Treatment of refractory hemophagocytic lymphohistiocytosis with emapalumab despite severe concurrent infections

Lounder, Dana T.; Bin, Qiong; Min, Cristina de; Jordan, Michael B.

doi:10.1182/bloodadvances.2018025858

Cited by 93 publications

(67 citation statements)

References 18 publications

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“…Patients with chronically elevated IFN signatures may clinically respond to treatments that block type-I IFN signaling (11). Likewise, patients with high serum IL-18 levels and an MAS predisposition might respond to treatments that target IL-18 (20) and/or the type-II IFN, IFN-γ (21).…”

Section: Funding the Intramural Research Program Of The Nih Niaid mentioning

confidence: 99%

“…Whether and how free IL-18 drives the IRG-S, directly via coregulating expression of IRGs or via promoting IFN-γ needs to be evaluated. Pathomechanisms underlying the promising results with JAK inhibition in MAS and hemophagocytic lymphohistiocytosis (52-54) may be partially attributable to IFN-γ receptor signaling blockade (21), but treatments targeting the IL-18/IFN-γ axis are promising (55).…”

Section: Statisticsmentioning

confidence: 99%

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Distinct interferon signatures and cytokine patterns define additional systemic autoinflammatory diseases

Jesus¹,

Hou²,

Brooks³

et al. 2020

Journal of Clinical Investigation

177

173

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onset in infancy (SAVI), and another by additive loss-of-function mutations in proteasome genes causing the proteasome-associated autoinflammatory syndromes (PRAAS) (also, chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperatures [CANDLE]), presented with chronically elevated interferon (IFN) signatures, suggesting a pathogenic role for type-I IFN in autoinflammatory diseases (2, 3). Type-I IFN was first discovered as a soluble antiviral factor over 50 years ago, and a role in sterile inflammation was proposed in patients with systemic lupus erythematosus (4). However, the discovery of genetic mutations that cause the autoinflammatory type-I interferonopathies CANDLE (2, 5), SAVI (3, 6-8), and Aicardi-Goutières syndrome (AGS) (9, 10) have shed light on pathomechanisms that drive chronic IFN signaling, and recent studies blocking IFN signaling validate a critical role for type-I IFNs (11). AGS-causing loss-of-function mutations in nucleases impair self-nucleic acid homeostasis, SAVI-causing

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Section: Funding the Intramural Research Program Of The Nih Niaid mentioning

confidence: 99%

Section: Statisticsmentioning

confidence: 99%

Distinct interferon signatures and cytokine patterns define additional systemic autoinflammatory diseases

Jesus¹,

Hou²,

Brooks³

et al. 2020

Journal of Clinical Investigation

177

173

View full text Add to dashboard Cite

show abstract

“…Excessive production of IFN- can induce immunopathology [57]- [65]. However, the AREs solely fine-tune post-transcriptional regulation of IFN- production, while leaving the requirement of antigen recognition and transcriptional regulation in murine and human T cells intact ( [46], this study).…”

Section: Discussionmentioning

confidence: 99%

Human T cells employ conserved AU-rich elements to fine-tune IFN-γ production

Heeren

Popović

Guislain

et al. 2019

Preprint

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Long-lasting CD8 + T cell responses are critical in combatting infections and tumors. The proinflammatory cytokine IFN-γ is a key effector molecule herein. We recently showed that in murine T cells, the production of IFN-γ is tightly regulated through AU-rich elements (AREs) that are located in the 3' Untranslated Region (UTR). Loss of AREs resulted in prolonged cytokine production in activated T cells and boosted anti-tumoral T cell responses. Here, we investigated whether these findings can be translated to primary human T cells. Utilizing CRISPR-Cas9 technology, we deleted the ARE region from the IFNG 3'UTR in peripheral blood-derived human T cells. Loss of AREs stabilized the IFNG mRNA in T cells and supported a higher proportion of sustained IFN-γ protein-producing T cells. Importantly, this was also true for tumor antigen-specific T cells. MART-1 TCR engineered T cells that were gene-edited for ARE-deletion showed increased percentages of IFN-γ producing MART-1specific ARE-Del T cells in response to MART-1 expressing tumor cells. Combined, our study reveals that ARE-mediated post-transcriptional regulation is highly conserved between murine and human T cells. Furthermore, generating antigen-specific ARE-Del T cells is feasible, a feature that could potentially be exploited for therapeutical purposes. elements. revealed that IFN- sensing is instrumental to protect the host from infections by Mycobacteria species [14]-[16]. IFN- also prevents the development of cancers. In fact, mice lacking the Ifng gene, or the signaling protein downstream of Ifngr1/2, Stat1, spontaneously develop tumors [17],[18]. Furthermore, a high IFNG-mediated gene signature correlates with clinical response rates to immunotherapy in humans [19],[20]. Conversely, copy number alterations of IFN- pathway genes correlates with poor response to immunotherapy [21]. The regulation of IFN- production is multi-layered. The IFNG locus is only demethylated in effector and memory T cells [22], allowing for locus accessibility and transcription upon T cell activation. While the production of T cell effector molecules has been mainly attributed to changes in transcription and the presence of transcription factors [23]-[27], recently, the role of post-transcriptional regulation in T cells has also become appreciated [28]-[33]. Posttranscriptional regulation is mediated by sequence elements and structures present in both the 5' and 3' untranslated regions (UTRs) of mRNA molecules [34]-[37] and nucleoside modifications, such as adenine methylation [38]. By facilitating the binding of RNA binding proteins (RBPs), microRNAs and long non-coding RNAs, these regulators combined determine the actual protein output of a cell [37]. One of these sequence elements are adenylate uridylate-rich elements (AREs). AREs are AUUUA pentamers present in multimers in the 3'UTR of mRNA molecules [39],[40]. Interestingly, many cytokine transcripts contain AREs [37],[39]. They function as binding hubs for RBPs and microRNAs [39]-[41]. Binding to AREs by these factors me...

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“…Sarilumab is an anti-IL-6Rα MoAb approved for moderate-to-severe rheumatoid arthritis [66] with a welldefined role also in blocking IL-6 action in cancer [67], while emapalumab, directed toward interferon (IFN)-γ, is used in the therapy of hemophagocytic lymphohistiocytosis [68,69] and is employed in combination with anakinra, an IL-1R antagonist, in RA patients [70]. As tocilizumab, also sarilumab and emapalumab can effectively counteract the massive cytokine release related with SARS-CoV-2 infection.…”

Section: Sarilumab and Emapalumabmentioning

confidence: 99%

Drug repurposing against COVID-19: focus on anticancer agents

Ciliberto

Mancini

Paggi³

2020

J Exp Clin Cancer Res

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Background: The very limited time allowed to face the COVID-19 pandemic poses a pressing challenge to find proper therapeutic approaches. However, synthesis and full investigation from preclinical studies to phase III trials of new medications is a time-consuming procedure, and not viable in a global emergency, such as the one we are facing. Main Body: Drug repurposing/repositioning, a strategy effectively employed in cancer treatment, can represent a valid alternative. Most drugs considered for repurposing/repositioning in the therapy of the COVID-19 outbreak are commercially available and their dosage and toxicity in humans is well known, due to years (or even decades) of clinical use. This can allow their fast-track evaluation in phase II-III clinical trials, or even within straightforward compassionate use. Several drugs being re-considered for COVID-19 therapy are or have been used in cancer therapy. Indeed, virusinfected cells are pushed to enhance the synthesis of nucleic acids, protein and lipid synthesis and boost their energy metabolism, in order to comply to the "viral program". Indeed, the same features are seen in cancer cells, making it likely that drugs interfering with specific cancer cell pathways may be effective as well in defeating viral replication. Short Conclusion: To our knowledge, cancer drugs potentially suitable for facing SARS-CoV-2 infection have not been carefully reviewed. We present here a comprehensive analysis of available information on potential candidate cancer drugs that can be repurposed for the treatment of COIVD-19.

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Treatment of refractory hemophagocytic lymphohistiocytosis with emapalumab despite severe concurrent infections

Abstract: Key Points Neutralization of IFN-γ with emapalumab can reverse severe, refractory hemophagocytic lymphohistiocytosis. Neutralizing IFN-γ did not impair control of multiple viral and other infections in a severely ill patient.

Cited by 93 publications

References 18 publications

Distinct interferon signatures and cytokine patterns define additional systemic autoinflammatory diseases

Distinct interferon signatures and cytokine patterns define additional systemic autoinflammatory diseases

Human T cells employ conserved AU-rich elements to fine-tune IFN-γ production

Drug repurposing against COVID-19: focus on anticancer agents

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