Hyperacute toxicity with combination ipilimumab and anti-PD1 immunotherapy

Dearden, Helen; Au, Lewis; Wang, Daniel; Zimmer, Lisa; Eroglu, Zeynep; Smith, Jessica L.; Cuvietto, Marcello; Khoo, Christine; Atkinson, Victoria; Lo, Serigne; Long, Georgina V.; Sandhu, Shahneen; Ascierto, Paolo A.; Carlino, Matteo S.; Johnson, Douglas B.; Larkin, James; Menzies, Alexander M.

doi:10.1016/j.ejca.2021.04.045

Cited by 18 publications

(5 citation statements)

References 18 publications

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“…Given the well-accepted notion in clinical outcomes that irAE could be considered a positive marker for immunotherapy, the molecular link and precise demarcation between beneficial cancer immunotherapeutic efficacy and unacceptable irAE is yet to be defined [ 60 ]. Commonly reported irAE responses in patients on ICI include inflammatory damage to solid organs, such as pneumonitis, myocarditis and colitis [ 61 , 62 ]. Overcoming irAE while retaining cancer immunotherapeutic efficacy is central for ICI success.…”

Section: Discussionmentioning

confidence: 99%

Low-Salt Diet Reduces Anti-CTLA4 Mediated Systemic Immune-Related Adverse Events while Retaining Therapeutic Efficacy against Breast Cancer

Khandekar

Dahunsi

Esteve

et al. 2022

Biology

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Immune checkpoint inhibitor (ICI) therapy has revolutionized the breast cancer treatment landscape. However, ICI-induced systemic inflammatory immune-related adverse events (irAE) remain a major clinical challenge. Previous studies in our laboratory and others have demonstrated that a high-salt (HS) diet induces inflammatory activation of CD4+T cells leading to anti-tumor responses. In our current communication, we analyzed the impact of dietary salt modification on therapeutic and systemic outcomes in breast-tumor-bearing mice following anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA4) monoclonal antibody (mAb) based ICI therapy. As HS diet and anti-CTLA4 mAb both exert pro-inflammatory activation of CD4+T cells, we hypothesized that a combination of these would lead to enhanced irAE response, while low-salt (LS) diet through blunting peripheral inflammatory action of CD4+T cells would reduce irAE response. We utilized an orthotopic murine breast tumor model by injecting Py230 murine breast cancer cells into syngeneic C57Bl/6 mice. In an LS diet cohort, anti-CTLA4 mAb treatment significantly reduced tumor progression (day 35, 339 ± 121 mm3), as compared to isotype mAb (639 ± 163 mm3, p < 0.05). In an HS diet cohort, treatment with anti-CTLA4 reduced the survival rate (day 80, 2/15) compared to respective normal/regular salt (NS) diet cohort (8/15, p < 0.05). Further, HS plus anti-CTLA4 mAb caused an increased expression of inflammatory cytokines (IFNγ and IL-1β) in lung infiltrating and peripheral circulating CD4+T cells. This inflammatory activation of CD4+T cells in the HS plus anti-CTLA4 cohort was associated with the upregulation of inflammasome complex activity. However, an LS diet did not induce any significant irAE response in breast-tumor-bearing mice upon treatment with anti-CTLA4 mAb, thus suggesting the role of high-salt diet in irAE response. Importantly, CD4-specific knock out of osmosensitive transcription factor NFAT5 using CD4cre/creNFAT5flox/flox transgenic mice caused a downregulation of high-salt-mediated inflammatory activation of CD4+T cells and irAE response. Taken together, our data suggest that LS diet inhibits the anti-CTLA4 mAb-induced irAE response while retaining its anti-tumor efficacy.

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Section: Discussionmentioning

confidence: 99%

Low-Salt Diet Reduces Anti-CTLA4 Mediated Systemic Immune-Related Adverse Events while Retaining Therapeutic Efficacy against Breast Cancer

Khandekar

Dahunsi

Esteve

et al. 2022

Biology

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“…Patients administered steroids are uniquely at risk of undermining the efficacy of their antineoplastics, including immune checkpoint inhibitors (ICIs). Multiple studies have documented an association of steroid use with decreased progression-free survival, including a meta-analysis and in a dose-dependent manner [10][11][12][13]. An overarching limitation of current studies is their retrospective nature and associated confounding factors, such as discontinuation of immunotherapy or indication for steroid use.…”

Section: Resultsmentioning

confidence: 99%

Safety of Immunomodulatory Systemic Therapies Used in the Management of Immune-Related Cutaneous Adverse Events

Gu,

Nath,

Markova

2023

Pharmaceuticals

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Immune-related cutaneous adverse events (ircAEs) commonly occur in patients on treatment with immune checkpoint inhibitors and can significantly reduce patient quality of life. These are often treated with immunomodulatory agents, including glucocorticoids, immunosuppressants, and biologics. While often effective at managing symptoms, these therapies can cause several adverse events which may limit their use. In addition, immunomodulatory agents should be used with particular caution in patients receiving immunotherapy, as the efficacy of the oncologic regimen may potentially be undermined. In this review, we summarize the safety of systemic therapies that are used in the management of ircAEs, with a particular focus on the resultant risk of secondary tumor progression in patients with active cancer.

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“…Diarrhea and colitis were only in grades 1–3 [ 31 ]. In a research study by Dearden et al, all 2 myocarditis cases were grade 5, and no other treatment-related mortality was reported [ 32 ]. There is no evidence that cardiac toxicity correlates with the ICI’s dose [ 33 ].…”

Section: Review and Discussionmentioning

confidence: 99%

Myocarditis Induced by Immunotherapy in Metastatic Melanoma—Review of Literature and Current Guidelines

Czarnecka

Kleibert

Płachta

et al. 2022

JCM

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Immunotherapy is a widely used treatment modality in oncology. Immune checkpoint inhibitors, as a part of immunotherapy, caused a revolution in oncology, especially in melanoma therapy, due to the significant prolongation of patients’ overall survival. These drugs act by activation of inhibited immune responses of T lymphocytes against cancer cells. The mechanism responsible for the therapy’s high efficacy is also involved in immune tolerance of the patient’s own tissues. The administration of ICI therapy to a patient can cause severe immune reactions against non-neoplastic cells. Among them, cardiotoxicity seems most important due to the high mortality rate. In this article, we present the history of a 79 year-old patient diagnosed with melanoma who died due to myocarditis induced by ICI therapy, despite the fast administration of recommended immunosuppressive therapy, as an illustration of possible adverse events of ICI. Additionally, we summarize the mechanism, risk factors, biomarkers, and clinical data from currently published guidelines and studies about ICI-related myocarditis. The fast recognition of this fatal adverse effect of therapy may accelerate the rapid introduction of treatment and improve patients’ outcomes.

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Hyperacute toxicity with combination ipilimumab and anti-PD1 immunotherapy

Cited by 18 publications

References 18 publications

Low-Salt Diet Reduces Anti-CTLA4 Mediated Systemic Immune-Related Adverse Events while Retaining Therapeutic Efficacy against Breast Cancer

Low-Salt Diet Reduces Anti-CTLA4 Mediated Systemic Immune-Related Adverse Events while Retaining Therapeutic Efficacy against Breast Cancer

Safety of Immunomodulatory Systemic Therapies Used in the Management of Immune-Related Cutaneous Adverse Events

Myocarditis Induced by Immunotherapy in Metastatic Melanoma—Review of Literature and Current Guidelines

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