Cytokine-Induced Vascular Leak Syndrome

Baluna, Roxana

doi:10.1007/978-1-59745-350-9_11

Cited by 6 publications

(6 citation statements)

References 151 publications

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“… 2 VLS is characterized by vascular damage, increased vascular permeability, leakage of fluids, proteins and electrolytes into interstitial spaces, tissue edema, hypotension and ultimately multiorgan failure that can be fatal. 3–5 IL-2 activates not only cells with antitumor function, including natural killer (NK) cells, gamma delta (γδ) T cells and CD4 + and CD8 + effector T cells, but also IL-2Rα + immunosuppressive regulatory T cells (Tregs) that likely limit efficacy. 1 6 IL-2 can signal with picomolar affinity to trimeric IL-2 receptor IL-2Rα/β/γ or with nanomolar affinity through dimeric IL-2Rβ/γ.…”

Section: Introductionmentioning

confidence: 99%

TransCon IL-2 β/γ: a novel long-acting prodrug with sustained release of an IL-2Rβ/γ-selective IL-2 variant with improved pharmacokinetics and potent activation of cytotoxic immune cells for the treatment of cancer

Rosen¹,

Kvarnhammar

Laufer³

et al. 2022

J Immunother Cancer

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BackgroundRecombinant interleukin-2 (IL-2, aldesleukin) is an approved cancer immunotherapy but causes severe toxicities including cytokine storm and vascular leak syndrome (VLS). IL-2 promotes antitumor function of IL-2Rβ/γ+ natural killer (NK) cells and CD8+, CD4+ and gamma delta (γδ) T cells. However, IL-2 also potently activates immunosuppressive IL-2Rα+ regulatory T cells (Tregs) and IL-2Rα+ eosinophils and endothelial cells, which may promote VLS. Aldesleukin is rapidly cleared requiring frequent dosing, resulting in high Cmax likely potentiating toxicity. Thus, IL-2 cancer immunotherapy has two critical drawbacks: potent activation of undesired IL-2Rα+ cells and suboptimal pharmacokinetics with high Cmax and short half-life.MethodsTransCon IL-2 β/γ was designed to optimally address these drawbacks. To abolish IL-2Rα binding yet retain strong IL-2Rβ/γ activity, IL-2 β/γ was created by permanently attaching a small methoxy polyethylene glycol (mPEG) moiety in the IL-2Rα binding site. To improve pharmacokinetics, IL-2 β/γ was transiently attached to a 40 kDa mPEG carrier via a TransCon (transient conjugation) linker creating a prodrug, TransCon IL-2 β/γ, with sustained release of IL-2 β/γ. IL-2 β/γ was characterized in binding and primary cell assays while TransCon IL-2 β/γ was studied in tumor-bearing mice and cynomolgus monkeys.ResultsIL-2 β/γ demonstrated selective and potent human IL-2Rβ/γ binding and activation without IL-2Rα interactions. TransCon IL-2 β/γ showed slow-release pharmacokinetics with a low Cmax and a long (>30 hours) effective half-life for IL-2 β/γ in monkeys. In mouse tumor models, TransCon IL-2 β/γ promoted CD8+ T cell and NK cell activation and antitumor activity. In monkeys, TransCon IL-2 β/γ induced robust activation and expansion of CD8+ T cells, NK cells and γδ T cells, relative to CD4+ T cells, Tregs and eosinophils, with no evidence of cytokine storm or VLS. Similarly, IL-2 β/γ enhanced proliferation and cytotoxicity of primary human CD8+ T cells, NK cells and γδ T cells.SummaryTransCon IL-2 β/γ is a novel long-acting prodrug with sustained release of an IL-2Rβ/γ-selective IL-2. It has remarkable and durable pharmacodynamic effects in monkeys and potential for improved clinical efficacy and tolerability compared with aldesleukin. TransCon IL-2 β/γ is currently being evaluated in a Phase 1/2 clinical trial (NCT05081609).

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Section: Introductionmentioning

confidence: 99%

TransCon IL-2 β/γ: a novel long-acting prodrug with sustained release of an IL-2Rβ/γ-selective IL-2 variant with improved pharmacokinetics and potent activation of cytotoxic immune cells for the treatment of cancer

Rosen¹,

Kvarnhammar

Laufer³

et al. 2022

J Immunother Cancer

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“…Although reversible when managed early enough, this may lead to a life-threatening response as seen in patients who suffered from cytokine storm after receiving the superagonistic anti-CD28 antibody TGN1412 during a phase I trial (Suntharalingam et al, 2006). It has been shown that VLS is one of the dose-limiting side effects of IL-2 in cancer patients or HIV patients receiving highly active antiretroviral therapy (Baluna, 2007;Kovacs et al, 1995;Lotze et al, 1986;Siegel and Puri, 1991). Because preclinical safety characterization of therapeutic cytokines and monoclonal antibodies becomes increasingly more important during development, there is a need for systems with the potential to assess vascular leakage early on.…”

mentioning

confidence: 99%

A Real-time Impedance-Based Screening Assay for Drug-Induced Vascular Leakage

Kustermann

Manigold

Ploix

et al. 2014

Toxicological Sciences

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Vascular leakage is a serious side effect of therapies based on monoclonal antibodies or cytokines which may lead to life-threatening situations. With the steady increase of new drug development programs for large molecules, there is an urgent need for reliable tools to assess this potential liability of new medicines in a rapid and cost-effective manner. Using human umbilical vein endothelial cells (HUVECs) as a model for endothelium, we established an impedance-based assay measuring the integrity of the endothelial cell monolayer in real time. We could demonstrate that the HUVEC monolayer in our system was a relevant model as cells expressed major junctional proteins known to be responsible for maintaining tightness as well as receptors targeted by molecules known to induce vascular leakage in vivo. We assessed the time-dependent loss of barrier function using impedance and confirmed that signals obtained corresponded well to those from standard transwell assays. We assayed a series of reference molecules which led to the expected change of barrier integrity. A nonspecific cytotoxic effect could be excluded by using human fibroblasts as a nonresponder cell line. Finally, we could show reversibility of vascular permeability induced by histamine, IL-1β, or TNF-α by coincubation with established antagonists, further demonstrating relevance of this new model. Taken together, our results suggest that impedance in combination with HUVECs as a specific model can be applied to assess clinically relevant vascular leakage on an in vitro level.

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“…Vascular leak syndrome (VLS): is a major dose-limiting toxicity of cytokine therapy, including IL-2, IL-12, granulocyte-macrophagecolony-stimulating factor (GM-CSF), IL-15, and other cytokines, that are used for cancer immunotherapy [57,58]. VLS is a major drawback for the use of cytokines as adjuvants in vaccines.…”

Section: Non Frequent Acute Systemic Reactionsmentioning

confidence: 99%

“…Several mechanisms for VLS have been proposed. They include the activation or damage of endothelial cells and leukocytes, the release of cytokines and inflammatory mediators (e.g., IL-1, TNF-α, components of the complement cascade), cytotoxicity of lymphokineactivated killer cells on vascular endothelial cells, perforins as well as alterations in cell-cell interactions, cell matrix adhesion and in cytoskeleton function resulting in disturbance of vascular integrity [57]. In another study, it was reported that therapeutic vaccination inducing antibodies against P277 (a 24-aa fragment of the HSP60 molecule, first discovered to be an antigen for diabetogenic T-cell clones in nonobese diabetic mice) mediates endothelial cells damage and induces VLS [60].…”

Section: Non Frequent Acute Systemic Reactionsmentioning

confidence: 99%

Efficacy and safety of immunological adjuvants. Where is the cut-off?

Batista-Duharte

Téllez-Martínez

Carlos

2018

Biomedicine & Pharmacotherapy

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Research over the past several decades has provided insight into the mode of action of adjuvants. However, the main focus of attention has been the efficacy in the induction of protective immunogenicity, while less effort has been devoted to the study of toxicity mechanisms. Evidences suggest that several mechanisms that are responsible for the immunostimulating effects are, at the same time, responsible of the adverse effects. In this context, it is often very difficult to establish the boundaries between immunostimulation and immunotoxicity to reach the ideal balance of efficacy/safety. During decades, hundreds of adjuvants and adjuvant formulations have been proposed as immunostimulants for vaccines but very few have been used in human vaccines due to toxicity concerns. In this review, relevant aspects about immunotoxicology of adjuvants, based on clinical and experimental studies are discussed. Some effects are only observed under hyperstimulating regimens using non-approved adjuvants for human use, but these are nonetheless useful to understanding basic principles of adjuvant toxicity. The acute local and systemic reactions, during the first hours and those that can be observed after the third day of vaccination in the inoculation site and systemically are discussed.

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Cytokine-Induced Vascular Leak Syndrome

Cited by 6 publications

References 151 publications

TransCon IL-2 β/γ: a novel long-acting prodrug with sustained release of an IL-2Rβ/γ-selective IL-2 variant with improved pharmacokinetics and potent activation of cytotoxic immune cells for the treatment of cancer

TransCon IL-2 β/γ: a novel long-acting prodrug with sustained release of an IL-2Rβ/γ-selective IL-2 variant with improved pharmacokinetics and potent activation of cytotoxic immune cells for the treatment of cancer

A Real-time Impedance-Based Screening Assay for Drug-Induced Vascular Leakage

Efficacy and safety of immunological adjuvants. Where is the cut-off?

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