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A phase I trial of the IL1-receptor antagonist anakinra in previously untreated CLL patients at risk for progression

ABSTRACT: Inflammatory factors that activate NFkB play an important role in the pathogenesis of chronic lymphocytic leukemia (CLL) but are not addressed specifically by current therapies. Interleukin-1 (IL-1) is a master-regulator of inflammation that is inhibited safely in humans by the IL-1 receptor antagonist anakinra. Anakinra was found to inhibit NFkB activity in CLL cells in an IL-1 receptor independent manner and had properties of an intracellular anti-oxidant in vitro. A phase I dose-escalation trial in 11 previously untreated CLL patients (NCT04691765) indicated anakinra was safe at doses up to 400 mg daily and produced transient clinical responses associated with down-regulation of NFkB and oxidative stress in circulating CLL cells in vivo. However, type 1 interferon (IFN)-signaling and c-MYC-regulated genes and proteins were induced at the same time.

ORGANISM(S): Homo sapiens

PROVIDER: GSE236606 | GEO | 2023/10/04

REPOSITORIES: GEO

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Project description:Background: Systemic-Onset Juvenile Idiopathic Arthritis (SJIA) is a rare disease associated with dysregulated interleukin (IL)-1 activity. Objectives: To assess the efficacy and safety of Anakinra, an IL-1 receptor antagonist in SJIA and its effects on gene expression profiling. Methods: We conducted a multicenter, randomized, double-blind placebo-controlled trial. The primary objective was to compare the efficacy of a one-month treatment with anakinra (2 mg/kg subcutaneoulsy daily, maximum 100 mg) to a placebo between 2 groups of 12 SJIA patients each. Response was defined by a 30% improvement of the pediatric American College of Rheumatology criteria for JIA, resolution of systemic symptoms and a decrease of at least 50% of both C-reactive protein and erythrocyte sedimentation rate compared to baseline. An intention-to-treat analyze was performed. After Month 1 (M1), patients taking placebo were switched to Anakinra. Secondary objectives included tolerance and efficacy assessment for 12 months. Results: At M1, concluding the randomized trial, there was a significant difference in the response rate between patients treated with Anakinra (8/12 responders) and placebo (1/12) (p=0.003). The number of adverse events, mainly pain to injections, was similar between both groups. Ten patients from the placebo group switched to Anakinra at M1; nine were responders at M2. Between M1 and M12, six patients stopped treatment for an adverse event (Crohn’s disease, hepatitis), a lack of efficacy or a disease flare (2 cases each). Blood gene expression profiling at enrollment and upon follow-up allowed us to identify one set of dysregulated genes that reverted to normal values in the clinical responders and a second set, including interferon-inducible genes, that was induced by Anakinra. Conclusion: Anakinra is an effective treatment of SJIA. Its effect is associated with normalization of blood gene expression profiles in clinical responders and de novo induction of an interferon signature. (Clinical trials registration number: NCT00339157)

Project description:Quantitative Analysis of cortical transcriptomes through Next Generation Sequencing (RNA-Seq) from wild-type mice, wild-type mice treated with IL1b (200 ng/mouse, 14h), IL-1R8-/- mice and IL-1R8-/- mice treated with IL1b antagonist Anakinra (25 mg/kg per day for 3 consecutive days, i.p. administration). mRNA profiles of cortical tissue from adult wild-type mice, wild-type mice treated with IL1b (200 ng/kg, 14h), IL-1R8-/- mice (Garlanda et al., 2004), and IL-1R8-/- mice treated with Anakinra (25 mg/kg per day for 3 consecutive days, i.p. administration) were generated by next-generation sequencing (RNA-seq) using Illumina HiSeq 2500 apparatus in paired-end configuration (2x125bp). Each condition was assessed in triplicate (12 mRNA-seq libraries) and, to reduce biological variability, each mRNA library was generated from pooled total RNA isolated from cortical tissue of 3 individual mice. In total, 9 mice per condition were used. Libraries were stranded and multiplexed. To increase sequencing depth, libraries were sequenced in two different lanes. All the libraries were loaded in each of the two lanes. Quality control of the raw data was performed with FastQC (http://www.bioinformatics.babraham.ac.uk/projects/fastqc/). Libraries were trimmed for adapter removal using Trimmomatic (Bolger et al., 2014) and mapped to reference genome (Ensembl GRCm38) using TopHat2 (Kim et al., 2013) and Bowtie2 (Langmead et al., 2009). Library sizes of primary mapped reads were between 70 and 96 million reads. Samtools was used to manipulate BAM files (Li et al., 2009). For calling of differentially expressed genes (DEG), mapped reads were counted with HTSeq v0.6.1 (Anders et al., 2014) and count tables were analysed using DeSeq2 v1.10.1 R-package (Love et al., 2014) with a design of one factor with four levels (“wild-type”, “wild-type + IL1”, “IL-1R8-/-”, “IL-1R8-/- + Anakinra"), and differences between groups were tested using contrasts for wild-type + IL1b versus wild-type; IL-1R8-/- versus wild-type; IL-1R8-/- + Kineret versus wild-type. For consideration of differentially regulated genes between conditions, we used adjusted p-value < 0.1 or adjusted p-value < 0.05 as indicated in the manuscript.

Project description:The metastatic colon cancer is a major public health problem despite advances in chemotherapy; few new drugs are in development for the treatment of this pathology. Many studies have shown that human colon cancer is a tumor that is recognized by the immune system and the presence of lymphocytic infiltrates in the tumor bed is associated with a better prognosis. Conversely, the effect of chemotherapy on the immune response is little studied. Recently the importance of myeloid suppressor cells (MDSC) in the development of colon cancer and the effect of 5- fluorouracil on this cell population has been highlighted. An accumulation of these cells in the blood and lymphoid organs during tumor progression is observed. Moreover, it has been established that the death of MDSC induced by 5-fluorouracil induces activation of caspase -1 and IL-1beta by these MDSC. These events promote the polarization of CD4 T cells in intratumoral Th17 lymphocytes. The IL- 17 produced by these cells exerts a pro-angiogenic effect in inducing proliferation of endothelial cells expressing and thus limits the effect of 5- fluorouracil endoglin. In humans, it has also been observed that chemotherapy using 5- fluorouracil and in particular LV5FU2 association +/- bevacizumab induces rapid death of blood MDSC as well as activation of caspase 1 in these cells. Thus, production of IL - 1 is detected in the serum of patients after 24 hours of the administration of 5-fluorouracil. Chronic inflammation and the production of interleukin- 1 can alter the effectiveness of anti -tumor immune responses and facilitate angiogenesis. Many preclinical data suggest a role of anti -tumor inhibition of IL- 1beta, but the effect of a combination of chemotherapy and an inhibitor of IL - 1beta has not yet been tested in human. Anakinra is a drug used in humans for many years to treat signs and symptoms of rheumatoid arthritis. In combination with methotrexate, in patients whose response to methotrexate alone is not satisfactory it had shown interesting results. The dose used clinically is 100 mg per day which is the dose that is proposed to be tested in this study. In this context it should be remembered that methotrexate is a chemotherapeutic agent from the class of antimetabolites such as 5- fluorouracil. RCP of this drug indicate that in studies originator toxicity was similar between the control arm and anakinra arm with an increase in serious infections (1.8 % vs 0.7 %) and an increased incidence of neutropenia (2.5 % neutropenia > grade = 1). The main toxicity observed is a painful inflammatory reaction at the injection site in 70 % of patients The investigators believe that this project could permit to validate in man preclinical observations showing an anti-tumor potential for combination anakinra and 5 fluorouracil.

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A phase I trial of the IL1-receptor antagonist anakinra in previously untreated CLL patients at risk for progression

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