Non-traditional #Antibacterial #Therapeutic #Options and #Challenges (Cell Host Microbe, abstract)

[Source: Cell, Host & Microbe, full page: (LINK). Abstract, edited.]

Non-traditional Antibacterial Therapeutic Options and Challenges

Ursula Theuretzbacher, Laura J.V. Piddock

DOI: https://doi.org/10.1016/j.chom.2019.06.004

 

Summary

The global challenges presented by drug-resistant bacterial infections have stimulated much activity in finding new treatments. This review summarizes the progress and setbacks of non-traditional approaches intent on circumventing bacterial drug resistance. These approaches include targeting virulence via toxin production and virulence factor secretion, impeding bacterial adhesion to host cells and biofilm formation, interrupting or inhibiting bacterial communication, and downregulating virulence. Other strategies include immune evasion, microbiome-modifying therapies, and the employment of phages as treatments or carriers. Finally, the prospects of nanoparticles, immunotherapy, antisense RNA, and drug-resistance-modulation approaches are discussed. The development of non-traditional treatments suffers similar challenges faced by developers of conventional antibiotics; however, most of these new strategies have additional and considerable hurdles before it can be shown that they are safe and efficacious for patient use. For the foreseeable future, it is likely that most of these treatments, if approved, will be used in combination with antibiotics.

Keywords: anti-virulence – quorum-sensing – microbiome – phage – nanoparticles – immunotherapy – antisense RNA – non-traditional antimicrobials

Keywords: Antibiotics; Drugs Resistance; Immunotherapy; Bacteriophages.

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Qß Virus-like particle-based #vaccine induces robust #immunity and protects against #tauopathy (npj Vaccines, abstract)

[Source: npj Vaccines, full page: (LINK). Abstract, edited.]

Article | OPEN | Published: 03 June 2019

Qß Virus-like particle-based vaccine induces robust immunity and protects against tauopathy

Nicole M. Maphis, Julianne Peabody, Erin Crossey, Shanya Jiang, Fadi A. Jamaleddin Ahmad, Maria Alvarez, Soiba Khalid Mansoor, Amanda Yaney, Yirong Yang, Laurel O. Sillerud, Colin M. Wilson, Reed Selwyn, Jonathan L. Brigman, Judy L. Cannon, David S. Peabody, Bryce Chackerian & Kiran Bhaskar

npj Vaccines 4, Article number: 2 (2019)

 

Abstract

Tauopathies, including frontotemporal dementia (FTD) and Alzheimer’s disease (AD) are progressive neurodegenerative diseases clinically characterized by cognitive decline and could be caused by the aggregation of hyperphosphorylated pathological tau (pTau) as neurofibrillary tangles (NFTs) inside neurons. There is currently no FDA-approved treatment that cures, slows or prevents tauopathies. Current immunotherapy strategies targeting pTau have generated encouraging data but may pose concerns about scalability, affordability, and efficacy. Here, we engineered a virus-like particle (VLP)-based vaccine in which tau peptide, phosphorylated at threonine 181, was linked at high valency to Qß bacteriophage VLPs (pT181-Qß). We demonstrate that vaccination with pT181-Qß is sufficient to induce a robust and long-lived anti-pT181 antibody response in the sera and the brains of both Non-Tg and rTg4510 mice. Only sera from pT181-Qß vaccinated mice are reactive to classical somatodendritic pTau in human FTD and AD post-mortem brain sections. Finally, we demonstrate that pT181-Qß vaccination reduces both soluble and insoluble species of hyperphosphorylated pTau in the hippocampus and cortex, avoids a Th1-mediated pro-inflammatory cell response, prevents hippocampal and corpus callosum atrophy and rescues cognitive dysfunction in a 4-month-old rTg4510 mouse model of FTD. These studies provide a valid scientific premise for the development of VLP-based immunotherapy to target pTau and potentially prevent Alzheimer’s diseases and related tauopathies.

Keywords: Alzheimer Disease; Tauopathy; Immunotherapy; Vaccines; Animal models.

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Treating #Influenza #Infection, From Now and Into the Future (Front Immunol., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Front Immunol. 2018 Sep 10;9:1946. doi: 10.3389/fimmu.2018.01946. eCollection 2018.

Treating Influenza Infection, From Now and Into the Future.

Davidson S1.

Author information: 1 Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.

 

Abstract

Influenza viruses (IVs) are a continual threat to global health. The high mutation rate of the IV genome makes this virus incredibly successful, genetic drift allows for annual epidemics which result in thousands of deaths and millions of hospitalizations. Moreover, the emergence of new strains through genetic shift (e.g., swine-origin influenza A) can cause devastating global outbreaks of infection. Neuraminidase inhibitors (NAIs) are currently used to treat IV infection and act directly on viral proteins to halt IV spread. However, effectivity is limited late in infection and drug resistance can develop. New therapies which target highly conserved features of IV such as antibodies to the stem region of hemagglutinin or the IV RNA polymerase inhibitor: Favipiravir are currently in clinical trials. Compared to NAIs, these treatments have a higher tolerance for resistance and a longer therapeutic window and therefore, may prove more effective. However, clinical and experimental evidence has demonstrated that it is not just viral spread, but also the host inflammatory response and damage to the lung epithelium which dictate the outcome of IV infection. Therapeutic regimens for IV infection should therefore also regulate the host inflammatory response and protect epithelial cells from unnecessary cell death. Anti-inflammatory drugs such as etanercept, statins or cyclooxygenase enzyme 2 inhibitors may temper IV induced inflammation, demonstrating the possibility of repurposing these drugs as single or adjunct therapies for IV infection. IV binds to sialic acid receptors on the host cell surface to initiate infection and productive IV replication is primarily restricted to airway epithelial cells. Accordingly, targeting therapies to the epithelium will directly inhibit IV spread while minimizing off target consequences, such as over activation of immune cells. The neuraminidase mimic Fludase cleaves sialic acid receptors from the epithelium to inhibit IV entry to cells. While type III interferons activate an antiviral gene program in epithelial cells with minimal perturbation to the IV specific immune response. This review discusses the above-mentioned candidate anti-IV therapeutics and others at the preclinical and clinical trial stage.

KEYWORDS: antiviral; immunomodulation; influenza; therapeutics; treatment

PMID: 30250466 PMCID: PMC6139312 DOI: 10.3389/fimmu.2018.01946

Keywords: Influenza A; Antivirals; Immunotherapy; COX-2 inhibitors; Statins.

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The #hallmarks of successful #anticancer #immunotherapy (Sci Transl Med., abstract)

[Source: Science Translational Medicine, full page: (LINK). Abstract, edited.]

The hallmarks of successful anticancer immunotherapy

Lorenzo Galluzzi1,2,3,*, Timothy A. Chan4,5,6, Guido Kroemer3,7,8,9,10,11, Jedd D. Wolchok6,12 and Alejandro López-Soto13,*

1 Department of Radiation Oncology, Weill Cornell Medical College, New York, NY 10065, USA. 2 Sandra and Edward Meyer Cancer Center, New York, NY 10065, USA. 3 Université Paris Descartes/Paris V, 75006 Paris, France. 4 Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. 5 Immunogenomics and Precision Oncology Platform, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. 6 Weill Cornell School of Medicine, New York, NY 10065, USA. 7 Equipe 11 labellisée Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, 75006 Paris, France. 8 INSERM, U1138, 75006 Paris, France. 8 Université Pierre et Marie Curie/Paris VI, 75006 Paris, France. 9 Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Center, 94805 Villejuif, France. 10 Pôle de Biologie, Hôpital Européen Georges-Pompidou, Assistance Publique–Hôpitaux de Paris, 75015 Paris, France. 11 Department of Women’s and Children’s Health, Karolinska University Hospital, 17176 Stockholm, Sweden. 12 Department of Medicine, Parker Institute and Ludwig Center, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. 13 Departamento de Biología Funcional, Área de Inmunología, Universidad de Oviedo, Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), 33006 Oviedo, Spain.

*Corresponding author. Email: deadoc@vodafone.it (L.G.); lopezsalejandro@uniovi.es (A.L.-S.)

Science Translational Medicine  19 Sep 2018: Vol. 10, Issue 459, eaat7807 / DOI: 10.1126/scitranslmed.aat7807

 

Abstract

Immunotherapy is revolutionizing the clinical management of multiple tumors. However, only a fraction of patients with cancer responds to immunotherapy, and currently available immunotherapeutic agents are expensive and generally associated with considerable toxicity, calling for the identification of robust predictive biomarkers. The overall genomic configuration of malignant cells, potentially favoring the emergence of immunogenic tumor neoantigens, as well as specific mutations that compromise the ability of the immune system to recognize or eradicate the disease have been associated with differential sensitivity to immunotherapy in preclinical and clinical settings. Along similar lines, the type, density, localization, and functional orientation of the immune infiltrate have a prominent impact on anticancer immunity, as do features of the tumor microenvironment linked to the vasculature and stroma, and systemic factors including the composition of the gut microbiota. On the basis of these considerations, we outline the hallmarks of successful anticancer immunotherapy.

Keywords: Cancer; Immunotherapy.

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#BCG-Induced Trained #Immunity Is Not Protective for Experimental #Influenza A/Anhui/1/2013 (#H7N9) Infection in Mice (Front Immunol., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Front Immunol. 2018 Apr 30;9:869. doi: 10.3389/fimmu.2018.00869. eCollection 2018.

Bacillus Calmette-Guérin-Induced Trained Immunity Is Not Protective for Experimental Influenza A/Anhui/1/2013 (H7N9) Infection in Mice.

de Bree CLCJ1,2,3,4, Marijnissen RJ5, Kel JM5, Rosendahl Huber SK5, Aaby P3, Benn CS3,4, Wijnands MVW5, Diavatopoulos DA2,6, van Crevel R1,2, Joosten LAB1,2, Netea MG1,2,7, Dulos J8.

Author information: 1 Department of Internal Medicine, Radboud University Medical Center, Nijmegen, Netherlands. 2 Radboud Centre for Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, Netherlands. 3 Research Center for Vitamins and Vaccines, Bandim Health Project, Statens Serum Institut, Copenhagen, Denmark. 4 Odense Patient Data Explorative Network, University of Southern Denmark, Odense University Hospital, Odense, Denmark. 5 Department of Immunology, Triskelion B.V., Zeist, Netherlands. 6 Laboratory of Pediatric Infectious Diseases, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands. 7 Department for Genomics and Immunoregulation, Life and Medical Sciences Institute (LIMES), University of Bonn, Bonn, Germany. 8 Aduro Biotech Europe, Oss, Netherlands.

 

Abstract

Avian influenza A of the subtype H7N9 has been responsible for almost 1,600 confirmed human infections and more than 600 deaths since its first outbreak in 2013. Although sustained human-to-human transmission has not been reported yet, further adaptations to humans in the viral genome could potentially lead to an influenza pandemic, which may have severe consequences due to the absence of pre-existent immunity to this strain at population level. Currently there is no influenza A (H7N9) vaccine available. Therefore, in case of a pandemic outbreak, alternative preventive approaches are needed, ideally even independent of the type of influenza virus outbreak. Bacillus Calmette-Guérin (BCG) is known to induce strong heterologous immunological effects, and it has been shown that BCG protects against non-related infection challenges in several mouse models. BCG immunization of mice as well as human induces trained innate immune responses, resulting in increased cytokine responses upon subsequent ex vivo peripheral blood mononuclear cell restimulation. We investigated whether BCG (Statens Serum Institut-Denmark)-induced trained immunity may protect against a lethal avian influenza A/Anhui/1/2013 (H7N9) challenge. Here, we show that isolated splenocytes as well as peritoneal macrophages of BCG-immunized BALB/c mice displayed a trained immunity phenotype resulting in increased innate cytokine responses upon ex vivo restimulation. However, after H7N9 infection, no significant differences were found between the BCG immunized and the vehicle control group at the level of survival, weight loss, pulmonary influenza A nucleoprotein staining, or histopathology. In conclusion, BCG-induced trained immunity did not result in protection in an oseltamivir-sensitive influenza A/Anhui/1/2013 (H7N9) challenge mouse model.

KEYWORDS: avian influenza A/Anhui/1/2013 (H7N9); bacillus Calmette–Guérin; innate immune memory; oseltamivir; trained immunity

PMID: 29760700 PMCID: PMC5936970 DOI: 10.3389/fimmu.2018.00869

Keywords: Avian Influenza; H7N9; Immunotherapy; BCG; Animal Models.

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#Tremelimumab combined with durvalumab in patients with #mesothelioma (NIBIT-MESO-1): an open-label, non-randomised, phase 2 study (Lancet Resp Med., abstract)

[Source: The Lancet Respiratory Medicine, full page: (LINK). Abstract, edited.]

Tremelimumab combined with durvalumab in patients with mesothelioma (NIBIT-MESO-1): an open-label, non-randomised, phase 2 study

Luana Calabrò, MD, Aldo Morra, MD, Diana Giannarelli, PhD, Giovanni Amato, PhD, Armida D’Incecco, MD, Alessia Covre, PhD, Arthur Lewis, BSc, Marlon C Rebelatto, PhD, Riccardo Danielli, MD, Maresa Altomonte, MD, Anna Maria Di Giacomo, MD, Michele Maio, MD

Published: 14 May 2018 / DOI: https://doi.org/10.1016/S2213-2600(18)30151-6

© 2018 Elsevier Ltd. All rights reserved.

 

Summary

Background

Tremelimumab, an anti-CTLA4 monoclonal antibody, initially showed good activity when used alone in patients with mesothelioma, but did not improve the overall survival of patients who failed on first-line or second-line chemotherapy compared with placebo in the DETERMINE study. We aimed to investigate the efficacy and safety of first-line or second-line tremelimumab combined with durvalumab, an anti-PD-L1 monoclonal antibody, in patients with malignant mesothelioma.

Methods

In this open-label, non-randomised, phase 2 trial, patients with unresectable pleural or peritoneal mesothelioma received intravenous tremelimumab (1 mg/kg bodyweight) and durvalumab (20 mg/kg bodyweight) every 4 weeks for four doses, followed by maintenance intravenous durvalumab at the same dose and schedule for nine doses. The primary endpoint was the proportion of patients with an immune-related objective response according to the immune-related modified Response Evaluation Criteria in Solid Tumors (RECIST; for pleural mesothelioma) or immune-related RECIST version 1.1 (for peritoneal mesothelioma). The primary analysis was done by intention to treat, whereas the safety analysis included patients who received at least one dose of study drug. This trial is registered with the European Clinical Trials Database, number 2015-001995-23, and ClinicalTrials.gov, number NCT02588131, and is ongoing but no longer recruiting patients.

Findings

From Oct 30, 2015, to Oct 12, 2016, 40 patients with mesothelioma were enrolled and received at least one dose each of tremelimumab and durvalumab. Patients were followed-up for a median of 19·2 months (IQR 13·8–20·5). 11 (28%) of 40 patients had an immune-related objective response (all partial responses; confirmed in ten patients), with a median response duration of 16·1 months (IQR 11·5–20·5). 26 (65%) patients had immune-related disease control and 25 (63%) had disease control. Median immune-related progression-free survival was 8·0 months (95% CI 6·7–9·3), median progression-free survival was 5·7 months (1·7–9·7), and median overall survival was 16·6 months (13·1–20·1). Baseline tumour PD-L1 expression did not correlate with the proportion of patients who had an immune-related objective response or immune-related disease control, with immune-related progression-free survival, or with overall survival. 30 (75%) patients experienced treatment-related adverse events of any grade, of whom seven (18%) had grade 3–4 treatment-related adverse events. Treatment-related toxicity was generally manageable and reversible with protocol guidelines.

Interpretation

The combination of tremelimumab and durvalumab appeared active, with a good safety profile in patients with mesothelioma, warranting further exploration.

Funding

Network Italiano per la Bioterapia dei Tumori Foundation, Associazione Italiana per la Ricerca sul Cancro, AstraZeneca, and Istituto Toscano Tumori.

Keywords: Cancer; Mesothelioma; Immunotherapy; Tremelimumab; Durvalumab.

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Tandem bispecific neutralizing #antibody eliminates #HIV-1 #infection in humanized mice (J Clin Invest., abstract)

[Source: Journal of Clinical Investigation, full page: (LINK). Abstract, edited.]

Tandem bispecific neutralizing antibody eliminates HIV-1 infection in humanized mice

Xilin Wu,1,2 Jia Guo,1 Mengyue Niu,1,2 Minghui An,1,3 Li Liu,1,2 Hui Wang,2 Xia Jin,4 Qi Zhang,5 Ka Shing Lam,1 Tongjin Wu,1 Hua Wang,5 Qian Wang,5 Yanhua Du,1 Jingjing Li,1 Lin Cheng,2 Hang Ying Tang,1 Hong Shang,3 Linqi Zhang,5 Paul Zhou,4 and Zhiwei Chen1,2

First published February 20, 2018

See the related Commentary at Tandem bispecific broadly neutralizing antibody — a novel approach to HIV-1 treatment.

 

Abstract

The discovery of an HIV-1 cure remains a medical challenge because the virus rebounds quickly after the cessation of combination antiretroviral therapy (cART). Here, we investigate the potential of an engineered tandem bispecific broadly neutralizing antibody (bs-bnAb) as an innovative product for HIV-1 prophylactic and therapeutic interventions. We discovered that by preserving 2 single-chain variable fragment (scFv) binding domains of each parental bnAb, a single gene–encoded tandem bs-bnAb, BiIA-SG, displayed substantially improved breadth and potency. BiIA-SG neutralized all 124 HIV-1–pseudotyped viruses tested, including global subtypes/recombinant forms, transmitted/founder viruses, variants not susceptible to parental bnAbs and to many other bnAbs with an average IC50 value of 0.073 μg/ml (range < 0.001–1.03 μg/ml). In humanized mice, an injection of BiIA-SG conferred sterile protection when administered prior to challenges with diverse live HIV-1 stains. Moreover, whereas BiIA-SG delayed viral rebound in a short-term therapeutic setting when combined with cART, a single injection of adeno-associated virus–transferred (AAV-transferred) BiIA-SG gene resulted dose-dependently in prolonged in vivo expression of BiIA-SG, which was associated with complete viremia control and subsequent elimination of infected cells in humanized mice. These results warrant the clinical development of BiIA-SG as a promising bs-bnAb–based biomedical intervention for the prevention and treatment of HIV-1 infection.

Keywords: Antivirals; Immunotherapy; HIV.

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