction of anti-tumor immunity. RLI-15 was designed to bypass the need of endogenous IL-15Rα, thereby leveraging the activity of IL-15 in vivo on target immune cells. RLI-15 stimulates the proliferation and the cytotoxic activity of natural killer (NK) cells and memory CD8+ T cells with no significant expansion and activation of regulatory T cell compartment. RLI-15 was previously shown to exhibit a potent anti-metastatic activity in B16F10 melanoma and Renca renal cell carcinoma mouse models. RLI-15 also significantly delayed tumor growth and prolonged survival when combined with anti-PD1 therapy in CT26 and MC38 colon carcinoma models. Here, we report that the combination treatment with clinical-grade RLI-15 and an anti-PD1 antibody leads to a significant anti-tumor efficacy in a TRAMP-C2 prostate cancer mouse model with 70 % of mice remaining tumor free after the treatment. We evaluated the optimal schedule of such combination therapy to set the basis for the design of upcoming clinical trials. We further tested how the administration schedule affects the pharmacodynamics properties of clinical-grade RLI-15 and translates into the anti-tumor efficacy in metastatic Renca and CT26 mouse models. In cynomolgous monkeys, various schedules of administration of RLI-15 showed a dose-dependent expansion of peripheral blood lymphocytes, predominantly of NK cell and memory CD8+ T cell compartments. The toxicity in mice and cynomolgous monkeys was evaluated to determine the maximal tolerated dose of RLI-15. Furthermore, the activity of clinical-grade RLI-15 was tested in vitro on human PBMCs and the superiority over IL-2 and IL-15 stimulatory capacity has been confirmed. The complex analysis of RLI-15 behavior and of the induced anti-tumor immune response will be explored in the design of a planned Phase I clinical study in patients with both solid tumors and hematological malignancies. Citation Format: Irena Adkins, Lenka Sadilkova, Nada Hradilova, Jakub Tomala, Barbora Tomalova, Marek Kovar, Romana Mikyskova, Milan Reinis, Guy de Martynoff, David Bechard, Ulrich Moebius, Radek Spisek. Use of RLI-15 a clinical grade fusion protein with IL-15 superagonistic activity for the activation of anti-tumor immune response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3775.
- Published
- 2018
33. P3.07-008 Development of Immunomonitoring Assays for Dendritic Cell-Based Lung Cancer Immunotherapy
- Author
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O. Palata, H. Mrazkova, D. Myšíková, L. Sadílková, Nada Hradilova, Irena Adkins, Radek Spisek, Robert Lischke, and Irena Vancurova
- Subjects
Pulmonary and Respiratory Medicine ,Oncology ,business.industry ,medicine.medical_treatment ,Cancer research ,Medicine ,Dendritic cell ,Immunotherapy ,business ,Lung cancer ,medicine.disease - Published
- 2017
34. P2.07-020 Distinct Immune Status in Patients with Adenocarcinoma and Squamous Cell Carcinoma: Implication for Immunotherapy of NSCLC
- Author
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Nada Hradilova, L. Sadilova, Robert Lischke, O. Palata, H. Mrazkova, Irena Adkins, D. Myšíková, and Radek Spisek
- Subjects
Pulmonary and Respiratory Medicine ,Oncology ,medicine.medical_specialty ,Immune status ,010405 organic chemistry ,business.industry ,medicine.medical_treatment ,Immunotherapy ,010402 general chemistry ,medicine.disease ,01 natural sciences ,0104 chemical sciences ,Internal medicine ,medicine ,Adenocarcinoma ,In patient ,Basal cell ,business - Published
- 2017
35. Y. enterocolitica inhibits antigen degradation in dendritic cells
- Author
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Stefan Borgmann, Sabine Gröbner, Erwin Bohn, Ingo B. Autenrieth, Martin Köberle, Irena Adkins, and Stella E. Autenrieth
- Subjects
Ovalbumin ,Virulence Factors ,media_common.quotation_subject ,Immunology ,Antigen presentation ,Clostridium difficile toxin B ,Yersinia ,Microbiology ,Mice ,chemistry.chemical_compound ,Bacterial Proteins ,Animals ,Antigens ,Yersinia enterocolitica ,Internalization ,media_common ,Cytochalasin D ,Antigen Presentation ,biology ,Dendritic Cells ,Dendritic cell ,biochemical phenomena, metabolism, and nutrition ,biology.organism_classification ,Enterobacteriaceae ,Molecular biology ,Infectious Diseases ,chemistry ,Female ,Plasmids - Abstract
Yersinia enterocolitica (Ye) disrupts the ability of dendritic cells (DC) to prime CD4+ T cells suggesting that Ye may subvert uptake and/or processing of soluble antigens (Ag). To investigate this Ye-infected DC were loaded with fluorescently labelled ovalbumins as markers for Ag uptake and processing, and analysed by flow cytometry, fluorometry and microscopy. Wild type pYV+ as well as plasmidless pYV(-) bacteria inhibited Ag degradation in DC by 40% compared to non-infected cells. Microscopic analyses of pYV(-)-infected DC revealed that 40% of DC contained intracellular bacteria, and that DC without intracellular bacteria had degraded more Ag. When internalization of pYV(-) was blocked by cytochalasin D, Ag degradation was no longer inhibited indicating the competition between degradation of bacteria and ovalbumin. In contrast, cytochalasin D pre-treated DC infected with pYV+ inhibited Ag degradation by a mechanism dependent on the presence of virulence plasmid pYV encoding YopE, YopH, YopM, YopP, YopT and YopO. As no single Yop inhibited Ag degradation, interaction of multiple Yops might account for this effect, possibly by inhibiting Rho GTPases, because of a significant decrease of Ag degradation observed in DC incubated with toxin B of C. difficile. However, the contribution of other pYV-encoded factors cannot be excluded.
- Published
- 2008
36. Differential roles of Yersinia outer protein P-mediated inhibition of nuclear factor-kappa B in the induction of cell death in dendritic cells and macrophages
- Author
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Sabine Gröbner, Ingo B. Autenrieth, Sebastian Schulz, Stefan Borgmann, and Irena Adkins
- Subjects
Microbiology (medical) ,Programmed cell death ,p38 mitogen-activated protein kinases ,Yersinia ,p38 Mitogen-Activated Protein Kinases ,Microbiology ,Cell Line ,Mice ,chemistry.chemical_compound ,Bacterial Proteins ,Animals ,Macrophage ,Propidium iodide ,Cells, Cultured ,Yersinia enterocolitica ,Mice, Inbred BALB C ,Cell Death ,biology ,Kinase ,Macrophages ,JNK Mitogen-Activated Protein Kinases ,NF-kappa B ,Dendritic Cells ,General Medicine ,Dendritic cell ,biology.organism_classification ,Cell biology ,chemistry ,Cell culture ,Gene Deletion ,Propidium - Abstract
Yersinia outer protein P (YopP) induces cell death in macrophages and dendritic cells (DC). In DC this YopP-dependent cell death coincides with the inhibition of nuclear factor-kappa B (NF-κB) activation. However, as shown by measurement of propidium iodide uptake via disrupted cellular membranes, the preincubation of DC with several NF-κB inhibitors prior to infection with Yersinia did not restore the death-inducing capacity of a YopP-deficient Yersinia mutant. These results suggest that in contrast to macrophages, in DC the YopP-dependent inhibition of NF-κB activation is not causative for the induction of cell death. Instead, in DC, the inhibition of mitogen-activated protein kinases (MAPKs), in particular, p38 and c-Jun N-terminal kinase, prior to infection with a YopP-deficient Yersinia mutant substituted the death-inducing capacity of the Yersinia wild-type strain, indicating that the YopP-dependent inhibition of MAPKs mediates Yersinia-induced DC death. The differences between DC and macrophages in the mechanisms of cell death induction by YopP presented herein might be crucial for the function of these antigen-presenting cells.
- Published
- 2008
37. Invasion of Dendritic Cells, Macrophages and Neutrophils by the Bordetella Adenylate Cyclase Toxin: A Subversive Move to Fool Host Immunity
- Author
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Peter Sebo, Giorgio Fedele, Irena Adkins, Nela Klimova, and Ilaria Schiavoni
- Subjects
0301 basic medicine ,Bordetella pertussis ,Neutrophils ,Whooping Cough ,Health, Toxicology and Mutagenesis ,Phagocytosis ,Respiratory System ,lcsh:Medicine ,Review ,T-helper cells ,Toxicology ,T-Lymphocytes, Regulatory ,immune response ,intracellular pathways ,Microbiology ,03 medical and health sciences ,Immune system ,Immunity ,Cyclic AMP ,Animals ,Humans ,Immunity, Mucosal ,Immunity, Cellular ,Innate immune system ,biology ,Macrophages ,lcsh:R ,phagocytosis ,Dendritic Cells ,cyaA ,biology.organism_classification ,Respiratory burst ,Cell biology ,030104 developmental biology ,Adenylate Cyclase Toxin ,Host-Pathogen Interactions ,Signal Transduction - Abstract
Adenylate cyclase toxin (CyaA) is released in the course of B. pertussis infection in the host’s respiratory tract in order to suppress its early innate and subsequent adaptive immune defense. CD11b-expressing dendritic cells (DC), macrophages and neutrophils are professional phagocytes and key players of the innate immune system that provide a first line of defense against invading pathogens. Recent findings revealed the capacity of B. pertussis CyaA to intoxicate DC with high concentrations of 3′,5′-cyclic adenosine monophosphate (cAMP), which ultimately skews the host immune response towards the expansion of Th17 cells and regulatory T cells. CyaA-induced cAMP signaling swiftly incapacitates opsonophagocytosis, oxidative burst and NO-mediated killing of bacteria by neutrophils and macrophages. The subversion of host immune responses by CyaA after delivery into DC, macrophages and neutrophils is the subject of this review.
- Published
- 2017
38. Abstract A47: Immunogenic cancer cell death induced by high hydrostatic pressure and hyperthermia: Calreticulin exposure pathway
- Author
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Lenka Sadilkova, Linda Urbanova, Nada Hradilova, Irena Moserova, Radek Spisek, Sarka Vosahlikova, and Irena Adkins
- Subjects
Cancer Research ,Programmed cell death ,biology ,Caspase 2 ,Hydrostatic pressure ,Cell ,Caspase 8 ,Cell biology ,medicine.anatomical_structure ,Oncology ,Cancer cell ,biology.protein ,medicine ,Immunogenic cell death ,Caspase - Abstract
Immunogenic cell death (ICD) is a type of cell death induced by various chemotherapeutics, physical modalities such as photodynamic therapy, radiotherapy, severe hyperthermia (sHT) or high hydrostatic pressure (HHP). HHP and sHT are able to trigger a specific antitumor immune response and induce the rapid translocation of calreticulin (CRT) to the plasma membrane surface (ecto-CRT). Ecto-CRT on dying tumor cells represents an “eat me” signal for dendritic cells as well as a major molecular determinant that makes the difference between immunogenic and non-immunogenic cell death. Nevertheless, the mechanisms implicated in CRT translocation after HHP treatment is unknown. Inducers of ICD trigger the ER stress response, Reactive Oxygen Species (ROS) generation and Ca2+ release. Kinetics of ecto-CRT was assessed in lung A549 and ovarian OV90 tumor cell lines. CRT localization in sHT- and HHP-treated tumor cells was tracked by endosomal staining (caveolin, clathrin, early and late endosomes) and visualized by confocal microscopy. For detection of CRT translocation pathway, the tumor cells were pretreated with selected cytoskeletal inhibitors, inhibitor of intracellular transport, ER stress activator or small interfering RNA followed by sHT and HHP treatment. The cells were analyzed by flow cytometry and confocal microscopy. Plasma membrane fraction and endosomes were isolated and analyzed by western blotting. Our results indicate that the ROS - PERK - eIF2α - caspase 2 - caspase 8 - caspase 8-mediated cleavage of the ER protein BAP31 is central for the perception of HHP-driven cell death as immunogenic. On the other hand our first results indicate that none of these processes are involve in exposure of CRT on cell surface in sHT treated tumor cells. We observed that sHT treatment does not lead to caspase 8 activation and Bap31 cleavage. However, we showed that translocation of CRT to the cell surface is dependent on endoplasmic reticulum-sessile kinase PERK and presence of Bax/Bak proteins. CRT colocalization with clathrin in tumor cells after HHP and particularly with early endosomes was detected. Surprisingly, we also did not observe colocalization with any endosomes in sHT treated tumor cells. Further, inhibition of microtubule-dependent transport with Nocodazole D results in decrease of CRT transport on cell surface in HHP treated tumor cells. Similar but less significant effect was seen when Brefeldin A was used to inhibit anterograde transport in both treatments. Inhibition of actin polymerization by Cytochalasin D did not significantly affect CRT translocation. In conclusion, PERK seems to play a central role in the exposure of CRT upon induction of ICD. However, up-stream and downstream signaling cascades differ depending the modality used to induce ICD, such as HHP or sHT. Citation Format: Sarka Vosahlikova, Irena Adkins, Linda Urbanova, Nada Hradilova, Lenka Sadilkova, Radek Spisek, Irena Moserova. Immunogenic cancer cell death induced by high hydrostatic pressure and hyperthermia: Calreticulin exposure pathway. [abstract]. In: Proceedings of the AACR Special Conference on Translational Control of Cancer: A New Frontier in Cancer Biology and Therapy; 2016 Oct 27-30; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2017;77(6 Suppl):Abstract nr A47.
- Published
- 2017
39. Generation of dendritic cell-based vaccine using high hydrostatic pressure for non-small cell lung cancer immunotherapy
- Author
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Robert Lischke, D. Myšíková, Nada Hradilova, Irena Adkins, Lenka Sadilkova, Hana Mrazkova, Radek Spisek, and Ondrej Palata
- Subjects
CD4-Positive T-Lymphocytes ,0301 basic medicine ,Lung Neoplasms ,Physiology ,medicine.medical_treatment ,lcsh:Medicine ,CD8-Positive T-Lymphocytes ,Lung and Intrathoracic Tumors ,White Blood Cells ,Spectrum Analysis Techniques ,0302 clinical medicine ,Cancer immunotherapy ,Animal Cells ,Carcinoma, Non-Small-Cell Lung ,Immune Physiology ,Medicine and Health Sciences ,Cytotoxic T cell ,Public and Occupational Health ,IL-2 receptor ,lcsh:Science ,Cells, Cultured ,Staining ,Vaccines ,Innate Immune System ,Multidisciplinary ,biology ,T Cells ,Chemistry ,Cell Staining ,Flow Cytometry ,Vaccination and Immunization ,Tumor antigen ,medicine.anatomical_structure ,Oncology ,Spectrophotometry ,030220 oncology & carcinogenesis ,Cytokines ,Immunotherapy ,Cytophotometry ,Cellular Types ,Cancer Prevention ,Research Article ,Immune Cells ,T cell ,Immunology ,Cytotoxic T cells ,Research and Analysis Methods ,Cancer Vaccines ,Interferon-gamma ,03 medical and health sciences ,Cell Line, Tumor ,Hydrostatic Pressure ,medicine ,Humans ,Blood Cells ,CD40 ,lcsh:R ,Biology and Life Sciences ,Cancers and Neoplasms ,Dendritic Cells ,Cell Biology ,Dendritic cell ,Molecular Development ,Non-Small Cell Lung Cancer ,030104 developmental biology ,Specimen Preparation and Treatment ,Immune System ,biology.protein ,Cancer research ,lcsh:Q ,Preventive Medicine ,Developmental Biology - Abstract
High hydrostatic pressure (HHP) induces immunogenic death of tumor cells which confer protective anti-tumor immunity in vivo. Moreover, DC pulsed with HHP-treated tumor cells induced therapeutic effect in mouse cancer model. In this study, we tested the immunogenicity, stability and T cell stimulatory activity of human monocyte-derived dendritic cell (DC)-based HHP lung cancer vaccine generated in GMP compliant serum free medium using HHP 250 MPa. DC pulsed with HHP-killed lung cancer cells and poly(I:C) enhanced DC maturation, chemotactic migration and production of pro-inflammatory cytokines after 24h. Moreover, DC-based HHP lung cancer vaccine showed functional plasticity after transfer into serum-containing media and stimulation with LPS or CD40L after additional 24h. LPS and CD40L stimulation further differentially enhanced the expression of costimulatory molecules and production of IL-12p70. DC-based HHP lung cancer vaccine decreased the number of CD4+CD25+Foxp3+ T regulatory cells and stimulated IFN-γ-producing tumor antigen-specific CD4+ and CD8+ T cells from non-small cell lung cancer (NSCLC) patients. Tumor antigen specific CD8+ and CD4+ T cell responses were detected in NSCLC patient's against a selected tumor antigens expressed by lung cancer cell lines used for the vaccine generation. We also showed for the first time that protein antigen from HHP-killed lung cancer cells is processed and presented by DC to CD8+ T cells. Our results represent important preclinical data for ongoing NSCLC Phase I/II clinical trial using DC-based active cellular immunotherapy (DCVAC/LuCa) in combination with chemotherapy and immune enhancers.
- Published
- 2017
40. Bordetella Adenylate Cyclase Toxin Differentially Modulates Toll-Like Receptor-Stimulated Activation, Migration and T Cell Stimulatory Capacity of Dendritic Cells
- Author
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Aneta Kocourkova, Hana Janova, Ludmila Tučková, Jana Kamanova, Marek Kovar, Jiri Masin, Ladislav Bumba, Kingston H. G. Mills, Martina Svedova, Pádraig J. Ross, Barbora Chladkova, Radek Spisek, Irena Adkins, Jakub Tomala, and Peter Sebo
- Subjects
Bacterial Diseases ,lcsh:Medicine ,CD8-Positive T-Lymphocytes ,Toxicology ,Lymphocyte Activation ,T-Lymphocytes, Regulatory ,Bordetella pertussis ,Adenylyl cyclase ,chemistry.chemical_compound ,Cell Movement ,Cellular types ,Medicine and Health Sciences ,Cytotoxic T cell ,Toxins ,IL-2 receptor ,lcsh:Science ,Toll-like receptor ,Multidisciplinary ,Cell Death ,Toll-Like Receptors ,Regulatory T cells ,3. Good health ,Cell biology ,medicine.anatomical_structure ,Infectious Diseases ,Medical Microbiology ,Adenylate Cyclase Toxin ,White blood cells ,Research Article ,Blood cells ,T cell ,Immune Cells ,Immunology ,Toxic Agents ,Bacterial Toxins ,T cells ,Antigen-Presenting Cells ,Biology ,Microbiology ,Antigens, CD ,medicine ,Cell Adhesion ,Animals ,Humans ,Classical Immunology ,T Helper Cells ,Immunity to Infections ,Microbial Pathogens ,Cell Proliferation ,Biology and life sciences ,lcsh:R ,Dendritic Cells ,cyaA ,Mice, Inbred C57BL ,chemistry ,Animal cells ,Solubility ,lcsh:Q ,CD8 - Abstract
Adenylate cyclase toxin (CyaA) is a key virulence factor of the whooping cough agent Bordetella pertussis. The toxin targets CD11b-expressing phagocytes and delivers into their cytosol an adenylyl cyclase (AC) enzyme that subverts cellular signaling by increasing cAMP levels. In the present study, we analyzed the modulatory effects of CyaA on adhesive, migratory and antigen presenting properties of Toll-like receptor (TLR)-activated murine and human dendritic cells (DCs). cAMP signaling of CyaA enhanced TLR-induced dissolution of cell adhesive contacts and migration of DCs towards the lymph node-homing chemokines CCL19 and CCL21 in vitro. Moreover, we examined in detail the capacity of toxin-treated DCs to induce CD4(+) and CD8(+) T cell responses. Exposure to CyaA decreased the capacity of LPS-stimulated DCs to present soluble protein antigen to CD4+ T cells independently of modulation of co-stimulatory molecules and cytokine production, and enhanced their capacity to promote CD4(+)CD25(+)Foxp3(+) T regulatory cells in vitro. In addition, CyaA decreased the capacity of LPS-stimulated DCs to induce CD8(+) T cell proliferation and limited the induction of IFN-γ producing CD8(+) T cells while enhancing IL-10 and IL-17-production. These results indicate that through activation of cAMP signaling, the CyaA may be mobilizing DCs impaired in T cell stimulatory capacity and arrival of such DCs into draining lymph nodes may than contribute to delay and subversion of host immune responses during B. pertussis infection.
- Published
- 2014
41. Bacterial Toxins Are Successful Immunotherapeutic Adjuvants and Immunotoxins
- Author
-
Irena Adkins
- Subjects
Immune system ,medicine.anatomical_structure ,Immunity ,Effector ,medicine.medical_treatment ,T cell ,Cancer cell ,medicine ,Secretion ,Immunotherapy ,Biology ,Antigen-presenting cell ,Microbiology - Abstract
Bacterial protein toxins of pathogenic bacteria play an important role in infectious diseases to hijack mammalian cells and manipulate host immune responses. Several bacterial toxins and their non-toxic mutants have been intensively studied over the past decades in order to harness their abilities to enter host cells for stimulation of adaptive T cell responses, direct elimination of cancer cells or to boost immunity as adjuvants. Moreover, another set of bacterial toxins called effectors, which are translocated into the host cells by specialized secretion systems, have been used to facilitate the delivery of heterologous antigens into antigen presenting cells. Some of the most powerful bacterial neurotoxins have found their application in treatment of various neurological disorders as well as in cosmetic industry. Whereas few bacterial toxins are currently in various phases of clinical cancer trials, the immunotherapeutic potential of others needs to be established further. This chapter will introduce bacterial toxins used in immunotherapy and present the major achievements in this field. Similarly, the hurdles and limitations of the use of bacterial toxins in human immunotherapy will be discussed together with other diagnostics applications.
- Published
- 2013
42. Calcium Influx Rescues Adenylate Cyclase-Hemolysin from Rapid Cell Membrane Removal and Enables Phagocyte Permeabilization by Toxin Pores
- Author
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Claude Leclerc, Radim Osicka, Lenka Sadilkova, Jana Kamanova, Jiri Masin, Marek Basler, Radovan Fišer, Irena Adkins, Ivo Konopásek, Jan Cerny, Peter Sebo, Eva Pospisilova, Ladislav Bumba, and Catherine Fayolle
- Subjects
Cell Membrane Permeability ,Phagocyte ,QH301-705.5 ,Immunology ,Endocytic cycle ,Biology ,Endocytosis ,Toxicology ,Biochemistry ,Microbiology ,Cell Line ,Cell membrane ,Mice ,Membrane Microdomains ,Virology ,Molecular Cell Biology ,Genetics ,medicine ,Animals ,Biology (General) ,Molecular Biology ,Lipid raft ,Ion Transport ,Macrophages ,Proteins ,RC581-607 ,cyaA ,Clathrin ,Cell biology ,Bacterial Pathogens ,Cytosol ,medicine.anatomical_structure ,Adenylate Cyclase Toxin ,Potassium ,Parasitology ,Immunologic diseases. Allergy ,Research Article - Abstract
Bordetella adenylate cyclase toxin-hemolysin (CyaA) penetrates the cytoplasmic membrane of phagocytes and employs two distinct conformers to exert its multiple activities. One conformer forms cation-selective pores that permeabilize phagocyte membrane for efflux of cytosolic potassium. The other conformer conducts extracellular calcium ions across cytoplasmic membrane of cells, relocates into lipid rafts, translocates the adenylate cyclase enzyme (AC) domain into cells and converts cytosolic ATP to cAMP. We show that the calcium-conducting activity of CyaA controls the path and kinetics of endocytic removal of toxin pores from phagocyte membrane. The enzymatically inactive but calcium-conducting CyaA-AC− toxoid was endocytosed via a clathrin-dependent pathway. In contrast, a doubly mutated (E570K+E581P) toxoid, unable to conduct Ca2+ into cells, was rapidly internalized by membrane macropinocytosis, unless rescued by Ca2+ influx promoted in trans by ionomycin or intact toxoid. Moreover, a fully pore-forming CyaA-ΔAC hemolysin failed to permeabilize phagocytes, unless endocytic removal of its pores from cell membrane was decelerated through Ca2+ influx promoted by molecules locked in a Ca2+-conducting conformation by the 3D1 antibody. Inhibition of endocytosis also enabled the native B. pertussis-produced CyaA to induce lysis of J774A.1 macrophages at concentrations starting from 100 ng/ml. Hence, by mediating calcium influx into cells, the translocating conformer of CyaA controls the removal of bystander toxin pores from phagocyte membrane. This triggers a positive feedback loop of exacerbated cell permeabilization, where the efflux of cellular potassium yields further decreased toxin pore removal from cell membrane and this further enhances cell permeabilization and potassium efflux., Author Summary The adenylate cyclase toxin (CyaA) of pathogenic Bordetellae eliminates the first line of host innate immune defense by inhibiting the oxidative burst and complement-mediated opsonophagocytic killing of bacteria. The toxin penetrates myeloid phagocytes, such as neutrophil, macrophage or dendritic cells, and subverts their signaling by catalyzing a rapid and massive conversion of intracellular ATP to the key signaling molecule cAMP. In parallel, the toxin forms cation-selective pores and permeabilizes the cytoplasmic membrane of phagocytes. This so-called ‘hemolysin’ activity synergizes with the enzymatic AC activity of CyaA in promoting apoptotic or necrotic cell death, depending on the toxin dose. Moreover, the pore-forming activity promotes activation of NALP3 inflammasome and release of interleukin IL-1β. We show here that the capacity of CyaA to permeabilize phagocytes depends on its ability to mediate influx of extracellular calcium ions into cells. This enables bystander CyaA pores to escape rapid macropinocytic removal from cell membrane and exacerbate the permeabilization of cells. These observations set a new paradigm for the mechanism of action of pore-forming RTX leukotoxins on phagocytes.
- Published
- 2012
43. Bacteria and their toxins tamed for immunotherapy
- Author
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Irena Adkins, Jana Holubova, Lenka Sadilkova, and Martina Kosova
- Subjects
Diphtheria toxin ,Host cell membrane ,biology ,Cholera toxin ,Bacterial Toxins ,Pharmaceutical Science ,Shiga toxin ,Enterotoxin ,biology.organism_classification ,medicine.disease_cause ,Pertussis toxin ,Virology ,Microbiology ,Bordetella ,Neoplasms ,medicine ,biology.protein ,Animals ,Humans ,Immunotherapy ,Antigens ,Exotoxin ,Biotechnology - Abstract
Bacterial toxins share the ability to enter host cells to target various intracellular proteins and to modulate host immune responses. Over the last 20 years, toxins and their mutated variants, as well as live attenuated bacteria, have been exploited for vaccination and immunotherapy of various infectious, malignant and autoimmune diseases. The ability of Bordetella pertussis adenylate cyclase toxin to translocate its adenylate cyclase domain across the host cell membrane, as well as the pathways of intracellular trafficking of Bacillus anthracis lethal and edema toxins, Shigella dysenteriae shiga toxin or Escherichia coli shiga-like toxin, have been repeatedly exploited for the delivery of antigenic epitopes into host cells and for stimulation of antigen-specific T cell responses. Similarly, E. coli α-hemolysin, or effector proteins of Yersinia and Salmonella secreted by the type III secretion systems, were used to facilitate the delivery of fused heterologous proteins or peptides for antigenic presentation. Vibrio cholerae cholera toxin, E. coli heat-labile enterotoxin, B. pertussis pertussis toxin or the Cry1A protein of Bacillus thuringiensis have shown a great potential to act as adjuvants and to stimulate mucosal as well as systemic immune responses. The immunotherapeutic potential of some toxins, like Clostridium perfringens perfringolysin O, Streptococcus intermedius intermedilysin, or Streptococcus pneumoniae pneumolysin needs to be evaluated further. The Bordetella adenylate cyclase toxoid used as a vaccine delivery tool, or Corynebacterium diphtheriae diphtheria toxin and Pseudomonas aeruginosa exotoxin A-based immunotoxins, are currently in various phases of clinical trials for cancer immunotherapy, as are some antigen-delivering Salmonella and Listeria monocytogenes strains.
- Published
- 2010
44. Catalytically active Yersinia outer protein P induces cleavage of RIP and caspase-8 at the level of the DISC independently of death receptors in dendritic cells
- Author
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Ingo B. Autenrieth, Kathleen Richter, Sabine Gröbner, Olivier Micheau, Klaus Ruckdeschel, Sebastian Wesselborg, Stefan Borgmann, Irena Adkins, and Sebastian Schulz
- Subjects
Cancer Research ,Programmed cell death ,Death Domain Receptor Signaling Adaptor Proteins ,Fas-Associated Death Domain Protein ,Lactams, Macrocyclic ,Clinical Biochemistry ,CASP8 and FADD-Like Apoptosis Regulating Protein ,Pharmaceutical Science ,Biology ,Caspase 8 ,chemistry.chemical_compound ,Mice ,Bacterial Proteins ,Benzoquinones ,Animals ,Humans ,FADD ,fas Receptor ,Enzyme Inhibitors ,Receptor ,Cells, Cultured ,Death domain ,Yersinia enterocolitica ,Pharmacology ,Mice, Knockout ,Mice, Inbred BALB C ,Cell Death ,Biochemistry (medical) ,Cell Biology ,Dendritic Cells ,Receptors, Death Domain ,Geldanamycin ,Fas receptor ,Cell biology ,Enzyme Activation ,Mice, Inbred C57BL ,Receptors, TNF-Related Apoptosis-Inducing Ligand ,chemistry ,Apoptosis ,Receptors, Tumor Necrosis Factor, Type I ,Receptor-Interacting Protein Serine-Threonine Kinases ,biology.protein ,Signal Transduction - Abstract
Yersinia outer protein P (YopP) is injected by Y. enterocolitica into host cells thereby inducing apoptotic and necrosis-like cell death in dendritic cells (DC). Here we show the pathways involved in DC death caused by the catalytic activity of YopP. Infection with Yersinia enterocolitica, translocating catalytically active YopP into DC, triggered procaspase-8 cleavage and c-FLIPL degradation. YopP-dependent caspase-8 activation was, however, not mediated by tumor necrosis factor (TNF) receptor family members since the expression of both CD95/Fas/APO-1 and TRAIL-R2 on DC was low, and DC were resistant to apoptosis induced by agonistic anti-CD95 antibodies or TNF-related apoptosis-inducing ligand (TRAIL). Moreover, DC from TNF-Rp55-/- mice were not protected against YopP-induced cell death demonstrating that TNF-R1 is also not involved in this process. Activation of caspase-8 was further investigated by coimmunoprecitation of FADD from Yersinia-infected DC. We found that both cleaved caspase-8 and receptor interacting protein 1 (RIP1) were associated with the Fas-associated death domain (FADD) indicating the formation of an atypical death-inducing signaling complex (DISC). Furthermore, degradation of RIP mediated by the Hsp90 inhibitor geldanamycin significantly impaired YopP-induced cell death. Altogether our findings indicate that Yersinia-induced DC death is independent of death domain containing receptors, but mediated by RIP and caspase-8 at the level of DISC.
- Published
- 2007
45. Yersinia outer proteins E, H, P, and T differentially target the cytoskeleton and inhibit phagocytic capacity of dendritic cells
- Author
-
Martin Köberle, Irena Adkins, Ingo B. Autenrieth, Erwin Bohn, Stefan Borgmann, and Sabine Gröbner
- Subjects
Microbiology (medical) ,Serotype ,Phagocytosis ,Mutant ,macromolecular substances ,Yersinia ,Microbiology ,Mice ,Bacterial Proteins ,Animals ,Cytoskeleton ,Cells, Cultured ,Mice, Inbred BALB C ,biology ,General Medicine ,Dendritic Cells ,biology.organism_classification ,Actin cytoskeleton ,Actins ,Cell biology ,Cysteine Endopeptidases ,Infectious Diseases ,Female ,Protein Tyrosine Phosphatases ,Bacteria ,Function (biology) ,Bacterial Outer Membrane Proteins - Abstract
Through Yersinia outer proteins (Yops) Yersinia disrupt the actin cytoskeleton of epithelial cells and macrophages, and this leads to a decreased capability of these cells to internalize bacteria. We examined the effects of different Yops of Y. enterocolitica serotype O8 on the cytoskeleton and phagocytic capacity of murine dendritic cells (DCs). DCs were infected with several Yersinia mutant strains deficient in one Yop or translocating only a single Yop. Analyses of infected DCs by microscopy showed that YopE, YopH and YopT cooperate to rapidly damage the actin cytoskeleton of DCs. Furthermore, microscopic analyses and gentamicin killing assays revealed that the maximum reduction of bacterial uptake was achieved by Yersinia mutant strains translocating only a single Yop (YopE or YopH) indicating that these Yops enable Yersinia to inhibit the phagocytic function of DCs.
- Published
- 2006
46. Physical modalities inducing immunogenic tumor cell death for cancer immunotherapy
- Author
-
Jitka Fucikova, Abhishek D. Garg, Radek Spisek, Patrizia Agostinis, and Irena Adkins
- Subjects
ionizing irradiation ,Hyperthermia ,Programmed cell death ,medicine.medical_treatment ,Immunology ,Hydrostatic pressure ,ICD, immunogenic cell death ,NDV, Newcastle Disease Virus ,RT, radiotherapy ,Photodynamic therapy ,Review ,Hyp-PDT, Hypericin-based Photodynamic therapy ,EGFR, endothelial growth factor receptor ,ER, endoplasmic reticulum ,CRT, calreticulin ,ROS, reactive oxygen species ,Cancer immunotherapy ,DC, dendritic cells ,immunogenic cell death ,eIF2α, eukaryotic translation initiation factor 2α ,Immunology and Allergy ,Medicine ,UVC, ultraviolet C light ,DAMPs, danger-associated molecular patterns ,IFNγ, interferon-γ ,HHP, high hydrostatic pressure, HMGB1, high-mobility group box 1 ,cancer immunotherapy ,high hydrostatic pressure ,business.industry ,Cancer ,hyperthermia ,medicine.disease ,Oncology ,HT, hyperthermia ,Cancer cell ,Cancer research ,Immunogenic cell death ,ATP, Adenosine triphosphate ,HSP, heat shock protein ,business ,photodynamic therapy with hypericin ,TLR, Toll-like receptor - Abstract
The concept of immunogenic cancer cell death (ICD), as originally observed during the treatment with several chemotherapeutics or ionizing irradiation, has revolutionized the view on the development of new anticancer therapies. ICD is defined by endoplasmic reticulum (ER) stress response, reactive oxygen species (ROS) generation, emission of danger-associated molecular patterns and induction of antitumor immunity. Here we describe known and emerging cancer cell death-inducing physical modalities, such as ionizing irradiation, ultraviolet C light, Photodynamic Therapy (PDT) with Hypericin, high hydrostatic pressure (HHP) and hyperthermia (HT), which have been shown to elicit effective antitumor immunity. We discuss the evidence of ICD induced by these modalities in cancer patients together with their applicability in immunotherapeutic protocols and anticancer vaccine development.
- Published
- 2014
47. In vitro activation of CMV-specific T-cell response using CyaA toxoids delivering peptide antigenic epitopes derived from pp65 protein
- Author
-
Jaroslav Michálek, Irena Adkins, Petr Šebo, and Jiří Jelínek
- Subjects
chemistry.chemical_classification ,Cancer Research ,medicine.medical_treatment ,T cell ,virus diseases ,Peptide ,Immunotherapy ,cyaA ,Biology ,Virology ,In vitro ,Epitope ,medicine.anatomical_structure ,Oncology ,chemistry ,Antigen ,Immunity ,Immunology ,medicine - Abstract
Presented data reveal the potential of CyaA constructs as a tool for fast and reliable detection of CMV-specific immunity and for immunoprophylactic, as well as immunotherapeutic application against CMV-associated diseases in immunocompromised patients.
- Published
- 2010
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