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The Effects of Recombinant Human Lactoferrin on Immune Activation and the Intestinal Microbiome Among Persons Living with Human Immunodeficiency Virus and Receiving Antiretroviral Therapy.
Sortino, O, Hullsiek, KH, Richards, E, Rupert, A, Schminke, A, Tetekpor, N, Quinones, M, Prosser, R, Schacker, T, Sereti, I, et al
The Journal of infectious diseases. 2019;(12):1963-1968
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Abstract
Lactoferrin modulates mucosal immunity and targets mechanisms contributing to inflammation during human immunodeficiency virus disease. A randomized placebo-controlled crossover clinical trial of recombinant human (rh) lactoferrin was conducted among 54 human immunodeficiency virus-infected participants with viral suppression. Outcomes were tolerability, inflammatory, and immunologic measures, and the intestinal microbiome. The median age was 51 years, and the median CD4+ cell count was 651/µL. Adherence and adverse events did not differ between rh-lactoferrin and placebo. There was no significant effect on plasma interleukin-6 or D-dimer levels, nor on monocyte/T-cell activation, mucosal integrity, or intestinal microbiota diversity. Oral administration of rh-lactoferrin was safe but did not reduce inflammation and immune activation. Clinical Trials Registration: NCT01830595.
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IL-1 blockade in autoinflammatory syndromes.
Jesus, AA, Goldbach-Mansky, R
Annual review of medicine. 2014;:223-44
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Abstract
Monogenic autoinflammatory syndromes present with excessive systemic inflammation including fever, rashes, arthritis, and organ-specific inflammation and are caused by defects in single genes encoding proteins that regulate innate inflammatory pathways. Pathogenic variants in two interleukin-1 (IL-1)-regulating genes, NLRP3 and IL1RN, cause two severe and early-onset autoinflammatory syndromes, CAPS (cryopyrin associated periodic syndromes) and DIRA (deficiency of IL-1 receptor antagonist). The discovery of the mutations that cause CAPS and DIRA led to clinical and basic research that uncovered the key role of IL-1 in an extended spectrum of immune dysregulatory conditions. NLRP3 encodes cryopyrin, an intracellular "molecular sensor" that forms a multimolecular platform, the NLRP3 inflammasome, which links "danger recognition" to the activation of the proinflammatory cytokine IL-1β. The success and safety profile of drugs targeting IL -1 in the treatment of CAPS and DIRA have encouraged their wider use in other autoinflammatory syndromes including the classic hereditary periodic fever syndromes (familial Mediterranean fever, TNF receptor-associated periodic syndrome, and hyperimmunoglobulinemia D with periodic fever syndrome) and additional immune dysregulatory conditions that are not genetically well defined, including Still's, Behcet's, and Schnitzler diseases. The fact that the accumulation of metabolic substrates such as monosodium urate, ceramide, cholesterol, and glucose can trigger the NLRP3 inflammasome connects metabolic stress to IL-1β-mediated inflammation and provides a rationale for therapeutically targeting IL-1 in prevalent diseases such as gout, diabetes mellitus, and coronary artery disease.
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Romiplostim: a review of its use in immune thrombocytopenia.
Keating, GM
Drugs. 2012;(3):415-35
Abstract
Romiplostim (Nplate®) is an Fc-peptide fusion protein (peptibody) that acts as a thrombopoietin receptor agonist; it has no amino acid sequence homology with endogenous thrombopoietin. This article reviews the clinical efficacy and tolerability of subcutaneous romiplostim in adults with immune thrombocytopenia (ITP), as well as summarizing its pharmacological properties. The efficacy of 12 or 24 weeks' therapy with subcutaneous romiplostim was compared with that of placebo in patients with ITP in three randomized, double-blind, multicentre, phase III trials. In the two 24-week trials, the durable platelet response rate (primary endpoint) was significantly higher with romiplostim than with placebo in both splenectomized and nonsplenectomized patients. In addition, the majority of romiplostim recipients were able to discontinue or reduce their concurrent ITP therapy, and romiplostim improved health-related quality of life (HR-QOL). In the 12-week trial in splenectomized or nonsplenectomized Japanese patients with ITP, the median number of weeks with a platelet response (primary endpoint) was significantly higher with romiplostim than with placebo. Two extension studies (with median durations of romiplostim treatment of 78 and 100 weeks) demonstrated that long-term therapy with romiplostim maintained platelet counts in the target range in patients with ITP. In a randomized, open-label, multicentre, 52-week, phase IIIb trial, romiplostim was more effective than the medical standard of care in nonsplenectomized patients with ITP who had received at least one prior ITP treatment. Significantly fewer patients receiving romiplostim versus the medical standard of care experienced treatment failure or required splenectomy (co-primary endpoints), and clinically meaningful improvements from baseline in HR-QOL scores were seen with romiplostim. Subcutaneous romiplostim was generally well tolerated in patients with ITP; in short-term trials, the majority of adverse events were of mild to moderate severity and appeared to be related to the underlying thrombocytopenia. The incidence of bleeding events of at least grade 3 severity did not significantly differ between romiplostim and placebo recipients, and was significantly lower with romiplostim than with the medical standard of care. Romiplostim did not appear to be associated with an increased risk of haematological malignancies or an increased risk of thrombotic events. Although binding antibodies against romiplostim or thrombopoietin developed in some romiplostim recipients, with neutralizing antibodies to romiplostim detected in two romiplostim recipients, antibodies cross reacting to thrombopoietin have not been detected. Romiplostim was associated with modest increases in bone marrow reticulin in some patients with ITP; reductions in reticulin were usually seen when romiplostim was discontinued. In conclusion, subcutaneous romiplostim is a valuable agent for use in patients with refractory chronic ITP.
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Complement inhibition by anti-C5 antibodies--from bench to bedside and back again.
Trendelenburg, M
Swiss medical weekly. 2007;(29-30):413-7
Abstract
The complement system is an important part of the innate immune system with pro-inflammatory and regulatory functions. Although many experimental studies have demonstrated that complement inhibition might be advantageous in a number of different human diseases, complement inhibition is still not part of the clinical treatment routine. With blocking antibodies against complement C5 a new generation of therapeutic complement inhibitors has now been investigated in some human diseases. This review gives an overview on the new complement inhibitors and the results obtained in clinical studies thus far.
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Targeting of tumor cells by lymphocytes engineered to express chimeric receptor genes.
Baxevanis, CN, Papamichail, M
Cancer immunology, immunotherapy : CII. 2004;(10):893-903
Abstract
Adoptive cellular immunotherapy of cancer has been limited to date mostly due to the poor immunogenicity of tumor cells, the immunocompromised status of cancer patients in advanced stages of their disease, and difficulties in raising sufficient numbers of autologous tumor-specific T lymphocytes. On the other hand, the slow tumor penetration and short half-life of exogenously administered tumor-specific monoclonal antibodies have provided major obstacles for an effective destruction of tumor cells by the humoral effector arm of the immune system. Attempts to improve the efficacy of adoptive cellular cancer immunotherapy have led to the development of novel strategies that combine advantages of T cell-based (i.e., efficient tumor penetration, cytokine release and cytotoxicity) and antibody-based (high specificity for tumor-associated antigens) immunotherapy by grafting cytotoxic T lymphocytes (CTLs) with chimeric receptors composed of antibody fragments (which recognize tumor-cell antigens) and a cellular activation motif. Antigen recognition is therefore not restricted by major histocompatibility genes, as the physiological T-cell receptor, but rather is directed to native cell surface structures. Since the requirements of major histocompatibility complex (MHC) restriction in the interaction of effector cells with target cells are bypassed, the tumor cell-binding of CTLs grafted with chimeric receptors is not affected by down-regulation of HLA class I antigens and by defects in the antigen-processing machinery. Ligand binding by the chimeric receptor triggers phosphorylation of immunoglobulin tyrosine activation motifs (ITAMs) in the cytoplasmic region of the molecule and this activates a signaling cascade that is required for the induction of cytotoxicity, cytokine secretion and proliferation. Here, the authors discuss the potential of lymphocytes grafted with chimeric antigen receptors in the immunotherapy of malignant disease.
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A Phase I trial of 90Y-anti-carcinoembryonic antigen chimeric T84.66 radioimmunotherapy with 5-fluorouracil in patients with metastatic colorectal cancer.
Wong, JY, Shibata, S, Williams, LE, Kwok, CS, Liu, A, Chu, DZ, Yamauchi, DM, Wilczynski, S, Ikle, DN, Wu, AM, et al
Clinical cancer research : an official journal of the American Association for Cancer Research. 2003;(16 Pt 1):5842-52
Abstract
PURPOSE Targeted systemic radiation therapy using radiolabeled antibodies results in tumor doses sufficient to produce significant objective responses in the radiosensitive hematological malignancies. Although comparable doses to tumor are achieved with radioimmunotherapy (RIT) in solid tumors, results have been modest primarily because of their relative lack of radiosensitivity. For solid tumors, as with external beam radiotherapy, RIT should have a more important clinical role if combined with other systemic, potentially radiation-enhancing chemotherapy agents and if used as consolidative therapy in the minimal tumor burden setting. The primary objective of this trial was to evaluate the feasibility and toxicities of systemic 90Y-chimeric T84.66 (cT84.66) anti-carcinoembryonic antigen RIT in combination with continuous infusion 5-fluorouracil (5-FU). EXPERIMENTAL DESIGN Patients with chemotherapy-refractory metastatic colorectal cancer were entered. The study was designed for each patient to receive 90Y-cT84.66 anti-carcinoembryonic antigen at 16.6 mCi/m2 as an i.v. bolus infusion combined with 5-FU delivered as a 5-day continuous infusion initiated 4 h before antibody infusion. Cohorts of patients were entered at 5-FU dose levels of 700, 800, 900, and 1000 mg/m2/day. Upon reaching the highest planned dose level of 5-FU, a final cohort received 90Y-cT84.66 at 20.6 mCi/m2 and 5-FU at 1000 mg/m2/day. For all patients, Ca-diethylenetriaminepentaacetic acid at 125 mg/m2 every 12 h was administered for the first 72 h after 90Y-cT84.66. Patients were eligible to receive up to three cycles of 90Y-cT84.66/5-FU every 6 weeks. RESULTS Twenty-one patients were treated on this study. All had been heavily pretreated with 19 having previously received 5-FU and 16 having failed two to four chemotherapy regimens. A maximum-tolerated dose of 16.6 mCi/m2 90Y-cT84.66 combined with 1000 mg/m2/day 5-FU was reached. These dose levels are comparable with maximum-tolerated dose levels of each agent alone. Thirteen patients received one cycle and 8 patients two cycles of therapy. Hematopoietic toxicity was dose-limiting and reversible. RIT did not appear to increase nonhematopoietic toxicities associated with 5-FU. Two of 19 patients assayed developed a human anti-chimeric antibody immune response after the first cycle of therapy, which is significantly less than that observed in a previous trial evaluating 90Y-cT84.66 alone. No objective responses were observed. However, 11 patients with progressive disease entering the study demonstrated radiological stable disease of 3-8 months duration and 1 patient demonstrated a mixed response. CONCLUSIONS Results from this trial are encouraging and demonstrate the feasibility and possible advantages of combining continuous infusion 5-FU with 90Y-cT84.66 RIT. The addition of 5-FU does not appear to significantly enhance hematological toxicities of the radiolabeled antibody. In addition, 5-FU reduces the development of human anti-chimeric antibody response, permitting multicycle therapy in a larger number of patients. Future efforts should continue to focus on integrating radiation therapy delivered by radiolabeled antibodies into established 5-FU regimens.