RESUMEN
Cytokine storm syndromes (CSSs) comprise a group of severe and often fatal hyperinflammatory conditions driven by the overproduction of pro-inflammatory cytokines by activated cells of the immune system. Many of the CSS-associated cytokines mediate their downstream effects by signaling through the Janus kinases (JAKs) and signal transducers and activators of transcription (STATs). In addition, several of these cytokines are produced downstream of JAK/STAT pathway activation. Therefore, targeting JAK/STAT signaling using small molecule JAK inhibitors has become an increasingly appealing therapeutic option to dampen hyperinflammation in patients with CSSs. Application of JAK inhibitors in preclinical CSS models has shown improvements in multiple sequelae of hyperinflammation, and there is growing clinical evidence supporting the efficacy of JAK inhibition in patients with these conditions. Although generally well tolerated, JAK inhibitor use is not without potential for toxicity, especially in settings like CSSs where end-organ dysfunction is common. More prospective clinical trials incorporating JAK inhibitors, alone or in combination with other immunomodulatory therapies, are necessary to determine the optimal dosing, schedule, efficacy, and tolerability of these agents for patients experiencing CSSs.
Asunto(s)
Síndrome de Liberación de Citoquinas , Inhibidores de las Cinasas Janus , Quinasas Janus , Humanos , Inhibidores de las Cinasas Janus/uso terapéutico , Inhibidores de las Cinasas Janus/efectos adversos , Síndrome de Liberación de Citoquinas/tratamiento farmacológico , Síndrome de Liberación de Citoquinas/inmunología , Quinasas Janus/antagonistas & inhibidores , Quinasas Janus/metabolismo , Transducción de Señal/efectos de los fármacos , Citocinas/metabolismo , Animales , Factores de Transcripción STAT/metabolismo , Factores de Transcripción STAT/antagonistas & inhibidoresRESUMEN
ABSTRACT: Hemophagocytic lymphohistiocytosis (HLH) comprises a severe hyperinflammatory phenotype driven by the overproduction of cytokines, many of which signal via the JAK/STAT pathway. Indeed, the JAK1/2 inhibitor ruxolitinib has demonstrated efficacy in preclinical studies and early-phase clinical trials in HLH. Nevertheless, concerns remain for ruxolitinib-induced cytopenias, which are postulated to result from the blockade of JAK2-dependent hematopoietic growth factors. To explore the therapeutic effects of selective JAK inhibition in mouse models of HLH, we carried out studies incorporating the JAK1 inhibitor itacitinib, JAK2 inhibitor fedratinib, and JAK1/2 inhibitor ruxolitinib. All 3 drugs were well-tolerated and at the doses tested, they suppressed interferon-gamma (IFN-γ)-induced STAT1 phosphorylation in vitro and in vivo. Itacitinib, but not fedratinib, significantly improved survival and clinical scores in CpG-induced secondary HLH. Conversely, in primary HLH, in which perforin-deficient (Prf1-/-) mice are infected with lymphocytic choriomeningitis virus (LCMV), itacitinib, and fedratinib performed suboptimally. Ruxolitinib demonstrated excellent clinical efficacy in both HLH models. RNA-sequencing of splenocytes from LCMV-infected Prf1-/- mice revealed that itacitinib targeted inflammatory and metabolic pathway genes in CD8 T cells, whereas fedratinib targeted genes regulating cell proliferation and metabolism. In monocytes, neither drug conferred major transcriptional impacts. Consistent with its superior clinical effects, ruxolitinib exerted the greatest transcriptional changes in CD8 T cells and monocytes, targeting more genes across several biologic pathways, most notably JAK-dependent proinflammatory signaling. We conclude that JAK1 inhibition is sufficient to curtail CpG-induced disease, but combined inhibition of JAK1 and JAK2 is needed to best control LCMV-induced immunopathology.
Asunto(s)
Modelos Animales de Enfermedad , Linfohistiocitosis Hemofagocítica , Nitrilos , Pirazoles , Pirimidinas , Animales , Pirimidinas/farmacología , Linfohistiocitosis Hemofagocítica/tratamiento farmacológico , Linfohistiocitosis Hemofagocítica/inducido químicamente , Linfohistiocitosis Hemofagocítica/patología , Pirazoles/farmacología , Pirazoles/uso terapéutico , Ratones , Janus Quinasa 1/antagonistas & inhibidores , Janus Quinasa 1/metabolismo , Janus Quinasa 1/genética , Pirroles/farmacología , Pirroles/uso terapéutico , Janus Quinasa 2/antagonistas & inhibidores , Janus Quinasa 2/genética , Janus Quinasa 2/metabolismo , Ratones Endogámicos C57BL , Sulfonamidas/farmacología , Sulfonamidas/uso terapéutico , Factor de Transcripción STAT1/metabolismo , Factor de Transcripción STAT1/genética , Inhibidores de las Cinasas Janus/farmacología , Inhibidores de las Cinasas Janus/uso terapéutico , Piperidinas/farmacología , Humanos , Bencenosulfonamidas , Hidrocarburos Aromáticos con Puentes , PirrolidinasRESUMEN
Background: Primary hemophagocytic lymphohistiocytosis (pHLH) is an inherited inflammatory syndrome driven by the exuberant activation of interferon-gamma (IFNg)-producing CD8 T cells. Towards this end, ruxolitinib treatment or IFNg neutralization (aIFNg) lessens immunopathology in a model of pHLH in which perforin-deficient mice (Prf1-/-) are infected with Lymphocytic Choriomeningitis virus (LCMV). However, neither agent completely eradicates inflammation. Two studies combining ruxolitinib with aIFNg report conflicting results with one demonstrating improvement and the other worsening of disease manifestations. As these studies used differing doses of drugs and varying LCMV strains, it remained unclear whether combination therapy is safe and effective. Methods: We previously showed that a ruxolitinib dose of 90 mg/kg lessens inflammation in Prf1-/- mice infected with LCMV-Armstrong. To determine whether this dose controls inflammation induced by a different LCMV strain, we administered ruxolitinib at 90mg/kg to Prf1-/- mice infected with LCMV-WE. To elucidate the impacts of single agent versus combination therapy, Prf1-/- animals were infected with LCMV, treated or not with ruxolitinib, aIFNg or both agents, and analyzed for disease features and the transcriptional impacts of therapy within purified CD8 T cells. Results: Ruxolitinib is well-tolerated and controls disease regardless of the viral strain used. aIFNg, administered alone or with ruxolitinib, is most effective at reversing anemia and reducing serum IFNg levels. In contrast, ruxolitinib appears better than aIFNg, and equally or more effective than combination therapy, at lessening immune cell expansion and cytokine production. Each treatment targets distinct gene expression pathways with aIFNg downregulating IFNg, IFNa, and IL-6-STAT3 pathways, and ruxolitinib downregulating IL-6-STAT3, glycolysis, and reactive oxygen species pathways. Unexpectedly, combination therapy is associated with upregulation of genes driving cell survival and proliferation. Conclusions: Ruxolitinib is tolerated and curtails inflammation regardless of the inciting viral strain and whether it is given alone or in combination with aIFNg. When administered at the doses used in this study, the combination of ruxolitinb and aIFNg appears no better than treatment with either drug alone in lessening inflammation. Further studies are warranted to elucidate the optimal doses, schedules, and combinations of these agents for the treatment of patients with pHLH.
Asunto(s)
Quinasas Janus , Linfohistiocitosis Hemofagocítica , Animales , Ratones , Interferón gamma/uso terapéutico , Linfohistiocitosis Hemofagocítica/tratamiento farmacológico , Linfohistiocitosis Hemofagocítica/genética , Linfohistiocitosis Hemofagocítica/patología , Interleucina-6 , Virus de la Coriomeningitis Linfocítica/fisiología , InflamaciónRESUMEN
Chimeric antigen receptor T-cell (CAR T-cell) therapy is associated with significant toxicities secondary to immune activation, including a rare but increasingly recognised severe toxicity resembling haemophagocytic lymphohistiocytosis (carHLH). We report the development of carHLH in 14·8% of paediatric patients and young adults treated with CD19-specific CAR T-cell therapy with carHLH, occurring most commonly in those with high disease burden. The diagnosis and treatment of carHLH required a high index of suspicion and included multidrug immunomodulation with variable response to therapies. Compared to patients without carHLH, patients with carHLH had both reduced response to CAR T-cell therapy (P-value = 0·018) and overall survival (P-value = < 0·0001).
Asunto(s)
Inmunoterapia Adoptiva/efectos adversos , Linfohistiocitosis Hemofagocítica/etiología , Adolescente , Adulto , Antígenos CD19/inmunología , Niño , Preescolar , Femenino , Humanos , Factores Inmunológicos/uso terapéutico , Linfohistiocitosis Hemofagocítica/diagnóstico , Linfohistiocitosis Hemofagocítica/inmunología , Linfohistiocitosis Hemofagocítica/terapia , Masculino , Análisis de Supervivencia , Adulto JovenRESUMEN
Choriocarcinoma syndrome is an uncommon, potentially fatal complication of germ cell tumors (GCTs) in adults, but it is not well documented in children. Pediatric central nervous system (CNS) GCTs comprise a rare group of malignancies not usually associated with extra-CNS metastatic disease. Here, we report the case of a pediatric patient with a suprasellar mixed GCT and pulmonary metastases who presented with intratumoral hemorrhage and stroke. Choriocarcinoma syndrome developed soon after initiating chemotherapy. The primary tumor and pulmonary metastases were successfully treated using a multidisciplinary approach, including neurovascular intervention, chemotherapy, and craniospinal irradiation.
Asunto(s)
Neoplasias Encefálicas/patología , Coriocarcinoma/patología , Neoplasias Pulmonares/secundario , Neoplasias de Células Germinales y Embrionarias/patología , Neoplasias Uterinas/patología , Neoplasias Encefálicas/tratamiento farmacológico , Niño , Coriocarcinoma/tratamiento farmacológico , Femenino , Hemorragia/patología , Humanos , Accidente Cerebrovascular Isquémico/patología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias de Células Germinales y Embrionarias/tratamiento farmacológico , Neoplasias Uterinas/tratamiento farmacológicoRESUMEN
Hemophagocytic lymphohistiocytosis (HLH) is a rare hyperinflammatory syndrome driven by overactive T cells and macrophages that abundantly secrete numerous pro-inflammatory cytokines, including interferon (IFN)-gamma, interleukin (IL)-1-beta, IL-2, IL-6, IL-10, IL-18, and tumor necrosis factor (TNF). The release of these and other cytokines underlies many of the clinical and pathologic manifestations of HLH, which if left untreated, can lead to multi-organ failure and death. The advent of etoposide-based regimens, such as the Histiocyte Society HLH-94 and HLH-2004 protocols, has substantially decreased the mortality associated with HLH. Nevertheless, the 5-year survival remains low at ~60%. To improve upon these results, studies have focused on the use of novel cytokine-directed therapies to dampen inflammation in HLH. Among the agents being tested is ruxolitinib, a potent inhibitor of the Janus Kinase (JAK) and Signal Transducer and Activation of Transcription (STAT) pathway, which functions downstream of many HLH-associated cytokines. Here, we review the basic biology of HLH, including the role of cytokines in disease pathogenesis, and discuss the use of ruxolitinib in the treatment of HLH.
Asunto(s)
Inhibidores de las Cinasas Janus/uso terapéutico , Linfohistiocitosis Hemofagocítica/tratamiento farmacológico , Terapia Molecular Dirigida , Pirazoles/uso terapéutico , Animales , Manejo de la Enfermedad , Susceptibilidad a Enfermedades , Predisposición Genética a la Enfermedad , Humanos , Inhibidores de las Cinasas Janus/farmacología , Linfohistiocitosis Hemofagocítica/diagnóstico , Linfohistiocitosis Hemofagocítica/epidemiología , Linfohistiocitosis Hemofagocítica/etiología , Nitrilos , Pronóstico , Pirazoles/farmacología , Pirimidinas , Resultado del TratamientoAsunto(s)
Ependimoma/patología , Glioma/patología , Neoplasias Infratentoriales/patología , Proteínas/genética , Neoplasias Supratentoriales/patología , Niño , Ependimoma/genética , Humanos , Neoplasias Infratentoriales/genética , Neoplasias Supratentoriales/genética , Factor de Transcripción ReIA/genética , Factor de Transcripción ReIA/metabolismoRESUMEN
Establishment of a permissive pre-malignant niche in concert with mutant stem are key triggers to initiate skin carcinogenesis. An understudied area of research is finding upstream regulators of both these triggers. IL27, a pleiotropic cytokine with both pro- and anti-inflammatory properties, was found to be a key regulator of both. Two step skin carcinogenesis model and K15-KRASG12D mouse model were used to understand the role of IL27 in skin tumors. CD11b-/- mice and small-molecule of ETAR signaling (ZD4054) inhibitor were used in vivo to understand mechanistically how IL27 promotes skin carcinogenesis. Interestingly, using in vivo studies, IL27 promoted papilloma incidence primarily through IL27 signaling in bone-marrow derived cells. Mechanistically, IL27 initiated the establishment of the pre-malignant niche and expansion of mutated stem cells in K15-KRASG12D mouse model by driving the accumulation of Endothelin A receptor (ETAR)-positive CD11b cells in the skin-a novel category of pro-tumor inflammatory identified in this study. These findings are clinically relevant, as the number of IL27RA-positive cells in the stroma is highly related to tumor de-differentiation in patients with squamous cell carcinomas.
Asunto(s)
Antígeno CD11b/genética , Interleucinas/metabolismo , Pirrolidinas/farmacología , Neoplasias Cutáneas/patología , Animales , Antígeno CD11b/metabolismo , Ratones , Mutación , Proteínas Proto-Oncogénicas p21(ras)/genética , Receptor de Endotelina A/metabolismo , Receptores de Citocinas/genética , Receptores de Interleucina , Neoplasias Cutáneas/inducido químicamente , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/metabolismo , Nicho de Células MadreRESUMEN
Injection of Dexamethasone (Dex) is commonly used in clinics to treat tendon injury such as tendinopathy because of its anti-inflammatory capabilities. However, serious adverse effects have been reported as a result of Dex treatment, such as impaired tendon healing and tendon rupture. Using both in vitro and in vivo approaches, this study was to determine the effects of Dex treatment on the proliferation and differentiation of human tendon stem cells (hTSCs), which can directly impact tendon healing. We found that Dex treatment stimulated cell proliferation at lower concentrations (<1,000 nM), whereas a high concentration (1,000 nM) decreased cell proliferation. Moreover, at all concentrations used (5, 10, 100, and 1,000 nM), Dex treatment induced non-tenocyte differentiation of hTSCs, as evidenced by a change in cell shape, a nearly complete suppression of collagen type I expression, and an upregulation of non-tenocyte related genes (PPARγ and Sox-9), which was especially evident when higher concentrations (>10 nM) of Dex were used. Implantation of Dex-treated hTSCs for a short time (3 weeks) resulted in the extensive formation of fatty tissues, cartilage-like tissues, and bony tissues. These findings suggest that Dex treatment in clinics may cause a paradoxical effect on the injured tendons it is supposed to treat: by inducing non-tenocyte differentiation of hTSCs, Dex treatment depletes the stem cell pool and leads to the formation of non-tendinous tissues (e.g., fatty and cartilage-like tissues), which make tendon susceptible to rupture.