Fatal Septic Shock Research Articles

A Phase 1 Study of ACTR087 in Combination with Rituximab, in Subjects with Relapsed or Refractory CD20-Positive B-Cell Lymphoma

Background: The Antibody-Coupled T-cell Receptor (ACTR) platform is an autologous engineered T-cell therapy that combines the cell-killing ability of T cells and the tumor-targeting ability of co-administered antibodies to exert potent antitumor immune responses. ACTR087 comprises the extracellular domain of CD16 linked to a CD3ζ-signaling domain and a 4-1BB co-stimulatory domain. Here we present the clinical experience from Study ATTCK-20-2 (NCT02776813), a multicenter, phase 1 study of ACTR087 in combination with rituximab in subjects with relapsed or refractory (R/R) CD20+ NHL. Methods: The main objectives of this first-in-human study were to evaluate the safety and antitumor activity of ACTR087+rituximab. Other objectives included evaluating ACTR T-cell persistence and other correlative biomarkers. Subjects must have had CD20+ NHL that was R/R after prior treatments, which must have included anti-CD20 antibody-containing chemotherapy. Subjects received lymphodepleting chemotherapy (cyclophosphamide and fludarabine) for 3 days, followed by rituximab and a single dose of ACTR087. Additional doses of rituximab were administered q3w until disease progression, unacceptable toxicity, or Investigator decision. The study included a dose escalation phase (increasing doses of ACTR087) and an expansion phase (ACTR087 at the preliminary recommended phase 2 dose [RP2D]); all subjects received rituximab at a fixed dose of 375 mg/m2 q3w. Results: Two dose levels (DL) of ACTR087 were evaluated during dose escalation (n=17). The MTD was exceeded at DL2, with severe cases of cytokine release syndrome (CRS) and neurotoxicity. Statistical analysis of the relationship between non-hematologic toxicity and ACTR+ T-cell doses was retrospectively performed (two-parameter Bayesian logistic regression model) to estimate an RP2D of 35×106 ACTR+ T cells. Nine subjects enrolled in an expansion cohort and received ACTR087 at this RP2D in combination with rituximab. Among all subjects treated (n=26), the majority (69%) were diagnosed with DLBCL. Subjects had received a median of 3 (range 1-9) prior lines of therapy, with 77% having received ≥3 prior lines. ACTR087 showed dose-dependent expansion with peak levels generally observed 7 to 14 days post administration. In subjects with ongoing clinical response (CR), ACTR remained detectable through the last timepoint evaluated. Across all cohorts, Grade ≥3 TEAEs reported in >3 subjects regardless of causality were limited to hematologic events. Potential T cell-mediated toxicities were observed, including 4 serious cases of CRS (Gr 4 in 2 subjects, both with fatal sepsis) and 2 serious cases of neurotoxicity (1 Gr 5, 1 Gr 4 in a subject with fatal septic shock). Elevated baseline inflammatory markers (eg, ferritin, CRP) were observed in patients who developed Gr ≥3 CRS and neurotoxicity post ACTR087. Of note, severe CRS presented without fever and events occurred >7 days post ACTR087. Clinical activity was reported with an ORR of 50% in all dose levels tested, including durable complete responses, with one subject in CR for 869+ days (Table 1). Conclusions: ACTR087+rituximab demonstrated antitumor activity, with observed safety events that are expected with other autologous T-cell products. The time to onset and clinical presentation of severe CRS and neurotoxicity events in this study informed the safety monitoring and adverse reaction management guidance across clinical studies of ACTR T-cell products. Data from this first-in-human study of ACTR087+rituximab confirm the proof of concept and will be used to guide further development for the ACTR platform. Updated clinical data, as well as expanded biomarker correlations to efficacy and safety, will be presented. Disclosures Munoz: Pharmacyclics /Janssen: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy; Fosunkite: Speakers Bureau; AstraZeneca: Speakers Bureau; Kyowa: Consultancy, Honoraria, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene/Juno: Consultancy, Research Funding; Genentech: Consultancy, Research Funding, Speakers Bureau; Kite/Gilead: Consultancy, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy; Alexion: Consultancy; Portola: Research Funding; Incyte: Research Funding; Bayer: Consultancy, Speakers Bureau; Merck: Consultancy. Jaglowski:Kite: Consultancy, Other: advisory board, Research Funding; Novartis: Consultancy, Other: advisory board, Research Funding; Unum Therapeutics Inc.: Research Funding; Juno: Consultancy, Other: advisory board. Isufi:Celgene: Consultancy; Novartis: Consultancy; Astra Zeneca: Consultancy. Stiff:Gamida-Cell: Research Funding; Incyte: Research Funding; Cellectar: Research Funding; Unum: Research Funding; Gilead/Kite Pharma: Consultancy, Honoraria, Research Funding; Amgen: Research Funding. Sachs:Unum Therapeutics Inc.: Employment. Ranger:Unum Therapeutics Inc.: Employment. Harris:Unum Therapeutics Inc.: Employment. Payumo:Unum Therapeutics Inc.: Employment. Akard:Bristol-Myers Squibb: Speakers Bureau; Gilead: Speakers Bureau; Takeda: Speakers Bureau; Novartis: Speakers Bureau; Celgene: Speakers Bureau.

Antibiotic-Resistant Septicemia in Pediatric Oncology Patients Associated with Post-Therapeutic Neutropenic Fever.

Death in cancer patients can be caused by the progression of tumors, their malignity, or other associated conditions such as sepsis, which is a multiphasic host response to a pathogen that can be significantly amplified by endogenous factors. Its incidence is continuously rising, which reflects the increasing number of sick patients at a higher risk of infection, especially those that are elderly, pediatric, or immunosuppressed. Sepsis appears to be directly associated with oncological treatment and fatal septic shock. Patients with a cancer diagnosis face a much higher risk of infections after being immunosuppressed by chemotherapy, radiotherapy, or anti-inflammatory therapy, especially caused by non-pathogenic, Gram-negative, and multidrug-resistant pathogens. There is a notorious difference between the incidence and mortality rates related to sepsis in pediatric oncologic patients between developed and developing countries: they are much higher in developing countries, where investment for diagnosis and treatment resources, infrastructure, medical specialists, cancer-related control programs, and post-therapeutic care is insufficient. This situation not only limits but also reduces the life expectancy of treated pediatric oncologic patients, and demands higher costs from the healthcare systems. Therefore, efforts must aim to limit the progression of sepsis conditions, applying the most recommended therapeutic regimens as soon as the initial risk factors are clinically evident—or even before they are, as when taking advantage of machine learning prediction systems to analyze data.

Fatal Sepsis and Septic Shock Secondary to Aeromonas hydrophila Pneumonia: Report of a Case and Review of the Literature

Fatal Sepsis and Septic Shock Secondary to Aeromonas hydrophila Pneumonia: Report of a Case and Review of the Literature

Monomicrobial non-neutrocytic bacterascites caused by aeromonas hydrophila in a patient with liver cirrhosis.

Aeromonas peritonitis is a rare, but serious infection, as associated with spontaneous bacterial peritonitis, peritonitis in chronic ambulatory peritoneal dialysis, and intestinal perforation. Here, we reported a case of monomicrobial non-neutrocytic bacterascites caused by Aeromonas hydrophila (A. hydrophila). The patient, a 57-year-old man who had a history of alcoholic liver disease and chronic hepatitis C-related Child- Pugh class C liver cirrhosis, was admitted to our hospital with fever, dyspnea and a localized wound pain over left ankle. Ascitic fluid analysis demonstrated that ascitic polymorphonuclear cell count was 30 cells/ mm3. Empirical antimicrobial treatment with a combination of ceftriaxone and clindamycin were administered. However, the patient died due to fatal septic shock on Day 3. His blood and ascites cultures were positive for A. hydrophila. The case report presents the diagnosis, management, and literature review of Aeromonas monomicrobial non-neutrocytic bacterascites.

A Case of Fatal Sepsis from Dog Exposure in a Young Stem Cell Transplant Patient

Capnocytophaga canimorsus is a fastidious, slow growing (up to 10 days), capnophillic gram-negative rod. It is most commonly associated with zoonotic exposure, particularly dog and cat bites. There is a growing body of literature for the recognition of septic shock caused by Capnocytophagia canimorsus in at-risk populations, including those with asplenia as well as current or previous hematologic malignancy. This is a case of a young man in remission from a hematologic malignancy, complicated by graft versus host disease, presenting many years later in fatal septic shock due to Capnocytophagia canimorsus infection.

Prophylactic Control Of Mycoplasma Contamination In Starting Biological Materials Used In Viral Vaccine Production

Mycoplasma contamination remains a major concern in the biopharmaceutical industry especially in tissue culture based viral vaccine and its presence and/or its endotoxin-like metabolites in the final products can result in pyrogenic responses ranging from fever and chills, to irreversible and fatal septic shock. This study was conducted by in vitro screening of mycoplasma in the different ingredients used in production of Foot and mouth Disease (FMD) vaccine using Polymerase Chain Reaction (PCR) using universal primers that are specific to the 16S rRNA region. Tested items include growth media, cell lines, trypsin, seed virus and working virus. Also the study evaluates the inhibitory effect of different concentrations of neomycin, kanamycin, gentamycin, polymyxin B and ciprofloxacin on mycoplasma contaminated cell lines. Our results showed that the prepared growth media, trypsin, seed virus as well as working virus were mycoplasma free and three tested cell lines were also free while another two lines were mycoplasma positive. The mycoplasma positive cell line are poorly grown in comparison with the free line using the same growth media and the virus yield from the apparently normal contaminated line was very low. Ciprofloxacin can be used for treating valuable cell line after 12 days in 25mg/L and after 18 days in 10mg/L. Ciprofloxacin plus regular antibiotic may keep the line sterile for prolonged time but treatment of contaminated cell line is not advisable. So, prophylactic control by strict personal hygiene and personal protective equipment (PPE) and adopt appropriate aseptic techniques is the core solution.

Current Progress in the Structural and Biochemical Characterization of Proteins Involved in the Assembly of Lipopolysaccharide.

The lipid component of the outer leaflet of the outer membrane of Gram-negative bacteria is primarily composed of the glycolipid lipopolysaccharide (LPS), which serves to form a protective barrier against hydrophobic toxins and many antibiotics. LPS is comprised of three regions: the lipid A membrane anchor, the nonrepeating core oligosaccharide, and the repeating O-antigen polysaccharide. The lipid A portion is also referred to as endotoxin as its overstimulation of the toll-like receptor 4 during systemic infection precipitates potentially fatal septic shock. Because of the importance of LPS for the viability and virulence of human pathogens, understanding how LPS is synthesized and transported to the outer leaflet of the outer membrane is important for developing novel antibiotics to combat resistant Gram-negative strains. The following review describes the current state of our understanding of the proteins responsible for the synthesis and transport of LPS with an emphasis on the contribution of protein structures to our understanding of their functions. Because the lipid A portion of LPS is relatively well conserved, a detailed description of the biosynthetic enzymes in the Raetz pathway of lipid A synthesis is provided. Conversely, less well-conserved biosynthetic enzymes later in LPS synthesis are described primarily to demonstrate conserved principles of LPS synthesis. Finally, the conserved LPS transport systems are described in detail.

Characterization of three strains of Capnocytophaga canis isolated from patients with sepsis.

Capnocytophaga canimorsus and Capnocytophaga cynodegmi, both commensal bacteria in the oral cavities of dogs and cats, are zoonotic pathogens. In particular, C. canimorsus causes sepsis and fatal septic shock. Recently, a novel Capnocytophaga species, C. canis, was isolated from the oral cavities of healthy dogs. It is reportedly oxidase-negative and therefore considered avirulent in humans. In the present study, three strains of C. canis were isolated from Japanese patients with sepsis. All three strains, HP20001, HP33001 and HP40001, were oxidase-positive. Nucleotide sequence identities of the 16S rRNA gene of the three strains to the C. canimorsus type strain ATCC35979, C. cynodegmi type strain ATCC49044 and C. canis type strain LMG29146 were 96.9-97.0%, 96.9-97.0% and 99.7-99.8%, respectively. Multi-locus sequence analysis based on seven house-keeping genes, dnaJ, fumC, glyA, gyrB, murG, trpB and tuf, revealed that the oxidase-positive C. canis strains isolated in Japan and oxidase-negative strains of C. canis from canine oral cavities in Switzerland were clustered in different genetic subgroups. These results indicate that the virulence of C. canis strains in humans is associated with oxidase activity.

Raoultella planticola bacteremia-induced fatal septic shock following burn injury

BackgroundRaoultella planticola, a Gram-negative, aerobic bacillus commonly isolated from soil and water, rarely causes invasive infections in humans. Septic shock from R. planticola after burn injury has not been previously reported.Case presentationA 79-year-old male was admitted to the emergency intensive care unit after extensive flame burn injury. He accidently caught fire while burning trash and plunged into a nearby tank filled with contaminated rainwater to extinguish the fire. The patient developed septic shock on day 10. The blood culture detected R. planticola, which was identified using the VITEK-2 biochemical identification system. Although appropriate antibiotic treatment was continued, the patient died on day 12.ConclusionsClinicians should be aware of fatal infections in patients with burn injury complicated by exposure to contaminated water.

Infection fulminante fatale à Capnocytophaga canimorsus : à propos d’un cas et revue de la littérature

IntroductionCapnocytophaga canimorsus is a Gram-negative bacterium present in normal dogs and cats mouths. It can be responsible for septic shocks after dog or cat bite, especially in asplenic patients. Case reportWe report here a case of C. canimorsus infection rapidly presenting as a multiple organ dysfonction syndrome in an immunocompetent 54 years old patient, who lives near a dog, without any sign of bite. The evolution was a rapidly fatal fulminant septic shock. ConclusionAmong patients with a septic shock of unknown etiology, fatal evolution due to C. canimorsus should be avoided by systematic use of early antibiotherapy with amoxicilline and clavulanic acid, especially in patients who live near a pet, even if they are immunocompetent.

Whole-Genome-Sequencing characterization of bloodstream infection-causing hypervirulent Klebsiella pneumoniae of capsular serotype K2 and ST374

ABSTRACT Hypervirulent K. pneumoniae variants (hvKP) have been increasingly reported worldwide, causing metastasis of severe infections such as liver abscesses and bacteremia. The capsular serotype K2 hvKP strains show diverse multi-locus sequence types (MLSTs), but with limited genetics and virulence information. In this study, we report a hypermucoviscous K. pneumoniae strain, RJF293, isolated from a human bloodstream sample in a Chinese hospital. It caused a metastatic infection and fatal septic shock in a critical patient. The microbiological features and genetic background were investigated with multiple approaches. The Strain RJF293 was determined to be multilocis sequence type (ST) 374 and serotype K2, displayed a median lethal dose (LD50) of 1.5 × 102 CFU in BALB/c mice and was as virulent as the ST23 K1 serotype hvKP strain NTUH-K2044 in a mouse lethality assay. Whole genome sequencing revealed that the RJF293 genome codes for 32 putative virulence factors and exhibits a unique presence/absence pattern in comparison to the other 105 completely sequenced K. pneumoniae genomes. Whole genome SNP-based phylogenetic analysis revealed that strain RJF293 formed a single clade, distant from those containing either ST66 or ST86 hvKP. Compared to the other sequenced hvKP chromosomes, RJF293 contains several strain-variable regions, including one prophage, one ICEKp1 family integrative and conjugative element and six large genomic islands. The sequencing of the first complete genome of an ST374 K2 hvKP clinical strain should reinforce our understanding of the epidemiology and virulence mechanisms of this bloodstream infection-causing hvKP with clinical significance.

Peripheral blood vessels are a niche for blood-borne meningococci

ABSTRACT Neisseria meningitidis is the causative agent of cerebrospinal meningitis and that of a rapidly progressing fatal septic shock known as purpura fulminans. Meningococcemia is characterized by bacterial adhesion to human endothelial cells of the microvessels. Host specificity has hampered studies on the role of blood vessels colonization in N. meningitidis associated pathogenesis. In this work, using a humanized model of SCID mice allowing the study of bacterial adhesion to human cells in an in vivo context we demonstrate that meningococcal colonization of human blood vessels is a prerequisite to the establishment of sepsis and lethality. To identify the molecular pathways involved in bacterial virulence, we performed transposon insertion site sequencing (Tn-seq) in vivo. Our results demonstrate that 36% of the genes that are important for growth in the blood of mice are dispensable when bacteria colonize human blood vessels, suggesting that human endothelial cells lining the blood vessels are feeding niches for N. meningitidis in vivo. Altogether, our work proposes a new paradigm for meningococcal virulence in which colonization of blood vessels is associated with metabolic adaptation and sustained bacteremia responsible for sepsis and subsequent lethality.

Perivalvular Mitral Abscess Fistulised to the Pericardial Cavity Revealing Staphylococcal Endocarditis

Fistula to the pericardial cavity is a very rare complication of perivalvular abscess during infective endocarditis, with Staphylococcus aureus being the most commonly associated microorganism. We report a fatal septic shock due to a mitral endocarditis revealed by a myocardial abscess fistulised toward the pericardial cavity. A 66-year-old female without previous valvular disease was admitted to intensive care for severe sepsis. A few hours after admission, an unexpected cardiac arrest occurred. Chest computed tomographic-scan and transoesophageal echocardiography revealed a pericardial effusion due to a perivalvular mitral abscess fistulised toward the pericardial cavity. Despite prompt management including surgical debridement and appropriate antibiotics, death occurred 36hours after intensive care admission. All blood cultures as well as native mitral valve and pericardial fluid grew methicillin-sensitive Staphylococcus aureus. Intensivists should consider this rare complication in patients with staphylococcal infective endocarditis and perivalvular abscess.

Melioidosis in Malaysia: A Review of Case Reports.

BackgroundMelioidosis is a tropical infectious disease associated with significant mortality due to early onset of sepsis.ObjectiveWe sought to review case reports of melioidosis from Malaysia.MethodsWe conducted a computerized search of literature resources including PubMed, OVID, Scopus, MEDLINE and the COCHRANE database to identify published case reports from 1975 to 2015. We abstracted information on clinical characteristics, exposure history, comorbid conditions, management and outcome.ResultsOverall, 67 cases were reported with 29 (43%) deaths; the median age was 44 years, and a male preponderance (84%) was noted. Forty-one cases (61%) were bacteremic, and fatal septic shock occurred in 13 (19%) within 24–48 hours of admission; nine of the 13 cases were not specifically treated for melioidosis as confirmatory evidence was available only after death. Diabetes mellitus (n = 36, 54%) was the most common risk factor. Twenty-six cases (39%) had a history of exposure to contaminated soil/water or employment in high-risk occupations. Pneumonia (n = 24, 36%) was the most common primary clinical presentation followed by soft tissue abscess (n = 22, 33%). Other types of clinical presentations were less common—genitourinary (n = 5), neurological (n = 5), osteomyelitis/septic arthritis (n = 4) and skin (n = 2); five cases had no evidence of a focus of infection. With regard to internal foci of infection, abscesses of the subcutaneous tissue (n = 14, 21%) was the most common followed by liver (18%); abscesses of the spleen and lung were the third most common (12% each). Seven of 56 males were reported to have prostatic abscesses. Mycotic pseudoaneurysm occurred in five cases. Only one case of parotid abscess was reported in an adult. Of the 67 cases, 13 were children (≤ 18 years of age) with seven deaths; five of the 13 were neonates presenting primarily with bronchopneumonia, four of whom died. Older children had a similar presentation as adults; no case of parotid abscess was reported among children.ConclusionsThe clinical patterns of cases reported from Malaysia are consistent for the most part from previous case reports from South and Southeast Asia with regard to common primary presentations of pneumonia and soft tissue abscesses, and diabetes as a major risk factor. Bacteremic melioidosis carried a poor prognosis and septic shock was strong predictor of mortality. Differences included the occurrence of: primary neurological infection was higher in Malaysia compared to reports outside Malaysia; internal foci of infection such as abscesses of the liver, spleen, prostate, and mycotic pseudoaneurysms were higher than previously reported in the region. No parotid abscess was reported among children. Early recognition of the disease is the cornerstone of management. In clinical situations of community-acquired sepsis and/or pneumonia, where laboratory bacteriological confirmation is not possible, empirical treatment with antimicrobials for B. pseudomallei is recommended.

Ruxolitinib Plus Pomalidomide in Myelofibrosis: Updated Results from the Mpnsg-0212 Trial (NCT01644110)

Background: Although ruxolitinib (RUX) reduces constitutional symptoms and splenomegaly in myelofibrosis (MF) therapy options for anemia are limited. In our prior MPNSG-0109 trial of pomalidomide (POM) in MF with cytopenia, anemia responses were reported in 14% and 29% of subjects receiving POM 0.5 mg/d and 2 mg/d, respectively (Schlenk RF et al., ASH 2013, abstract #2822). We designed a phase-Ib/-II combination study of RUX plus POM to evaluate synergistic effects in subjects with anemia and splenomegaly (MPNSG-0212 trial, NCT01644110; Stegelmann et al., ASH 2015, abstract #826).Study Design: Primary endpoints are response rate after 12 treatment cycles (28 days each) according to IWG-MRT criteria (Tefferi et al., Blood 2006) and achievement of RBC transfusion independence (Gale et al., Leuk Res 2011). Secondary endpoints are safety, quality-of-life, progression-free survival (PFS) and survival. Main inclusion criterion is pre-treated or untreated MF with anemia (Hb <10 g/dL and/or RBC transfusion dependence). Key exclusion criteria are transplant-eligibility, platelets <100x10E+9/L and neutrophils <0.5x10E+9/L). POM is given at 0.5 mg/d QD. RUX is started at 10 mg BID with dose modifications to optimize efficacy and to manage toxicity. According to a 2-stage design, 37 subjects will be tested in the 1st cohort before starting a 2ndcohort of 38 subjects.Results: Data from 37 subjects are reported. Median age was 73 years (range, 49-83 years). 17 subjects (46%) previously received therapy such as hydroxyurea, ruxolitinib, EPO, pomalidomide, and/or steroids. Median hemoglobin at study entry was 8.6 g/dL (range, 5.4-11.7 g/dL); 11 subjects (30%) were RBC-transfusion-dependent. Median spleen size by ultrasound was 18 cm (range, 13-28 cm). 29 subjects (78%) had constitutional symptoms at baseline; 25 (68%) were intermediate-2 risk and 9 (24%) high-risk according to the ´Dynamic International Prognostic Scoring System´ (DIPSS). Adverse prognosis of the study cohort was underlined by the detection of one or more high-molecular risk markers in 21 subjects (57%) [i.e. mutation in ASXL1, EZH2, IDH1/2 and/or SRSF2].Median time on-treatment is 11 cycles (range, 1-26 cycles). 563 adverse events (AE) of any grade (CTCAE 1-5) were recorded. Worsening of anemia within the first 6 cycles was the most frequent AE occurring in 13 subjects (35%) followed by fatigue in 11 (30%). Treatment interruptions and dose reductions of RUX and/or POM were rare. There were 26 serious AE (SAE) CTCAE grade 2-5. Pneumonia (N=3), leukemia transformation (N=3), thoracic pain (N=3), abdominal pain (N=2) and septic shock (N=2) occurred in 13 subjects (35%) of which 4 were fatal (cardiac decompensation, pneumonia, and septic shock [N=2]). Only 2 SAE (hemoglobin, grade 4 and neuropathy, grade 3) were considered therapy-related.18 subjects (49%) are on-study treatment; 19 (51%) discontinued because of AE (N=5), leukemia transformation (N=3), stable disease (SD) without objective response after 12 cycles (N=4), death (N=3) or withdrawal of consent (N=3). 6 subjects (16%) responded with spleen reduction (N=3) or ≥2 mg/dL hemoglobin increase / RBC transfusion independence (N=3). Mean hemoglobin increased from 8.6 g/dL at baseline to 9.3 g/dL at the end of cycle 12. 12 subjects (32%) continued treatment after cycle 12 because of response or SD plus clinical benefit (hemoglobin increase <2g/dL or prolongation of RBC-transfusion intervals and/or improvement of symptoms). 3 subjects (8%) are on treatment for >24 cycles.Conclusions: Combined RUX and POM was safe and feasible and achieved an objective response rate of 16%. One third of the subjects had clinical benefit with the combination therapy. Based on these results and our MPNSG-0109 data a step-wise increase of POM dose to 2 mg QD is intended for the 2nd study cohort to further improve anemia response. DisclosuresKoschmieder:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. von Bubnoff:Amgen: Honoraria; Novartis: Honoraria, Research Funding; BMS: Honoraria. Hochhaus:Pfizer: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; ARIAD: Honoraria, Research Funding. Scheid:Janssen: Other: funding outside this work; Celgene: Other: funding outside this work; Novartis: Other: funding outside this work. Schlenk:Pfizer: Honoraria, Research Funding; Amgen: Research Funding.

Subcutaneous Injections of IMMU-114 (Anti-HLA-DR IgG4 Monoclonal Antibody): Initial Results of a Phase I First-in-Man Study in Hematologic Malignancies

Introduction. HLA-DR is expressed in non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL), and other B-cell malignancies at significantly higher levels than typical B-cell markers, including CD20. Prior attempts to develop anti-HLA-DR antibodies in this population have been hampered by toxicity, notably infusion-related toxicities (Lin et al, Leuk Lymphoma, 2009). In preclinical studies, a novel anti-HLA-DR IgG4 antibody, L243, was consistently more cytotoxic than rituximab in the cell lines studied, with minimal CDC and ADCC, but activating internal signaling and inducing apoptosis via the AKT survival pathway (Stein et al, Blood, 2006 & 2010). After demonstrating safety in canine lymphoma (Stein et al, Leuk Lymphoma, 2011), this Phase I first-in-man study was undertaken to evaluate IMMU-114 (humanized L243) administered via subcutaneous (SQ) injection in patients with B-cell NHL or CLL.Methods. Eligible patients had recurrent/relapsed NHL/CLL with at least one prior therapy, ECOG performance status <3, normal baseline renal and liver function, with platelets ≥ 50,000/mm3 and ANC ≥ 1000/mm3. Cohorts of 3-6 patients received 200 mg IMMU-114 administered once-, twice-, or thrice-weekly for the first 3 weeks of a 4-week cycle. All patients received 2 consecutive treatment cycles, followed 4 weeks later by elective maintenance therapy (one week of treatment every 4 weeks x 4). NCI-CTCAE v. 4.0 was used to grade adverse events (AEs). Treatment response was assessed 4 weeks after cycle 2, then every 3 months until progression, using 2007 IWG-NHL or 2008 IW-CLL criteria.Results. Eleven patients (46-80 years old) with 2 median prior treatments (range, 1-5; all had received rituximab) have now been treated at dose level (DL) 1 (200 mg weekly, n=3), 2 (400 mg weekly, n=5), and 3 (600 mg weekly, n=3). They had diffuse large B-cell lymphoma (DLBCL, n=5); follicular lymphoma (FL, n=3); CLL (n=1), small lymphocytic lymphoma (SLL, n=1), or marginal zone lymphoma (MZL, n=1). Administration reactions were limited and all were Grade 1-2 events, predominantly injection site erythema. No serious adverse events (SAEs) occurred at DL1 or DL2, but at DL3, one DLBCL patient with unrelated anorexia/hypovolemia withdrew prior to cycle 2 with acute renal failure and fatal gastrointestinal bleeding and one MZL patient developed fatal septic shock after completing cycle 2. Safety laboratories were unremarkable and there has been no evidence of human anti-IMMU-114 antibodies in 5 patients currently evaluated. Circulating leukemic cells in the single CLL patient decreased with each cycle, but normal B-cell changes in the NHL patients were modest. At DL1, 2 DLBCL patients progressed after cycle 2, but one FL patient had stable disease (47% tumor shrinkage, progressing 3 months later after completing maintenance treatment). At DL 2, one DLBCL patient with unrelated pneumonia withdrew after one dose, one DLBCL patient had a partial response (PR, 60% shrinkage, next scan pending), one FL patient progressed after cycle 2, one FL patient achieved a PR (83% shrinkage, continuing now 10 months later), and one CLL patient had an unconfirmed PR during cycle 1 (WBC 84% decreased, progressing after 2 months). At DL3, one patient with SLL progressed after cycle 2 and the other 2 patients with SAEs were not assessed for treatment response. In total, 4/8 (50%) assessable patients (CLL, DLBCL, FL X 2) demonstrated objective evidence of treatment activity.Conclusion. SQ injections of IMMU-114 appears to avoid the significant administration reactions that has limited the development of other anti-HLA-DR antibodies given IV. With lack of toxicity and preliminary efficacy observed at the two lowest dose levels, DL 2 was declared an acceptable choice for subsequent expansion cohorts. While IMMU-114 demonstrated activity in this population relapsed/refractory to rituximab-containing therapies, the presence of short responses in some patients suggests treatment should be maintained beyond 2 cycles. Thus, the dosing scheme is being amended to allow treatment cycles to be repeated until disease progression, with a goal of determining an appropriate dosing schedule for undertaking a phase II study. DisclosuresStephens:Acerta Pharma BV: Research Funding; Immunomedics: Research Funding. Off Label Use: IMMU-114 for treatment of hematologic malignancies. Starodub:Immunomedics: Research Funding. Horne:Immunomedics: Employment. Wegener:Immunomedics: Employment. Goldenberg:Immunomedics, Inc.: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Other: Stock Options, Patents & Royalties. Christian:Celgene: Consultancy; Seattle Genetics: Consultancy, Research Funding; Acerta: Research Funding; Pharmacyclics: Research Funding; Janssen: Research Funding; Immunomedics: Research Funding; Novartis: Other: IDSM.

Capnocytophaga canimorsus: an emerging cause of sepsis, meningitis, and post-splenectomy infection after dog bites.

Newly named in 1989, Capnocytophaga canimorsus is a bacterial pathogen found in the saliva of healthy dogs and cats, and is transmitted to humans principally by dog bites. This review compiled all laboratory-confirmed cases, animal sources, and virulence attributes to describe its epidemiology, clinical features, and pathogenesis. An estimated 484 patients with a median age of 55 years were reported, two-thirds of which were male. The case-fatality rate was about 26%. Its clinical presentations included severe sepsis and fatal septic shock, gangrene of the digits or extremities, high-grade bacteremia, meningitis, endocarditis, and eye infections. Predispositions were prior splenectomy in 59 patients and alcoholism in 58 patients. Dog bites before illness occurred in 60%; additionally, in 27%, there were scratches, licking, or other contact with dogs or cats. Patients with meningitis showed more advanced ages, higher male preponderance, lower mortality, and longer incubation periods after dog bites than patients with sepsis (p < 0.05). Patients with prior splenectomy presented more frequently with high-grade bacteremia than patients with intact spleens (p < 0.05). The organism possesses virulence attributes of catalase and sialidase production, gliding motility, cytotoxin production, and resistance to killing by serum complement due to its unique lipopolysaccharide. Penicillin is the drug of choice, but some practitioners prefer third-generation cephalosporins or beta-lactamase inhibitor combinations. C. canimorsus has emerged as a leading cause of sepsis, particularly post-splenectomy sepsis, and meningitis after dog bites.

Septic shock sera containing circulating histones induce dendritic cell-regulated necrosis in fatal septic shock patients.

Innate immune system alterations, including dendritic cell loss, have been reproducibly observed in patients with septic shock and correlated to adverse outcomes or nosocomial infections. The goal of this study is to better understand the mechanisms behind this observation in order to better assess septic shock pathogenesis. Prospective, controlled experimental study. Research laboratory at an academic medical center. The study enrolled 71 patients, 49 with septic shock and 22 with cardiogenic shock. Seventeen healthy controls served as reference. In vitro monocyte-derived dendritic cells were generated from healthy volunteers. Sera were assessed for their ability to promote in vitro dendritic cell death through flow cytometry detection in each group of patients. The percentage of apoptotic or necrotic dendritic cells was evaluated by annexin-V and propidium iodide staining. We observed that only patients with septic shock and not patients with pure cardiogenic shock were characterized by a rapid and profound loss of circulating dendritic cells. In vitro analysis revealed that sera from patients with septic shock induced higher dendritic cell death compared to normal sera or cardiogenic shock (p<0.005). Sera from surviving patients induced dendritic cell death through a caspase-dependent apoptotic pathway, whereas sera from nonsurviving patients induced dendritic cell-regulated necrosis. Dendritic cell necrosis was not due to necroptosis but was dependent of the presence of circulating histone. The toxicity of histones toward dendritic cell could be prevented by recombinant human activated protein C. Finally, we observed a direct correlation between the levels of circulating histones in patients and the ability of the sera to promote dendritic cell-regulated necrosis. The study demonstrates a differential mechanism of dendritic cell death in patients with septic shock that is dependent on the severity of the disease.

Capnocytophaga canimorsus: Rare cause of Fatal Septic Shock. Case report

Introduction: Capnocytophaga canimorsus is a common bacterium in oral cavity of dogs and cats. Severe sepsis can develop following a dog or cat bite or scratch in susceptible individuals. Main risk factor for severe infections is immune deficit. Case presentation: We describe a case of eighty-one-years old woman with significant comorbidities admitted to the hospital with fever and non-specific symptoms following a fall at home. She was bitten by her dog 3 days prior to admission with a small wound on her hand. She had cardiac arrest with cardiopulmonary resuscitation eleven hours after admission and died ten hours later in ICU from refractory septic shock. PCR confirmed C. canimorsus as a causative organism. Conclusions: Severe infections caused by C. canimorsus can develop following a bite or a scratch by dog or cat. Fulminant sepsis with fatal outcome can rapidly evolve and the main risk factor among patient population is present immune deficiency. Clinicians should be aware of this fact and any person at risk presenting to the hospital with recent bite or scratch injury by dog or cat should be given adequate antibiotic treatment.

Pathogenic Neisseria meningitidis utilizes CD147 for vascular colonization.

Neisseria meningitidis is a cause of meningitis epidemics worldwide and of rapidly progressing fatal septic shock. A crucial step in the pathogenesis of invasive meningococcal infections is the adhesion of bloodborne meningococci to both peripheral and brain endothelia, leading to major vascular dysfunction. Initial adhesion of pathogenic strains to endothelial cells relies on meningococcal type IV pili, but the endothelial receptor for bacterial adhesion remains unknown. Here, we report that the immunoglobulin superfamily member CD147 (also called extracellular matrix metalloproteinase inducer (EMMPRIN) or Basigin) is a critical host receptor for the meningococcal pilus components PilE and PilV. Interfering with this interaction potently inhibited the primary attachment of meningococci to human endothelial cells in vitro and prevented colonization of vessels in human brain tissue explants ex vivo and in humanized mice in vivo. These findings establish the molecular events by which meningococci target human endothelia, and they open new perspectives for treatment and prevention of meningococcus-induced vascular dysfunctions.