Low-Dose Interleukin 2 for the Treatment of Moderate to Severe Ulcerative Colitis

Allegretti, Jessica R.; Mitsialis, Vanessa; Canavan, James B.; Snapper, Scott B.; Hamilton, Matthew J.; Barends, Jared; Carrellas, Madeline; Freer, Katherine; Gringauz, Jordan; Green, Julia; Herwood, Noah; Hurtado, Jonathan; Mitri, Jennifer; Rourke, Caroline; Saccocia, Gwen; Whitcomb, Sydney; Liu, Enju; Klatzmann, David; Silva, Punyanganie S. de; Farraye, Frank A.; Feuerstein, Joseph D.; Moss, Alan C.; Shah, Samir A.; Korzenik, Joshua R.; Bousvaros, Athos; Koreth, John; Soiffer, Robert J.; Ritz, Jérôme; Logvinenko, Tanya; Ananthakrishnan, Ashwin N.; Herfath, Hans

doi:10.1053/j.gastro.2023.03.230

Cited by 13 publications

(5 citation statements)

References 10 publications

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“…17 Aldesleukin, a recombinant form of IL-2 approved for cancer indications, is currently under investigation in a phase-2 clinical trial for CD (ClinicalTrials.gov ID: NCT04263831). 43 Also, compounds targeting IL-1 signaling, anakinra or canakinumab, represent established treatment algorithms for inflammatory joint diseases like rheumatoid arthritis (RA) or juvenile arthritis. 44,45…”

Section: Resultsmentioning

confidence: 99%

The Genomic Architecture of Circulating Cytokine Levels Points to Drug Targets for Immune-Related Diseases

Konieczny,

Omarov,

Malik

et al. 2024

Preprint

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Circulating cytokines orchestrate immune reactions and are promising drug targets for immune-mediated and inflammatory diseases. Exploring the genetic architecture of circulating cytokine levels could yield key insights into causal mediators of human disease. Here, we performed genome-wide association studies (GWAS) for 40 circulating cytokines in meta-analyses of 74,783 individuals. We detected 359 significant associations between cytokine levels and variants in 169 independent loci, including 150 trans- and 19 cis-acting loci. Integration with transcriptomic data point to key regulatory mechanisms, such as the buffering function of ACKR1 acting as scavenger for multiple chemokines and the role of TRAFD1 in modulating the cytokine storm triggered by TNF signaling. Applying Mendelian randomization (MR), we detected a network of complex cytokine interconnections with TNF-b, VEGF, and IL-1ra exhibiting pleiotropic downstream effects on multiple cytokines. Drug target cis-MR paired with colocalization revealed G-CSF/CSF-3 and CXCL9/MIG as potential causal mediators of asthma and Crohns disease, respectively, but also a potentially protective role of TNF-b in multiple sclerosis. Our results provide an overview of the genetic architecture of circulating cytokines and could guide the development of targeted immunotherapies.

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Section: Resultsmentioning

confidence: 99%

The Genomic Architecture of Circulating Cytokine Levels Points to Drug Targets for Immune-Related Diseases

Konieczny,

Omarov,

Malik

et al. 2024

Preprint

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“… 59 A phase Ib/IIa trial of 26 patients with moderate-to-severe UC reported on the safety, tolerability, and efficacy of daily SC low dose IL-2 (Proleukin). 60 Three different dosage regimens were administered to determine the maximum tolerated dose: 0.3 × 10 6 IU/m 2 /d (dose A), 1 × 10 6 IU/m 2 /d (dose B), or 1.5 × 10 6 IU/m 2 /d (dose C). The drug was well tolerated without serious adverse events.…”

Section: Other Interleukin Modulatorsmentioning

confidence: 99%

“…At week 8, clinical response (decrease in total Mayo score of ≥3 or ≥30% at week 8) was achieved in 52.6%, while clinical remission (Mayo score ≤2, with no individual sub-score >1, including Mayo endoscopic sub-score) was achieved in 21.1%. 60 Dose B was considered the maximum effective dose with a week 8 clinical response rate of 69.2% and clinical remission rate of 30.8%. These data support further development of low-dose IL-2 in the treatment of moderate-to-severe UC.…”

Section: Other Interleukin Modulatorsmentioning

confidence: 99%

Section: Risankizumabmentioning

confidence: 99%

“…The most common adverse events were mild and included injection reactions, malaise, and fever. At week 8, clinical response (decrease in total Mayo score of ≥3 or ≥30% at week 8) was achieved in 52.6%, while clinical remission (Mayo score ≤2, with no individual sub-score >1, including Mayo endoscopic sub-score) was achieved in 21.1% 60. Dose B was considered the maximum effective dose with a week 8 clinical response rate of 69.2% and clinical remission rate of 30.8%.…”

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confidence: 99%

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Emerging Therapies for Ulcerative Colitis: Updates from Recent Clinical Trials

AlAmeel,

AlMutairdi,

Al-Bawardy

2023

CEG

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Ulcerative colitis (UC) is a chronic and progressive inflammatory disorder that affects the colon. The advent of advanced therapies such as biologic agents and small molecules has revolutionized the management of UC. Despite the expanding therapeutic armamentarium of advanced therapies to treat UC, the overall net remission rates and durability of currently available agents are relatively low. This highlights the need for further drug development and more innovative clinical trial design. There are currently multiple emerging agents in the pipeline for the management of UC. This includes agents with alternative routes of administration such as oral or subcutaneous tumor necrosis factor inhibitors or novel mechanisms of action such as toll-like receptor 9 (TLR9) agonist cobitolimod and phosphodiesterase 4 inhibitor apremilast. In this review, we will highlight novel and emerging advanced therapies currently in the pipeline for the management of UC.

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TGF‐β1 signaling and Smad7 control T‐cell responses in health and immune‐mediated disorders

Laudisi,

Stolfi,

Monteleone

et al. 2023

Eur J Immunol

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Transforming growth factor (TGF)‐β1, a member of the TGF‐β superfamily, is produced by many immune and non‐immune cells and has pleiotropic effects on both innate and adaptive immunity, especially in the control of T cell differentiation and function. Consistently, loss of TGF‐β1 function is associated with exacerbated T cell‐dependent inflammatory responses that culminate in pathological processes in allergic and immune‐mediated diseases. In this review, we highlight the roles of TGF‐β1 in immunity, focusing mainly on its ability to promote differentiation of regulatory T cells, T helper (Th)‐17, and Th9 cells, thus contributing to amplifying or restricting T cell responses in health and human diseases (e.g. inflammatory bowel diseases, type I diabetes, asthma, and multiple sclerosis), In addition, we discuss the involvement of Smad7, an inhibitor of TGF‐β1 signaling, in immune‐mediated disorders (e.g. psoriasis, rheumatoid arthritis, multiple sclerosis, and inflammatory bowel diseases), as well as the discordant results of clinical trials with mongersen, an oral pharmaceutical compound containing a Smad7 antisense oligonucleotide, in patients with Crohn's disease. Further work is needed to ascertain the reasons for such a discrepancy as well as to identify better candidates for treatment with Smad7 inhibitors.This article is protected by copyright. All rights reserved

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Low-Dose Interleukin 2 for the Treatment of Moderate to Severe Ulcerative Colitis

Cited by 13 publications

References 10 publications

The Genomic Architecture of Circulating Cytokine Levels Points to Drug Targets for Immune-Related Diseases

The Genomic Architecture of Circulating Cytokine Levels Points to Drug Targets for Immune-Related Diseases

Emerging Therapies for Ulcerative Colitis: Updates from Recent Clinical Trials

TGF‐β1 signaling and Smad7 control T‐cell responses in health and immune‐mediated disorders

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