Tadekinig Alfa for Cytokine Release Syndrome

Age: 18+

Sex: Any

Trial Phase: Phase < 1

Sponsor: University of Pennsylvania

Disqualifiers: Pregnant, Nursing, Hypersensitivity, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 3

Duration: 5 days

10 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the safety and practicality of using Tadekinig alfa (IL-18 binding protein) to treat cytokine release syndrome (CRS) and a related condition, HLH-like syndrome, in patients undergoing CAR T cell therapy. These conditions can occur as side effects during certain cancer treatments, causing fever, fatigue, and difficulty breathing. Participants might qualify if they are already part of a CAR T cell therapy trial at the University of Pennsylvania. As an Early Phase 1 trial, this research focuses on understanding how Tadekinig alfa works in people, offering participants the opportunity to be among the first to receive this new treatment.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

Is there any evidence suggesting that Tadekinig alfa is likely to be safe for humans?

Research has shown that tadekinig alfa is generally well-tolerated. In a study with patients who have adult-onset Still's disease, tadekinig alfa demonstrated a good safety record, with few serious side effects. Additionally, studies on mice with high levels of IL-18BP (the active component of tadekinig alfa) did not reveal any harmful effects on their tissues.

This trial is in its early stages, so limited information exists about its safety as a treatment for cytokine release syndrome. However, these early results suggest it might be safe for humans. More research is needed to fully understand its safety for this specific condition. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for cytokine release syndrome (CRS), which often rely on corticosteroids and IL-6 inhibitors like tocilizumab, Tadekinig alfa offers a fresh approach by targeting interleukin-18 binding protein (IL-18BP). This new mechanism focuses on modulating IL-18, a cytokine involved in inflammatory responses, potentially providing a more direct method to control the inflammatory process in CRS. Researchers are excited about Tadekinig alfa because it could offer faster relief from symptoms and a novel pathway to manage CRS more effectively, especially in patients who may not respond adequately to existing therapies.

What evidence suggests that Tadekinig alfa might be an effective treatment for cytokine release syndrome?

Research has shown that tadekinig alfa, also known as IL-18BP, is a promising treatment because it targets a specific protein involved in inflammation. This protein, IL-18, plays a major role in conditions like cytokine release syndrome (CRS), which can occur after some cancer treatments. In this trial, participants will receive tadekinig alfa to evaluate its effectiveness in reducing inflammation associated with CRS. Studies have found early signs that tadekinig alfa reduces inflammation in patients with conditions similar to CRS. Additionally, other trials have proven tadekinig alfa safe, making it a potential option for managing the severe symptoms of CRS. These findings suggest that tadekinig alfa could help treat CRS by calming the body's intense inflammatory response. ^{1 2 3 5 6}

Are You a Good Fit for This Trial?

This trial is for adults over 18 who are already part of a University of Pennsylvania CAR T cell study. They must be able to have children and agree to use birth control as described in the protocol. Pregnant or nursing women, or those allergic to the drug's ingredients, cannot join.

Inclusion Criteria

Signed, written informed consent

Subjects of reproductive potential must agree to use acceptable birth control methods, as described in protocol

Have been co-enrolled in a University of Pennsylvania-Sponsored, CCI-Initiated CAR T cell clinical trial

Exclusion Criteria

Known hypersensitivity to the active substance or one of the excipients of the investigational product(s)

Pregnant or nursing (lactating) women

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Tadekinig alfa injections as rescue therapy for CAR T cell related CRS and HLH-like syndrome

5 days

3 visits (in-person)

Continued Dosing (Optional)

Continued dosing approximately every 48-72 hours if the subject is responsive to initial therapy but has ongoing symptoms

Follow-up

Participants are monitored for safety and effectiveness after treatment

28 days

What Are the Treatments Tested in This Trial?

Interventions

• Tadekinig alfa (IL-18BP)

Trial Overview The study is testing Tadekinig alfa (IL-18BP) as a rescue therapy for severe immune reactions called CRS and HLH-like syndrome that can happen after CAR T cell treatments. It's an early-stage trial to see if it's safe and workable.

How Is the Trial Designed?

Group I: Tadekinig alfa Experimental Treatment 1 Intervention

* Injection #1/Day 1: As clinically indicated in accordance with Figure 1.1-1. * Repeat Injection(s): Missed doses will not be made up. * Injection #2/Day 3: Approximately 48 hours (+/- 5 hours) after receipt of the 1st injection. * Injection #3/Day 5: Approximately 48 hours (+/- 5 hours) after receipt of the 2nd injection. * Continued Dosing (Optional): Approximately q48-72 hours; If the subject is responsive to initial therapy, but has ongoing symptoms of CRS/CRHLS. * Retreatment (Optional): May be considered

Who Is Running the Clinical Trial?

University of Pennsylvania

Lead Sponsor

Trials

2,118

Recruited

45,270,000+

Published Research Related to This Trial

Interleukin-18 binding protein (IL-18BP) acts as a decoy receptor that effectively inhibits the functions of IL-18, which is important in inflammatory diseases and cancers.

Gene expression of IL-18BP is significantly increased in response to interferon-gamma (IFN-gamma) in various human cell types, suggesting a negative feedback mechanism that regulates IL-18 activity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Interferon-gamma mediates gene expression of IL-18 binding protein in nonleukocytic cells. Mühl, H., Kämpfer, H., Bosmann, M., et al.[2022]

A newly discovered interleukin 18 binding protein (IL18BP) effectively neutralizes IL18, which is crucial for regulating immune responses, particularly by suppressing interferon gamma production.

Two specific human isoforms of IL18BP demonstrated high affinity for IL18, neutralizing over 95% of its activity, suggesting their potential as therapeutic agents in diseases where IL18 plays a role.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting interleukin 18 with interleukin 18 binding protein. Dinarello, CA.[2019]

IL-18 binding protein (IL-18BP) effectively inhibits the proinflammatory cytokine IL-18 by forming a stable complex, which is crucial in regulating inflammation, especially in conditions like sepsis.

In septic patients, serum levels of IL-18BP were significantly elevated (21.9 ng/ml) compared to healthy individuals (2.15 ng/ml), indicating its potential role in managing IL-18 activity during severe infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A novel IL-18BP ELISA shows elevated serum IL-18BP in sepsis and extensive decrease of free IL-18. Novick, D., Schwartsburd, B., Pinkus, R., et al.[2022]

IL-18 binds to its receptor IL-18R alpha/beta complex, which has a high affinity for IL-18, and this binding is crucial for activating immune responses, including the activity of NK and T cells.

A specific neutralizing antibody, 125-2H, can inhibit IL-18 binding to IL-18R alpha, but not to the alpha/beta complex, suggesting that the receptor's structure changes upon dimerization, which is important for signal transduction.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

IL-18 receptor beta-induced changes in the presentation of IL-18 binding sites affect ligand binding and signal transduction. Wu, C., Sakorafas, P., Miller, R., et al.[2019]

Interleukin-18 binding protein (IL-18BP) acts as a soluble antagonist that regulates immune responses by binding to IL-18 ligands, preventing them from activating their receptors on cell membranes, which is crucial for balancing Th1 and Th2 cytokine responses.

IL-18BP is distinct from other IL-18 receptors and is being studied in clinical trials for its potential therapeutic role in autoimmune diseases, highlighting its importance in immune regulation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Interleukin-18 Binding Protein in Immune Regulation and Autoimmune Diseases. Park, SY., Hisham, Y., Shin, HM., et al.[2022]

The study successfully cloned and expressed interleukin-18 binding protein from both mice and humans, demonstrating its potential as a therapeutic target.

Both recombinant interleukin-18 binding proteins effectively inhibited interleukin-18 from binding to its receptor and reduced IFN-gamma production, suggesting they may act as antagonists to interleukin-18.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cloning and expression of interleukin-18 binding protein. Aizawa, Y., Akita, K., Taniai, M., et al.[2019]

IL-18 is a pro-inflammatory cytokine linked to various inflammatory and cardiovascular diseases, and its activity can be inhibited by IL-18 binding protein (IL-18BP), which has a higher affinity for IL-18 than the IL-18 receptor.

This study is the first to examine the biological activity of recombinant human Fc-IL-18BPc, showing its potential to inhibit IL-18-induced cytokines like IFNγ and IL-6, suggesting a promising therapeutic avenue for conditions involving IL-18.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recombinant Fc-IL-18BPc isoform inhibits IL-18-induced cytokine production. Hong, K., Oh, K., Lee, S., et al.[2012]

The human interleukin-18-binding protein (hIL-18BP) effectively inhibits the proinflammatory cytokine IL-18 by binding to it, which could be crucial for developing treatments for inflammatory diseases.

Research identified seven key amino acids in hIL-18BP that significantly affect its binding affinity to IL-18, with tyrosine 97 and phenylalanine 104 being particularly important, potentially guiding the design of new molecular antagonists.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Determination of the functional epitopes of human interleukin-18-binding protein by site-directed mutagenesis. Xiang, Y., Moss, B.[2021]

IL-18 is a key cytokine involved in autoimmune diseases and cancer, and its activity is regulated by IL-18-binding protein (IL-18BP), which creates a feedback loop that can complicate the assessment of IL-18's biological activity.

Accurate measurement of both active IL-18 and IL-18BP is crucial for understanding disease activity and for developing targeted anti-IL-18 therapies, highlighting the need for advanced techniques to assess these biomarkers in various biological samples.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Detection of Free Bioactive IL-18 and IL-18BP in Inflammatory Disorders. Fauteux-Daniel, S., Girard-Guyonvarc'h, C., Caruso, A., et al.[2023]

Transgenic mice expressing high levels of human IL-18 binding protein (IL-18BP) were found to be viable and fertile, with no organ abnormalities, indicating that IL-18BP is safe for use in vivo.

These IL-18BP-Tg mice showed significantly reduced inflammatory responses, including lower levels of IFN-gamma and protection against liver damage in inflammatory models, demonstrating the efficacy of IL-18BP in modulating immune responses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Generation and characterization of mice transgenic for human IL-18-binding protein isoform a. Fantuzzi, G., Banda, NK., Guthridge, C., et al.[2008]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05306080

Tadekinig Alfa (IL-18BP) Rescue Therapy for CAR T Cell ... IL-18 is a key mediator in systemic inflammatory conditions such as MAS/HLH, which may contribute to the severity of CAR T cell-related cytokine release ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/29472362/

Open-label, multicentre, dose-escalating phase II clinical ... Our results indicate that tadekinig alfa appears to have a favourable safety profile and is associated with early signs of efficacy in patients with AOSD.

3. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39769266/

IL-18 and IL-18BP: A Unique Dyad in Health and Disease Tadekinig alfa, the drug form of IL-18BP, represents a targeted therapy that modulates the IL-18/IL-18BP axis, offering a safe adverse-effect- ...

4. immunenetwork.org immunenetwork.org/DOIx.php?id=10.4110/in.2024.24.e1

Interleukin-18 Binding Protein (IL-18BP) Open-label, multicentre, dose-escalating phase II clinical trial on the safety and efficacy of tadekinig alfa (IL-18BP) in adult-onset Still's ...

5. withpower.com withpower.com/trial/early-phase-1-syndrome-3-2022-db228

Tadekinig Alfa for Cytokine Release Syndrome The study successfully cloned and expressed interleukin-18 binding protein from both mice and humans, demonstrating its potential as a therapeutic target. Both ...

6. clinicaltrials.eu clinicaltrials.eu/inn/tadekinig-alfa/

Tadekinig Alfa – Application in Therapy and Current ... Tadekinig alfa, also known as r-hIL-18BP or IL-18BP, is an innovative medication being studied for the treatment of rare inflammatory conditions.