Trial in Progress: A Phase 2, Single-Arm, Open-Label Study of Itacitinib (ITA) for the Prevention of Chimeric Antigen Receptor (CAR) T-Cell–Induced Cytokine Release Syndrome (CRS)

Park, Jae H.; Frigault, Matthew J.; Maziarz, Richard T.; Naim, Ahmad; Burke, Lea; Tian, Chen; Porter, David L.

doi:10.1016/j.bbmt.2019.12.436

Cited by 9 publications

(7 citation statements)

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“…JAK-1 inhibitors have been investigated as well: itacitinib exerted greater control over inflammatory cytokines than tocilizumab in vitro and reduced serum levels of CRS-linked cytokines without impacting CART cell function in vivo ( 73 ). An ongoing phase II clinical trial is investigating itacitinib for the prevention of CRS in patients treated with CART cells ( 74 ).…”

Section: Cytokine Release Syndromementioning

confidence: 99%

Neurotoxicity and Cytokine Release Syndrome After Chimeric Antigen Receptor T Cell Therapy: Insights Into Mechanisms and Novel Therapies

2020

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Chimeric antigen receptor T (CART) cell immunotherapy has been remarkably successful in treating certain relapsed/refractory hematological cancers. However, CART cell therapy is also associated with toxicities which present an obstacle to its wider adoption as a mainstay for cancer treatment. The primary toxicities following CART cell administration are cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). New insights into the mechanisms of these toxicities have spurred novel treatment options. In this review, we summarize the available literature on the clinical manifestations, mechanisms, and treatments of CART-associated CRS and ICANS.

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Section: Cytokine Release Syndromementioning

confidence: 99%

Neurotoxicity and Cytokine Release Syndrome After Chimeric Antigen Receptor T Cell Therapy: Insights Into Mechanisms and Novel Therapies

2020

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“…Cell and animal models and phase II studies have shown potent, pre-and clinical efficacy of itacitinib against psoriasis and rheumatoid arthritis in a JAK2-independent manner [109][110][111][112][113]. As with other JAK inhibitors, such as baricitinib or tofacitinib, itacitinib is being studied for the prevention of the so-called cytokine release syndrome (CRS) or cytokine storm syndrome (CSS) [114], an acute systemic inflammatory syndrome characterized by fever and multiple organ dysfunction [115]. It is now known that a subgroup of patients with severe COVID-19 have had a CSS that occurred 7-10 days after the disease onset, coinciding with the peak of respiratory distress [14,15,116,117]; immune dysregulation, rather than the level of peak viremia, is responsible for the SARS-CoV-2 infection driving a too-little-and-too-late type-I-interferon response accompanied by aberrant proinflammatory cytokine secretion by alveolar macrophages and subsequent CD4 + and CD8 + T-cell dysfunction.…”

Section: Itacitinibmentioning

confidence: 99%

Potential Drugs Targeting Early Innate Immune Evasion of SARS-Coronavirus 2 via 2’-O-Methylation of Viral RNA

Encinar

Menendez

2020

Viruses

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The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causing the COVID-19 respiratory disease pandemic utilizes unique 2′-O-methyltransferase (2′-O-MTase) capping machinery to camouflage its RNA from innate immune recognition. The nsp16 catalytic subunit of the 2′-O-MTase is unusual in its requirement for a stimulatory subunit (nsp10) to catalyze the ribose 2′-O-methylation of the viral RNA cap. Here we provide a computational basis for drug repositioning or de novo drug development based on three differential traits of the intermolecular interactions of the SARS-CoV-2-specific nsp16/nsp10 heterodimer, namely: (1) the S-adenosyl-l-methionine-binding pocket of nsp16, (2) the unique “activating surface” between nsp16 and nsp10, and (3) the RNA-binding groove of nsp16. We employed ≈9000 U.S. Food and Drug Administration (FDA)-approved investigational and experimental drugs from the DrugBank repository for docking virtual screening. After molecular dynamics calculations of the stability of the binding modes of high-scoring nsp16/nsp10–drug complexes, we considered their pharmacological overlapping with functional modules of the virus–host interactome that is relevant to the viral lifecycle, and to the clinical features of COVID-19. Some of the predicted drugs (e.g., tegobuvir, sonidegib, siramesine, antrafenine, bemcentinib, itacitinib, or phthalocyanine) might be suitable for repurposing to pharmacologically reactivate innate immune restriction and antagonism of SARS-CoV-2 RNAs lacking 2′-O-methylation.

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“…Only a small number of patients were treated with ruxolitinb (10 patients). Itacitinib is currently being studied as CRS prophylaxis in an ongoing phase II study ( 34 ).…”

Section: Jak/stat Pathway and Crsmentioning

confidence: 99%

“…Furthermore, the JAK/STAT pathways are critical for cytokine signaling suggesting a potential role for JAK inhibition in the management of CRS ( 33 ). The JAK1 inhibitor itacitinib is currently being studied for CRS prophylaxis in recipients of IECT ( 34 ). In this review, we will present an overview of the role of JAK/STAT pathways in GVHD and inflammatory conditions relevant to cell therapies such as CRS and present recent clinical developments in the field.…”

Section: Introductionmentioning

confidence: 99%

Janus Kinase Inhibitors and Cell Therapy

Assal

Mapara

2021

Front. Immunol.

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Cellular therapies such as allogeneic hematopoietic stem cell transplantation (HSCT) and immune-effector cell therapy (IECT) continue to have a critical role in the treatment of patients with high risk malignancies and hematologic conditions. These therapies are also associated with inflammatory conditions such as graft-versus-host disease (GVHD) and cytokine release syndrome (CRS) which contribute significantly to the morbidity and mortality associated with these therapies. Recent advances in our understanding of the immunological mechanisms that underly GVHD and CRS highlight an important role for Janus kinases (JAK). JAK pathways are important for the signaling of several cytokines and are involved in the activation and proliferation of several immune cell subsets. In this review, we provide an overview of the preclinical and clinical evidence supporting the use of JAK inhibitors for acute and chronic GVHD and CRS.

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Trial in Progress: A Phase 2, Single-Arm, Open-Label Study of Itacitinib (ITA) for the Prevention of Chimeric Antigen Receptor (CAR) T-Cell–Induced Cytokine Release Syndrome (CRS)

Cited by 9 publications

References 0 publications

Neurotoxicity and Cytokine Release Syndrome After Chimeric Antigen Receptor T Cell Therapy: Insights Into Mechanisms and Novel Therapies

Neurotoxicity and Cytokine Release Syndrome After Chimeric Antigen Receptor T Cell Therapy: Insights Into Mechanisms and Novel Therapies

Potential Drugs Targeting Early Innate Immune Evasion of SARS-Coronavirus 2 via 2’-O-Methylation of Viral RNA

Janus Kinase Inhibitors and Cell Therapy

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