The PI3Kδ inhibitor idelalisib impairs the function of human dendritic cells

Braun, Christiane; Schlaweck, Sebastian; Daecke, Solveig Nora; Brossart, Peter; Heine, Annkristin

doi:10.1007/s00262-021-02988-3

Cited by 8 publications

(4 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, with the launch of PI3K inhibitors, serious safety issues related to p110δ are increasingly exposed (Curigliano and Shah 2019 ). p110δ is preferentially expressed mainly in the haematopoietic system and affects immune cell development and function (Braun et al 2021 ). On one hand, PI3Kδ inhibitors, thus, show significant efficacy in the treatment of haematological malignancies due to the regulation of immune cells (Xenou and Papakonstanti 2020 ).…”

Section: Discussionmentioning

confidence: 99%

“…As the first approved PI3K inhibitor, many preclinical studies on idelalisib are still ongoing to address the high incidence of adverse events. Recent reports imply that idelalisib exposure deeply impairs human dendritic cell differentiation and function in vitro, which partly explains the mechanisms of idelalisib-associated infections (Braun et al 2021 ). In addition, idelalisib might increase the risk of infections in all B cell malignancies by inducing dysfunction of natural killer cells and T cells (Rohrbacher et al 2021 ).…”

Section: The Typical Pi3k Inhibitors Approved or In Clinical Trialsmentioning

confidence: 99%

See 1 more Smart Citation

Development and safety of PI3K inhibitors in cancer

Chen

et al. 2023

Arch Toxicol

View full text Add to dashboard Cite

The phosphatidylinositol 3-kinase (PI3K) signalling pathway regulates cell survival, proliferation, migration, metabolism and other vital cellular life processes. In addition, activation of the PI3K signalling pathway is important for cancer development. As a result, a variety of PI3K inhibitors have been clinically developed to treat malignancies. Although several PI3K inhibitors have received approval from the Food and Drug Administration (FDA) for significant antitumour activity, frequent and severe adverse effects have greatly limited their clinical application. These toxicities are mostly on-target and immune-mediated; nevertheless, the underlying mechanisms are still unclear. Current management usually involves intervention through symptomatic treatment, with discontinuation if toxicity persists. Therefore, it is necessary to comprehensively understand these adverse events and ensure the clinical safety application of PI3K inhibitors by establishing the most effective management guidelines, appropriate intermittent dosing regimens and new combination administration. Here, the focus is on the development of PI3K inhibitors in cancer therapy, with particular emphasis on isoform-specific PI3K inhibitors. The most common adverse effects of PI3K inhibitors are also covered, as well as potential mechanisms and management approaches.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: The Typical Pi3k Inhibitors Approved or In Clinical Trialsmentioning

confidence: 99%

Development and safety of PI3K inhibitors in cancer

Chen

et al. 2023

Arch Toxicol

View full text Add to dashboard Cite

show abstract

“…After 2 hours of incubation at 37°C/5% CO 2 , non-adherent cells were removed and cryopreserved at −80°C to be used for later analyses. Adherent cells were treated with human recombinant granulocyte macrophage-colony stimulating factor (GM-CSF; 100 ng/ml; Leukine Liquid Sargramostim; Bayer HealthCare Pharmaceuticals, USA) and interleukin-4 (20 ng/ml; R&D Systems, Wiesbaden-Nordenstadt, Germany) every second day starting at day 0 of culture as previously described ( 21 ). Maturation was induced on day 6 by adding LPS.…”

Section: Methodsmentioning

confidence: 99%

Spoilt for choice: different immunosuppressive potential of anaplastic lymphoma kinase inhibitors for non small cell lung cancer

Heine,

Held,

Daecke

et al. 2023

Front. Immunol.

Self Cite

View full text Add to dashboard Cite

IntroductionSeveral anaplastic lymphoma kinase (ALK)-inhibitors (ALKi) have been approved for the treatment of ALK-translocated advanced or metastatic Non Small Cell Lung Cancer (NSCLC), amongst crizotinib and alectinib. This forces physicians to choose the most suitable compound for each individual patient on the basis of the tumor´s genetic profile, but also in regard to toxicities and potential co-treatments. Moreover, targeted therapies might be combined with or followed by immunotherapy, which underlines the importance to gain detailed knowledge about potential immunomodulatory effects of these inhibitors. We here aimed to 1.) determine whether ALKi display an immunosuppressive effect on human dendritic cells (DCs) as important mediators of antigen-specific immunity and to 2.) dissect whether this immunosuppression differs among ALKi.MethodsWe investigated the effect of alectinib and crizotinib on human monocyte-derived DCs (moDC) as most powerful antigen-presenting cells. We performed immunophenotyping by flow cytometry, migration, antigen uptake and cytokine assays.ResultsCrizotinib-treated DCs showed reduced activation markers, such as CD83, decreased chemokine-guided migration, lower antigen uptake and produced inferior levels of pro-inflammatory cytokines, especially Interleukin-12. In contrast, the immunosuppressive potential of alectinib was significantly less pronounced. This indicates that crizotinib might profoundly dampen anti-tumor immunity, while alectinib had no unfavourable immunosuppressive effects.ConclusionsOur results implicate that current ALKi differ in their capacity to suppress the activation, migration and cytokine production of DCs as essential mediators of T cell immunity. We show that crizotinib, but not alectinib, had immunosuppressive effects on DCs phenotype and reduced DC function, thereby potentially impairing anti-tumor immunity.

show abstract

“…Idelalisib, targeting the phosphoinositide-3-kinase (PI3Kδ) of B cells and used in lymphoproliferative diseases could as well increase the risk of PCP [74,75]. However, this monoclonal antibody also has an impact on T lymphocytes and dendritic cells [76].…”

Section: B-lymphocytes Deficiencymentioning

confidence: 99%

Immune Response in Pneumocystis Infections According to the Host Immune System Status

Charpentier

Ménard

Marques

et al. 2021

JoF

View full text Add to dashboard Cite

The host immune response is critical in Pneumocystis pneumonia (PCP). Immunocompetent hosts can eliminate the fungus without symptoms, while immunodeficient hosts develop PCP with an unsuitable excessive inflammatory response leading to lung damage. From studies based on rodent models or clinical studies, this review aimed to better understand the pathophysiology of Pneumocystis infection by analysing the role of immune cells, mostly lymphocytes, according to the immune status of the infected host. Hence, this review first describes the immune physiological response in infected immunocompetent hosts that are able to eliminate the fungus. The objective of the second part is to identify the immune elements required for the control of the fungus, focusing on specific immune deficiencies. Finally, the third part concentrates on the effect of the different immune elements in immunocompromised subjects during PCP, to better understand which cells are detrimental, and which, on the contrary, are beneficial once the disease has started. This work highlights that the immune response associated with a favourable outcome of the infection may differ according to the immune status of the host. In the case of immunocompetency, a close communication between B cells and TCD4 within tertiary lymphocyte structures appears critical to activate M2 macrophages without much inflammation. Conversely, in the case of immunodeficiency, a pro-inflammatory response including Th1 CD4, cytotoxic CD8, NK cells, and IFNγ release seems beneficial for M1 macrophage activation, despite the impact of inflammation on lung tissue.

show abstract

The PI3Kδ inhibitor idelalisib impairs the function of human dendritic cells

Cited by 8 publications

References 23 publications

Development and safety of PI3K inhibitors in cancer

Development and safety of PI3K inhibitors in cancer

Spoilt for choice: different immunosuppressive potential of anaplastic lymphoma kinase inhibitors for non small cell lung cancer

Immune Response in Pneumocystis Infections According to the Host Immune System Status

Contact Info

Product

Resources

About