Long-term, continuous infusion of single-agent dinutuximab beta for relapsed/refractory neuroblastoma: an open-label, single-arm, Phase 2 study.

Background: Short-term infusions of dinutuximab beta plus isotretinoin and cytokines administered in previous immunotherapy studies in neuroblastoma were associated with severe pain. Here, long-term, continuous infusion of single-agent dinutuximab beta was evaluated in patients with relapsed/refractory neuroblastoma.

Methods: In this open-label, single-arm, Phase 2 study, patients with either refractory or relapsed high-risk neuroblastoma received dinutuximab beta by continuous infusion over 10 days of each cycle, for up to five cycles.

Immune Response and Outcome of High-Risk Neuroblastoma Patients Immunized with Anti-Idiotypic Antibody Ganglidiomab: Results from Compassionate-Use Treatments.

(1) Background: High-risk neuroblastoma (HR-NB) is associated with a poor prognosis despite a multimodal high-intensity treatment regimen, including immunotherapy with anti-GD2 monoclonal antibodies (mAb). Here, we investigated the effects of an anti-idiotypic vaccine based on the mAb ganglidiomab that structurally mimics GD2. (2) Methods: Patients with HR-NB treated with anti-GD2 mAb dinutuximab beta and who achieved complete remission after frontline or salvage therapy were offered the vaccine (0.

Investigation of the Role of Dinutuximab Beta-Based Immunotherapy in the SIOPEN High-Risk Neuroblastoma 1 Trial (HR-NBL1).

To explore the effects of immunotherapy in the International Society of Paediatric Oncology Europe Neuroblastoma Group SIOPEN high-risk neuroblastoma 1 trial (HR-NBL1 trial), two cohorts were studied: one prior to and one after the introduction of dinutuximab beta. All patients received standard induction and high-dose therapy (HDT) with autologous stem cell rescue (ASCR); the local control comprised surgery and radiotherapy to the primary tumour site, followed by isotretinoin. A landmark timepoint of 109 days, resulting from the median time between ASCR and initiation of immunotherapy, was used to define patients' eligibility in the pre-immunotherapy analysis cohort.

Low CD4⁺/CD25⁺/CD127⁻ regulatory T cell- and high INF-γ levels are associated with improved survival of neuroblastoma patients treated with long-term infusion of ch14.18/CHO combined with interleukin-2.

Immunotherapy with the anti-GD antibody (Ab) ch14.18/CHO in combination with interleukin 2 (IL-2) has improved survival of high-risk neuroblastoma (NB) patients. Here, we report immunotherapy-related effects on circulating NK cells, regulatory T cells (T), granulocytes as well as on Ab-dependent cell-mediated cytotoxicity (ADCC) and cytokines IFN-γ, IL-6, IL-10, IL-18 and CCL2 and their association with progression-free survival (PFS).

Interleukin 2 with anti-GD2 antibody ch14.18/CHO (dinutuximab beta) in patients with high-risk neuroblastoma (HR-NBL1/SIOPEN): a multicentre, randomised, phase 3 trial.

Background: Immunotherapy with the chimeric anti-GD2 monoclonal antibody dinutuximab, combined with alternating granulocyte-macrophage colony-stimulating factor and intravenous interleukin-2 (IL-2), improves survival in patients with high-risk neuroblastoma. We aimed to assess event-free survival after treatment with ch14.18/CHO (dinutuximab beta) and subcutaneous IL-2, compared with dinutuximab beta alone in children and young people with high-risk neuroblastoma.

Impact of HACA on Immunomodulation and Treatment Toxicity Following ch14.18/CHO Long-Term Infusion with Interleukin-2: Results from a SIOPEN Phase 2 Trial.

GD₂-directed immunotherapies improve survival of high-risk neuroblastoma (NB) patients (pts). Treatment with chimeric anti-GD₂ antibodies (Ab), such as ch14.18, can induce development of human anti-chimeric Ab (HACA).

Pilot trial of the hu14.18-IL2 immunocytokine in patients with completely resectable recurrent stage III or stage IV melanoma.

Phase I testing of the hu14.18-IL2 immunocytokine (IC) in melanoma patients showed immune activation, reversible toxicities, and a maximal tolerated dose of 7.5 mg/m/day.

Tumor-Specific Inhibition of Vaccination by Distant Untreated Tumor Sites.

vaccination is an emerging cancer treatment strategy that uses local therapies to stimulate a systemic antitumor immune response. We previously reported an vaccination effect when combining radiation (RT) with intratumor (IT) injection of tumor-specific immunocytokine (IC), a fusion of tumor-specific antibody and IL2 cytokine. In mice bearing two tumors, we initially hypothesized that delivering RT plus IT-IC to the "primary" tumor would induce a systemic antitumor response causing regression of the "secondary" tumor.

Tolerability, response and outcome of high-risk neuroblastoma patients treated with long-term infusion of anti-GD antibody ch14.18/CHO.

Immunotherapy with short term infusion (STI) of monoclonal anti-GD antibody (mAb) ch14.18 (4 × 25 mg/m/d; 8-20 h) in combination with cytokines and 13-cis retinoic acid (RA) prolonged survival in high-risk neuroblastoma (NB) patients. Here, we investigated long-term infusion (LTI) of ch14.

The Combyn™ ECG: Adding haemodynamic and fluid leads for the ECG. Part II: Prediction of total body water (TBW), extracellular fluid (ECF), ECF overload, fat mass (FM) and "dry" appendicular muscle mass (AppMM).

Simultaneous with a 12 channel ECG, body composition was analysed by segmental multi-frequency impedance analysis in 101 healthy subjects and in 118 patients with chronic heart failure (CHF, n= 40), chronic renal failure with haemodialysis (HD, n= 20), and miscellaneous internal diseases (n= 58). Whole body DXA and sodium bromide dilution were used as reference methods for total body water (TBW), extracellular fluid (ECF), appendicular muscle mass (AppMM) and fat mass (FM). Empirical prediction equations were developed in a randomized evaluation sample and then evaluated in unknowns.

Effective Combination of Innate and Adaptive Immunotherapeutic Approaches in a Mouse Melanoma Model.

Most cancer immunotherapies include activation of either innate or adaptive immune responses. We hypothesized that the combined activation of both innate and adaptive immunity will result in better antitumor efficacy. We have previously shown the synergy of an agonistic anti-CD40 mAb (anti-CD40) and CpG-oligodeoxynucleotides in activating macrophages to induce tumor cell killing in mice.

Charge heterogeneity: Basic antibody charge variants with increased binding to Fc receptors.

We identified active isoforms of the chimeric anti-GD2 antibody, ch14.18, a recombinant antibody produced in Chinese hamster ovary cells, which is already used in clinical trials. We separated the antibody by high resolution ion-exchange chromatography with linear pH gradient elution into acidic, main and basic charge variants on a preparative scale yielding enough material for an in-depth study of the sources and the effects of microheterogeneity.

Microheterogeneity of therapeutic monoclonal antibodies is governed by changes in the surface charge of the protein.

It has previously been shown for individual antibodies, that the microheterogenity pattern can have a significant impact on various key characteristics of the product. The aim of this study to get a more generalized understanding of the importance of microheterogeneity. For that purpose, the charge variant pattern of various different commercially available therapeutic mAb products was compared using Cation-Exchange Chromatography with linear pH gradient antigen affinity, Fc-receptor affinity, antibody dependent cellular cytotoxicity (ADCC) and conformational stability.

Pharmacokinetics and pharmacodynamics of ch14.18/CHO in relapsed/refractory high-risk neuroblastoma patients treated by long-term infusion in combination with IL-2.

Ch14.18 manufactured in Chinese hamster ovary (CHO) cells is currently being evaluated in clinical trials. Short-term infusion (STI) (8-20 h/day; 4-5 days) of 100 mg/m2 ch14.

Neutrophil/Lymphocyte ratio has no predictive or prognostic value in breast cancer patients undergoing preoperative systemic therapy.

Background: The primary goal of preoperative systemic treatment (PST) in patients with breast cancer is downsizing of tumors to enhance the rate of breast conserving surgery. Additionally, preoperative systemic treatment offers the possibility to assess for chemosensitivity of early stage disease. In various cancers the prognostic value of neutrophil/lymphocyte ratio (NLR) was demonstrated, indicating that high NLR determines worse prognosis of the patients.

Preoperative neutrophil-to-lymphocyte ratio predicts clinical outcome in patients with stage II and III colon cancer.

Unlabelled: AIM/ BACKGROUND: The neutrophil-to-lymphocyte ratio (NLR), a combined indicator of inflammation and immunology, is as yet unidentified regarding the clinical outcome of stage II and III colon cancer patients. We evaluated the effect of NLR on time-to-recurrence (TTR) and overall survival (OS) in selected patients.

Patients And Methods: A total of 504 patients with stage II and III colon cancer were included in this retrospective study.

Increased neutrophil-lymphocyte ratio is a poor prognostic factor in patients with primary operable and inoperable pancreatic cancer.

Background: The neutrophil-lymphocyte ratio (NLR) has been proposed as an indicator of systemic inflammatory response. Previous findings from small-scale studies revealed conflicting results about its independent prognostic significance with regard to different clinical end points in pancreatic cancer (PC) patients. Therefore, the aim of our study was the external validation of the prognostic significance of NLR in a large cohort of PC patients.

Pharmacokinetics and pharmacodynamics of recombinant human angiotensin-converting enzyme 2 in healthy human subjects.

Background And Objectives: Angiotensin-converting enzyme 2 (ACE2) converts angiotensin II (Ang1-8) to angiotensin 1-7 (Ang1-7), a functional antagonist of Ang1-8, with vasodilatory, antiproliferative, antiangiogenic, and anti-inflammatory properties. In conditions with an unbalanced renin-angiotensin-aldosterone system with elevated Ang1-8, administration of ACE2 has shown promising effects in a variety of animal models. Enhancing ACE2 activity by exogenous administration of ACE2 might also be beneficial in human diseases with pathologically elevated Ang1-8.

Recombinant Expression and Characterization of Human and Murine ACE2: Species-Specific Activation of the Alternative Renin-Angiotensin-System.

Angiotensin-converting enzyme 2 (ACE2) is a monocarboxypeptidase of the renin-angiotensin-system (RAS) which is known to cleave several substrates among vasoactive peptides. Its preferred substrate is Angiotensin II, which is tightly involved in the regulation of important physiological functions including fluid homeostasis and blood pressure. Ang 1-7, the main enzymatic product of ACE2, became increasingly important in the literature in recent years, as it was reported to counteract hypertensive and fibrotic actions of Angiotensin II via the MAS receptor.

Recombinant angiotensin-converting enzyme 2 suppresses pulmonary vasoconstriction in acute hypoxia.

Objective: Alveolar hypoxia as a result of high altitude leads to increased pulmonary arterial pressure. The renin-angiotensin system is involved in the regulation of pulmonary arterial pressure through angiotensin-converting enzyme 2 (ACE2). It remains unknown whether ACE2 administration alters pulmonary vascular pressure in hypoxia.

Angiotensin converting enzyme 2 abrogates bleomycin-induced lung injury.

Despite substantial progress, mortality and morbidity of the acute respiratory distress syndrome (ARDS), a severe form of acute lung injury (ALI), remain unacceptably high. There is no effective treatment for ARDS/ALI. The renin-angiotensin system (RAS) through Angiotensin-converting enzyme (ACE)-generated Angiotensin II contributes to lung injury.

Cytoskeletal defects in Bmpr2-associated pulmonary arterial hypertension.

The heritable form of pulmonary arterial hypertension (PAH) is typically caused by a mutation in bone morphogenic protein receptor type 2 (BMPR2), and mice expressing Bmpr2 mutations develop PAH with features similar to human disease. BMPR2 is known to interact with the cytoskeleton, and human array studies in PAH patients confirm alterations in cytoskeletal pathways. The goal of this study was to evaluate cytoskeletal defects in BMPR2-associated PAH.

Prevention of angiotensin II-mediated renal oxidative stress, inflammation, and fibrosis by angiotensin-converting enzyme 2.

Angiotensin-converting enzyme 2 (ACE2) is a monocarboxypeptidase capable of metabolizing angiotensin (Ang) II into Ang 1 to 7. We hypothesized that ACE2 is a negative regulator of Ang II signaling and its adverse effects on the kidneys. Ang II infusion (1.

Telmisartan attenuates aortic hypertrophy in hypertensive rats by the modulation of ACE2 and profilin-1 expression.

Profilin-1 has recently been linked to vascular hypertrophy and remodeling. Here, we assessed the hypothesis that angiotensin (Ang) II type I receptor antagonist telmisartan improves vascular hypertrophy by modulation of expression of profilin-1 and angiotensin-converting enzyme 2 (ACE2). Ten-week-old male spontaneously hypertensive rats (SHR) were received oral administration of telmisartan (5 or 10mg/kg; daily) or saline for 10 weeks.