Characteristics of tumor-infiltrating lymphocytes prior to and during immune checkpoint inhibitor therapy

The tumor immune contexture plays a major role for the clinical outcome of patients. High densities of CD45RO + T helper 1 cells and CD8 + T cells are associated with improved survival of patients with various cancer entities. In contrast, a higher frequency of tumor-infiltrating M2 macrophages is correlated with poor prognosis. Recent studies provide evidence that the tumor immune architecture also essentially contributes to the clinical efficacy of immune checkpoint inhibitor (CPI) therapy in patients. Pretreatment melanoma samples from patients who experienced a clinical response to anti-programmed cell death protein 1 (PD-1) treatment show higher densities of infiltrating CD8 + T cells compared to samples from patients that progressed during therapy. Anti-PD-1 therapy results in an increased density of tumor-infiltrating T lymphocytes in treatment responders. In addition, elevated frequencies of melanoma-infiltrating TCF7 + CD8 + T cells are correlated with beneficial clinical outcome of anti-PD-1-treated patients. In contrast, a high density of tumor-infiltrating, dysfunctional PD-1 + CD38 hi CD8 + cells in melanoma patients is associated with anti-PD-1 resistance. Such findings indicate that comprehensive tumor immune contexture profiling prior to and during CPI therapy may lead to the identification of underlying mechanisms for treatment response or resistance, and the design of improved immunotherapeutic strategies. Here, we focus on studies exploring the impact of intratumoral T and B cells at baseline on the clinical outcome of CPI-treated cancer patients. In addition, recent findings demonstrating the influence of CPIs on tumor-infiltrating lymphocytes are summarized

Different Patterns of Inappropriate Antimicrobial Use in Surgical and Medical Units at a Tertiary Care Hospital in Switzerland: A Prevalence Survey

Audits of individual patient care provide important data to identify local problems in antimicrobial prescription practice. In our study, antimicrobial prescriptions without indication, and divergence from institutional guidelines were frequent errors. Based on these results, we will tailor education, amend institutional guidelines and further develop the infectious diseases consultation service

Human CLEC9A antibodies deliver Wilms' tumor 1 (WT1) antigen to CD141+ dendritic cells to activate naïve and memory WT1‐specific CD8+ T cells

Objectives Vaccines that prime Wilms' tumor 1 (WT1)‐specific CD8+ T cells are attractive cancer immunotherapies. However, immunogenicity and clinical response rates may be enhanced by delivering WT1 to CD141+ dendritic cells (DCs). The C‐type lectin‐like receptor CLEC9A is expressed exclusively by CD141+ DCs and regulates CD8+ T‐cell responses. We developed a new vaccine comprising a human anti‐CLEC9A antibody fused to WT1 and investigated its capacity to target human CD141+ DCs and activate naïve and memory WT1‐specific CD8+ T cells. Methods WT1 was genetically fused to antibodies specific for human CLEC9A, DEC‐205 or β‐galactosidase (untargeted control). Activation of WT1‐specific CD8+ T‐cell lines following cross‐presentation by CD141+ DCs was quantified by IFNγ ELISPOT. Humanised mice reconstituted with human immune cell subsets, including a repertoire of naïve WT1‐specific CD8+ T cells, were used to investigate naïve WT1‐specific CD8+ T‐cell priming. Results The CLEC9A‐WT1 vaccine promoted cross‐presentation of WT1 epitopes to CD8+ T cells and mediated priming of naïve CD8+ T cells more effectively than the DEC‐205‐WT1 and untargeted control‐WT1 vaccines. Conclusions Delivery of WT1 to CD141+ DCs via CLEC9A stimulates CD8+ T cells more potently than either untargeted delivery or widespread delivery to all Ag‐presenting cells via DEC‐205, suggesting that cross‐presentation by CD141+ DCs is sufficient for effective CD8+ T‐cell priming in humans. The CLEC9A‐WT1 vaccine is a promising candidate immunotherapy for malignancies that express WT1

Antimicrobial Photodynamic Therapy: Study of Bacterial Recovery Viability and Potential Development of Resistance after Treatment

Antimicrobial photodynamic therapy (aPDT) has emerged in the clinical field as a potential alternative to antibiotics to treat microbial infections. No cases of microbial viability recovery or any resistance mechanisms against it are yet known. 5,10,15-tris(1-Methylpyridinium-4-yl)-20-(pentafluorophenyl)-porphyrin triiodide (Tri-Py+-Me-PF) was used as photosensitizer. Vibrio fischeri and recombinant Escherichia coli were the studied bacteria. To determine the bacterial recovery after treatment, Tri-Py+-Me-PF (5.0 μM) was added to bacterial suspensions and the samples were irradiated with white light (40 W m−2) for 270 minutes. Then, the samples were protected from light, aliquots collected at different intervals and the bioluminescence measured. To assess the development of resistance after treatment, bacterial suspensions were exposed to white light (25 minutes), in presence of 5.0 μM of Tri-Py+-Me-PF (99.99% of inactivation) and plated. After the first irradiation period, surviving colonies were collected from the plate and resuspended in PBS. Then, an identical protocol was used and repeated ten times for each bacterium. The results suggest that aPDT using Tri-Py+-Me-PF represents a promising approach to efficiently destroy bacteria since after a single treatment these microorganisms do not recover their viability and after ten generations of partially photosensitized cells neither of the bacteria develop resistance to the photodynamic process

In vitro activity of daptomycin alone and in combination with various antimicrobials against Gram-positive cocci

WOS: 000236102600004PubMed ID: 16572890The increasing prevalence of resistant Gram-positive cocci requires the need to search for more effective agents and synergistic combinations. Forty-two vancomycin-resistant Enterococcus faecium (VREF), 30 methicillin-resistant Staphylococcus aureus (MRSA) and 36 Staphylococcus epidermidis (MRSE) strains were studied. Minimum inhibitory concentrations (MICs) were determined and synergy testing was performed by using E test for daptomycin, ampicillin-sulbactam, piperacillin-tazobactam and ticarcillin-clavulanate against staphylococci; for daptomycin, ampicillin, rifampin, and gentamicin against enterococci. Daptomycin in combination with ampicillin, rifampin, and gentamicin was tested against enterococci; daptomycin in combination with ampicillin-sulbactam, piperacillin-tazobactam, and ticarcillin-clavulanate was tested against staphylococci. Interaction categories were defined by the fractional inhibitory concentration (FIC) index. All Strains of staphylococci and enterococci were susceptible to daptomycin. All three combinations showed synergy against more than 70% of the MRSA strains. Daptomycin in combination with ampicillin, rifampin, and gentamicin against enterococci showed synergies of 64.2%, 57.1% and 21.4%, respectively. This study indicates that daptomycin alone and combined with beta-lactams seems to be effective against MRSA, but further in vitro and in vivo studies on the subject are required before clinical use can be recommended

In vitro Activity of Fluoroquinolones against Common Respiratory Pathogens

The treatment of respiratory infections is often empiric, necessitating the use of agents with a broad range of antimicrobial activity. The fluoroquinolones, having activity against common respiratory pathogens, fit this description. New fluoroquinolones have been developed in an attempt to improve the in vitro activity against a wide variety of respiratory tract pathogens. The objective of the study is to compare in vitro activity of newest fluoroquinolones, gatifloxacin and moxifloxacin, with levofloxacin and ciprofloxacin using three major respiratory pathogens, Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis. Minimum inhibitory concentrations (MICs) of four fluoroquinolones were tested against 93 S pneumoniae, 62 H influenzae and 60 M catarrhalis, ie 215 isolates by the E-test method. National Committee for Clinical Laboratory Standards (NCCLS)-approved interpretive criteria were used throughout. All isolates were susceptible to the tested fluoro-quinolones. Ninety per cent of S pneumoniae strains were inhibited by ciprofloxacin at concentrations of 2 mg/L. The gatifloxacin and moxifloxacin MICs were lower than the ciprofloxacin and levofloxacin MICs against S pneumoniae. In contrast to S pneumoniae, in vitro activities of gatifloxacin and moxifloxacin offered no apparent advantages over ciprofloxacin and levofloxacin for H influenzae and M catarrhalis. "La Actividad in Vitro de las Fluorquinolonas Contra los Patógenos Respiratorios" RESUMEN La terapia de las infecciones respiratorias es a menudo empírica, y exige por ende el uso de agentes con un amplio espectro de actividad antimicrobiana. Por su actividad contra los patógenos respiratorios comunes, las fluorquinolonas se ajustan a esta descripción. Nuevas fluorquinolonas han sido desarrolladas, en un intento por mejorar la actividad in vitro contra una variedad de patógenos de las vías respiratorias. El objetivo de este estudio es comparar la actividad in vitro de las fluorquinolonas más recientes – la gatifloxacina y la moxifloxacina – con la levofloxacina y la ciprofloxacina, usando tres de los más importantes patógenos respiratorios: Streptococcus pneumoniae, Haemophilus influenzae y Moraxella catarrhalis. Las concentraciones inhibitorias mínimas (CIMs) de las cuatro fluorquinolonas fueron sometidas a prueba contra 93 S pneumoniae, 62 H influenzae y 60 M catarrhalis, para un total de 215 aislados mediante el método de E-test. En todos los casos se aplicaron criterios interpretativos aprobados por el Comité Nacional para Normas del Laboratorio Clínico (NCCLS). Todos los aislados resultaron sensibles a las fluorquinolonas ensayadas. El noventa por ciento de las cepas de S pneumoniae fueron inhibidas por la ciprofloxacina a concentrationes of 2 mg/L. Las CIMs de la gatifloxacina y la moxifloxacina fueron más bajas que las CIMs de la ciprofloxacina y la levofloxacina contra S pneumoniae. En contraste con S pneumoniae, la actividad in vitro de la gatifloxacina y la moxifloxacina no ofrecieron ventajas aparentes por encima de la ciprofloxacina y la levofloxacina frente a H influenzae y M catarrhalis

Treatment of CAPD peritonitis with oral trimethoprim/sulfamethoxazole and intraperitoneal aminoglycoside combination [1]

PubMed ID: 10433171[No abstract available