Interleukin Inhibitors in Cytokine Release Syndrome and Neurotoxicity Secondary to CAR-T Therapy

Ferreros, Puri; Trapero, Isabel

doi:10.3390/diseases10030041

Cited by 13 publications

(6 citation statements)

References 72 publications

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“…For example, IL-6 suppression decreased susceptibility to Castleman's illness and the cytokine storms brought on by chimeric antigen receptor (CAR) T-cell therapy. Investigations into the clinical etiology of the disease in critically ill COVID-19 patients revealed noticeably high levels of IL-6, and tocilizumab was proven to be beneficial in these patients [67]. It would seem advantageous to develop an IL-6 inhibitor with a short half-life that might be utilized to treat pathogeninduced cytokine storms, such as those brought on by sepsis, because infections are a severe side effect of using tocilizumab.…”

Section: Discussionmentioning

confidence: 99%

Targeting IL-6 Signaling Pathways for Musculoskeletal Disorders Treatment: Risks and Benefits

Shanshal¹,

Aljorani²,

Hussain³

2023

Al-Rafidain J Med Sci

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Pro-inflammatory mediators like IL-6 effectively mediated the majority of musculoskeletal disorders such rheumatoid arthritis (RA), osteoarthritis (OA), and tendinitis. Increased levels of IL-6 are found in the serum or synovial fluid of patients with these disorders, and these levels are correlated with the incidence and severity of the disease. IL-6 is crucial for the development of cartilage pathology, for example, by inducing a variety of pathways that are involved in the induction and spread of inflammation. The expression of anti-catabolic factors is similarly increased by IL-6, indicating a protective function. The differential impacts of IL-6 classic and trans-signaling may be the reason for this dual role of IL-6, which has so far remained poorly understood. In this article, the experimental and clinical data on the function of inhibiting IL-6 signaling in the development and progression of pathologies of the synovium, cartilage, and bones were thoroughly reviewed. By evaluating the IL-6 targeting approaches that are currently being considered in research and clinical practice, it may provide a glimpse into the future of these illnesses' treatment.

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Section: Discussionmentioning

confidence: 99%

Targeting IL-6 Signaling Pathways for Musculoskeletal Disorders Treatment: Risks and Benefits

Shanshal¹,

Aljorani²,

Hussain³

2023

Al-Rafidain J Med Sci

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“…Introduction of CAR T-cells or T-cell engagers will trigger a systemic immune response leading to the production of inflammatory cytokines and chemokines such as interleukins (IL), tumour necrosis factors and interferons that attack cancer cells; however, they can also attack healthy cells. 3,6 The 2 most common adverse events (AEs) associated with CAR T-cell therapy and T-cell engager therapy are CRS and ICANS. 3,6 The American Society for Transplantation and Cellular Therapy (ASTCT) guidelines established a consensus grading system (grade 1 to 4) for both CRS and ICANS.…”

Section: Context and Policy Issuesmentioning

confidence: 99%

“…3,6 The 2 most common adverse events (AEs) associated with CAR T-cell therapy and T-cell engager therapy are CRS and ICANS. 3,6 The American Society for Transplantation and Cellular Therapy (ASTCT) guidelines established a consensus grading system (grade 1 to 4) for both CRS and ICANS. 7 CRS usually appears within 1 to 2 weeks after infusion.…”

Section: Context and Policy Issuesmentioning

confidence: 99%

Anticytokine Therapy and Corticosteroids for Cytokine Release Syndrome and for Neurotoxicity Following T-Cell Engager or CAR T-Cell Therapy

CADTH

2024

cjht

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What Is the Issue? Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are the most common toxicities secondary to T-cell engager or chimeric antigen receptor (CAR) T-cell therapy. The US FDA and Health Canada approved tocilizumab, an anti-interleukin-6 receptor antagonist, for the management of severe or life-threatening cases of CRS. Corticosteroids also play an important role in CRS management and are the mainstay of ICANS management. Decision-makers are interested in understanding the use of anticytokine drugs (i.e., tocilizumab, anakinra, siltuximab) and/or corticosteroids in the management of CRS and ICANS following T-cell engager or CAR T-cell therapy. What Did We Do? We identified and summarized the literature comparing the clinical effectiveness and safety of anticytokine therapy and/or corticosteroids with alternative care or treatment as usual for treating and preventing of CRS and ICANS. We also searched for evidence-based recommendations for the use of anticytokine therapy and/or corticosteroids to treat and prevent CRS and ICANS. A research information specialist conducted a literature search of peer-reviewed and grey literature sources published between January 1, 2019 and February 26, 2024 for CRS; and between January 1, 2019 and March 4, 2024 for ICANS. One reviewer screened citations for inclusion based on predefined criteria, critically appraised the included studies, and narratively summarized the findings. What Did We Find? This report presents evidence-based findings on 3 retrospective chart review studies, 2 prospective cohort studies, and 4 consensus guidelines. Limited and low-quality clinical evidence from studies with a high risk of bias suggested that early use of tocilizumab or corticosteroids, or prophylactic use of tocilizumab or anakinra may reduce the risk of a high-grade CRS without a negative impact on neurotoxicity or immunotherapy treatment outcomes. The included guidelines recommend the use of tocilizumab for treatment of higher-grade CRS, or for treatment of grade 1 CRS if symptoms persist for 3 days or more. Corticosteroids could be added in conjunction if there is no improvement or persistent symptoms after tocilizumab therapy. For the management of ICANS in the absence of concurrent CRS, supportive care is the preferred treatment option for grade 1 ICANS, while corticosteroids are recommended for the management of grade 2 to 4 ICANS. In the presence of concurrent CRS, guidelines recommend tocilizumab therapy as per management of CRS, and corticosteroids should be continued until improvement to grade 1. We did not identify any clinical evidence regarding the clinical efficacy and safety of anticytokine therapy and/or corticosteroids for treatment of CRS and ICANS compared with alternative treatment or treatment as usual. We also did not identify any guidelines for the use of prophylactic anticytokine therapy, corticosteroids, or both for the prevention of CRS and ICANS. What Does This Mean? Despite limited and low-quality evidence, the findings suggest some potential benefits of prophylactic or early use of anticytokine therapy and corticosteroids for the management of immunotherapy-related toxicities. Guidelines offer guidance on the management of CRS, ICANS and other less common toxicities related to immunotherapy based on the available low-quality evidence. When using the clinical evidence and recommendations summarized in this report to inform decisions, decision-makers should consider that the evidence is limited and of low quality. To improve the certainty of findings, there is a need for more robust prospective clinical trials with larger sample sizes, and lower risk of bias.

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“…To mitigate the risk of CRS and neurotoxicity, the FDA approved the use of the humanized anti-IL6 receptor antibody tocilizumab in 2017 for CAR T cell therapy. Other potential treatments for these adverse events include the IL-1 receptor antagonist anakinra and the anti-IL6 chimeric antibody siltuximab ( 78 , 79 ). The underlying mechanisms of CRS and ICANS are complex.…”

Section: Major Challenges To Overcome For Car T Cell Therapymentioning

confidence: 99%

From bench to bedside: the history and progress of CAR T cell therapy

et al. 2023

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Chimeric antigen receptor (CAR) T cell therapy represents a major breakthrough in cancer care since the approval of tisagenlecleucel by the Food and Drug Administration in 2017 for the treatment of pediatric and young adult patients with relapsed or refractory acute lymphocytic leukemia. As of April 2023, six CAR T cell therapies have been approved, demonstrating unprecedented efficacy in patients with B-cell malignancies and multiple myeloma. However, adverse events such as cytokine release syndrome and immune effector cell-associated neurotoxicity pose significant challenges to CAR T cell therapy. The severity of these adverse events correlates with the pretreatment tumor burden, where a higher tumor burden results in more severe consequences. This observation is supported by the application of CD19-targeted CAR T cell therapy in autoimmune diseases including systemic lupus erythematosus and antisynthetase syndrome. These results indicate that initiating CAR T cell therapy early at low tumor burden or using debulking strategy prior to CAR T cell infusion may reduce the severity of adverse events. In addition, CAR T cell therapy is expensive and has limited effectiveness against solid tumors. In this article, we review the critical steps that led to this groundbreaking therapy and explore ongoing efforts to overcome these challenges. With the promise of more effective and safer CAR T cell therapies in development, we are optimistic that a broader range of cancer patients will benefit from this revolutionary therapy in the foreseeable future.

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Interleukin Inhibitors in Cytokine Release Syndrome and Neurotoxicity Secondary to CAR-T Therapy

Cited by 13 publications

References 72 publications

Targeting IL-6 Signaling Pathways for Musculoskeletal Disorders Treatment: Risks and Benefits

Targeting IL-6 Signaling Pathways for Musculoskeletal Disorders Treatment: Risks and Benefits

Anticytokine Therapy and Corticosteroids for Cytokine Release Syndrome and for Neurotoxicity Following T-Cell Engager or CAR T-Cell Therapy

From bench to bedside: the history and progress of CAR T cell therapy

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