Interleukin-2 Receptor Alpha Research Articles

Abstract 2446: IL4 receptor-induced proliferation is mediated via Glut1 activity in metastatic breast cancer

Abstract Breast cancer is the leading cause of cancer mortality in women. The breast cancer microenvironment supplies immune signals that influence tumor growth and metastatic behavior. The cytokine, Interleukin-4 (IL4), promotes increased survival, proliferation and invasion upon stimulation of the type II IL4 receptor alpha (IL4Rα) which is aberrantly expressed on epithelial cancer cells. Previously, we have shown that metastatic mouse mammary cancer cells have a strong dependence on IL4 signaling for colonization of metastatic sites in the lung and liver. Additionally, these cells uptake more glucose when treated with IL4 in vitro. Here, we assessed the importance of glucose consumption on pro-tumorigenic phenotypes induced by IL4/IL4Rα. In 4T1 cells, IL4/IL4Rα signaling increased protein expression of the glucose transporter, Glut1. IL4/IL4Rα activation also increased global glycosylation of Glut1. In human metastatic breast cancer cells (MDA-MB-231 and BT549), Crispr-mediated knockout (KO) of Glut1 significantly reduced glucose consumption when assayed by 2-NBDG uptake, a fluorescently labelled glucose analog. Additionally, Glut1 KO reversed the proliferative effects of IL4/IL4Rα stimulation on human cancer cells in vitro. Our data suggest that IL4-induced Glut1 expression supports the increased metabolic activity necessary for cancer cell proliferation. Targeting the IL4/IL4Rα signaling axis could potentially be a therapeutic strategy to impede tumor-associated metabolism and reduce tumor burden at primary and metastatic sites. Citation Format: Ebony Hargrove-Wiley, Daniel Valent, Demond Williams, Wendy Bindeman, Barbara Fingleton. IL4 receptor-induced proliferation is mediated via Glut1 activity in metastatic breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2446.

High serum cytokine levels may predict the responsiveness of patients with severe asthma to benralizumab

Objective: Benralizumab, a humanized monoclonal antibody against human IL-5 receptor alpha, is effective in treating eosinophilic severe asthma. However, patients’ response to benralizumab varies widely. In this study, we aimed to identify a new serum biomarker to accurately predict benralizumab response. Methods: Seventeen benralizumab-treated patients with severe eosinophilic asthma were enrolled. Blood samples were collected; pulmonary function tests were performed and questionnaires were disseminated at baseline and after 1, 2, 4, and 6 months of treatment. Blood cytokine levels were measured. Response was defined as an elevation in forced expiratory volume in 1 s of at least 10.4% from baseline after 4 months of treatment. Results: There were nine respondents and eight non-respondents. The non-responders showed significantly higher baseline serum interferon-γ; interleukin (IL)-4, -5, -6, -7, and -12p70; IL-17/IL-17A; IL-17E/IL-25; IL-18/IL-1F4; chemokine (C-C motif) ligand (CCL)3/macrophage inflammatory protein (MIP)-1α; CCL4/MIP-1β; CCL11/eotaxin; matrix metalloproteinase-12; tumor necrosis factor-α, and thymic stromal lymphopoietin levels. After benralizumab administration, the serum CCL3/MIP-1α and CCL11/eotaxin levels significantly and persistently increased in the responders (CCL3/MIP-1α, responders: 144.5 ± 37.9 pg/ml (baseline) vs. 210.3 ± 59.4 pg/ml (4 months), p = 0.009; non-responders: 270.8 ± 139.8 pg/ml (baseline) vs. 299.5 ± 159.9 pg/ml (4 months), p = 0.33; CCL11/eotaxin, responders: 167.9 ± 62.6 pg/ml (baseline) vs. 326.7 ± 134.4 pg/ml (4 months), p = 0.038; non-responders: 420.9 ± 323.1 pg/ml (baseline) vs. 502.1 ± 406.0 pg/ml (4 months), p = 0.30). Conclusion: Low baseline serum inflammatory cytokine levels may be useful in predicting a good benralizumab response. Supplemental data for this article is available online at at www.tandfonline.com/ijas .

IL-4-Responsive B Cells Are Detrimental During Chronic Tuberculosis Infection in Mice.

In tuberculosis, T cell-mediated immunity is extensively studied whilst B cells received limited attention in human and mice. Of interest, Mycobacterium tuberculosis (Mtb) does increase IL-4 Receptor-alpha (IL4Rα) expression in murine B cells. To better understand the role of IL4Rα signalling in B cells, we compared wild type mice with B cell-specific IL4Rα deficient mice (mb1creIL-4Rα-/lox mice). Chronic Mtb aerosol infection in mb1creIL-4Rα-/lox mice reduced lung and spleen bacterial burdens, compared to littermate (IL-4Rα-/lox) control animals. Consequently, lung pathology, inflammation and inducible nitric oxide synthase (iNOS) expression were reduced in the lungs of mb1creIL-4Rα-/lox mice, which was also accompanied by increased lung IgA and decreased IgG1 levels. Furthermore, intratracheal adoptive transfer of wild-type B cells into B cell-specific IL4Rα deficient mice reversed the protective phenotype. Moreover, constitutively mCherry expressing Mtb showed decreased association with B cells from mb1creIL-4Rα-/lox mice ex vivo. In addition, supernatants from Mtb-exposed B cells of mb1creIL-4Rα-/lox mice also increased the ability of macrophages to produce nitric oxide, IL-1β, IL-6 and TNF. Together, this demonstrates that IL-4-responsive B cells are detrimental during the chronic phase of tuberculosis in mice with perturbed antibody profiles, inflammatory cytokines and tnf and stat1 levels in the lungs.

Blastic Plasmacytoid Dendritic Cell Neoplasm: Progress in Cell Origin, Molecular Biology, Diagnostic Criteria and Therapeutic Approaches

SummaryBlastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematological malignancy characterized by recurrent skin nodules, an aggressive clinical course with rapid involvement of hematological organs, and a poor prognosis with poor overall survival. BPDCN is derived from plasmacytoid dendritic cells (pDCs) and its pathogenesis is unclear. The tumor cells show aberrant expression of CD4, CD56, interleukin-3 receptor alpha chain (CD123), blood dendritic cell antigen 2 (BDCA 2/CD303), blood dendritic cell antigen 4 (BDCA4) and transcription factor (E protein) E2-2 (TCF4). The best treatment drugs are based on experience by adopting those used for either leukemia or lymphoma. Relapse with drug resistance generally occurs quickly. Stem cell transplantation after the first complete remission is recommended and tagraxofusp is the first targeted therapy. In this review, we summarize the differentiation of BPDCN from its cell origin, its connection with normal pDCs, clinical characteristics, genetic mutations and advances in treatment of BPDCN. This review provides insights into the mechanisms of and new therapeutic approaches for BPDCN.

Oncolytic Vaccinia Virus Gene Modification and Cytokine Expression Effects on Tumor Infection, Immune Response, and Killing.

Oncolytic vaccinia viruses have promising efficacy and safety profiles in cancer therapy. Although antitumor activity can be increased by manipulating viral genes, the relative efficacy of individual modifications has been difficult to assess without side-by-side comparisons. This study sought to compare the initial antitumor activity after intravenous administration of five vaccinia virus variants of the same Western Reserve backbone and thymidine kinase gene deletion in RIP-Tag2 transgenic mice with spontaneous pancreatic neuroendocrine tumors. Tumors had focal regions of infection at 5 days after all viruses. Natural killer (NK) cells were restricted to these sites of infection, but CD8+ T cells and tumor cell apoptosis were widespread and varied among the viruses. Antitumor activity of virus VV-A34, bearing amino acid substitution A34K151E to increase viral spreading, and virus VV-IL2v, expressing a mouse IL2 variant (mIL2v) with attenuated IL2 receptor alpha subunit binding, was similar to control virus VV-GFP. However, antitumor activity was significantly greater after virus VV-A34/IL2v, which expressed mIL2v together with A34K151E mutation and viral B18R gene deletion, and virus VV-GMCSF that expressed mouse GM-CSF. Both viruses greatly increased expression of CD8 antigens Cd8a/Cd8b1 and cytotoxicity genes granzyme A, granzyme B, Fas ligand, and perforin-1 in tumors. VV-A34/IL2v led to higher serum IL2 and greater tumor expression of death receptor ligand TRAIL, but VV-GMCSF led to higher serum GM-CSF, greater expression of leukocyte chemokines and adhesion molecules, and more neutrophil recruitment. Together, the results show that antitumor activity is similarly increased by viral expression of GM-CSF or IL2v combined with additional genetic modifications.

Explainable prediction of survival using clinical, molecular, and radiomic profiles in recurrent high-grade glioma patients treated with CAR T-cell therapy.

104 Background: High-grade glioma (HGG) is an aggressive heterogeneous primary CNS neoplasm with high recurrence rate and poor survival. Multiple ongoing clinical trials are leveraging targeted molecular and immunologic therapeutics (e.g., pembrolizumab, Chimeric Antigen Receptor [CAR] T-cell therapy) in effort to improve survival. Explainable predictive models have shown value in identifying biomarkers predictive of treatment response as well as informing prognosis. In this study, we developed an explainable machine learning model leveraging clinical, molecular and radiomic (imaging) features to predict overall survival in patients suffering from HGG treated with CAR T-cell therapy. Methods: In this IRB-approved phase 1 clinical trial, 60 patients (39 males, median age = 49) suffering from HGG underwent surgical resection and CAR T-cell therapy1. All patients underwent baseline MRI scans prior to both surgical resection and CAR T-cell administration in the resection cavity. Using contrast-enhanced T1-weighted MRIs, we segmented the enhancing tumor (ET) and generated radiomic features. For predictive modeling, we incorporated the following features: Age, gender, race, ethnicity, histology, tumor grade (WHO), IL-13 receptor alpha 2 (IL-13Rα2) expression (H score), unifocal or multifocal lesions, tumor location (lobe), shape-based radiomics (tumor volume, surface area, and sphericity). We utilized gradient-boosted tree models to classify whether survival is above or below 180 days with two-loop nested cross-validation. For the inner validation loop, we optimized the model with hyper-parameter tuning. For the outer validation loop, we tested the optimal model on the hold-out data and the predictions were used as survival scores (0 – 1). Larger scores imply better predicted survival. For prediction explanations, we adopted the Shapley additive explanation (SHAP) framework. Results: The outer validation loop Area Under the Receiver Operating Characteristic Curve and Area under the Precision-Recall Curve were 0.76 and 0.81, respectively. Among the top five most important features calculated from SHAP; patients with larger tumor surface area, tumor volume and age have reduced survival scores while patients with larger IL-13Rα2 and tumor sphericity have increased survival scores. We stratified the patients into two distinct prognostic sub-groups (30 patients each group) using the survival scores obtained from the outer loop, with a log-rank test p < 0.01. Conclusions: In patients with HGG treated with CAR T-cell therapy, we found that tumor surface area/volume and age are inversely related to survival while increased IL-13Rα2 expression and tumor sphericity were positive predictor of survival. Our model can potentially be used to optimize clinical trial enrollment through more precise patient screening and treatment planning.

Phase I dose escalation of KD033, a PDL1-IL15 bispecific molecule, in advanced solid tumors.

2568 Background: IL-2 and IL-15 signal through the shared IL-2/15 βγ receptor, but unlike IL-2, IL-15 does not expand regulatory T cells (Tregs), does not mediate activation-induced cell death and may have an improved therapeutic index. KD033 is a fusion antibody combining a fully human, high affinity anti-human Programmed Death Ligand 1 (PD-L1) IgG1 antibody with the human IL-15 receptor alpha (IL15Rα) sushi domain and human IL-15 (IL-15). KD033 (or its mouse cross reactive surrogate molecule, srKD033) has been extensively characterized in multiple in vitro and in vivo nonclinical studies. The fusion of anti-PD-L1 antibody to IL-15 significantly increases the maximal-tolerated dose (MTD) of srKD033 in mice compared to free IL-15. In addition, srKD033 has exhibited increased efficacy in rejecting tumors in mice as compared to the combination of its individual components, anti-PD-L1 antibody and IL-15. Methods: This is a phase 1, open-label, multiple ascending dose, multi-center clinical trial being conducted in patients with metastatic or locally advanced solid tumors (NCT04242147). The primary objective is to determine the safety and tolerability and the MTD of KD033. Secondary objectives include characterization of PK and immunogenicity, evaluation of CD8 T and NK cell activation and assessment of best overall response and duration of response. KD033 is administered by IV infusion over 30 minutes every 14 days. Accelerated intra-patient dose escalation across the initial three dose levels, followed by 3+3 escalation thereafter, is investigating dose ranges from 3 µg/kg to 600 µg/kg. Efficacy evaluation is planned in an expansion cohort of patients with PD-1/L1 refractory tumors. Results: A total of 7 patients have received treatment. Three patients were dosed in Cohort 1 and four patients were dosed in Cohort 2. Through two dose escalation cohorts (3 µg/kg – 25 µg/kg), no dose-limiting toxicities have been reported. Grade 1-2 treatment-related toxicities, when observed, resolved within 24 hours with supportive management. 6 patients are evaluable for treatment response with one patient (adenoid cystic carcinoma) in the first cohort having stable disease for more than 6 months. Conclusions: KD033 has been well tolerated early in dose escalation with on-mechanism pharmacodynamics consistent with IL-15 agonism. Clinical trial information: NCT04242147.

Development of a Core Outcome Set for Therapeutic Studies in Eosinophilic Esophagitis (COREOS): An International Multidisciplinary Consensus

Development of a Core Outcome Set for Therapeutic Studies in Eosinophilic Esophagitis (COREOS): An International Multidisciplinary Consensus

Dupilumab rapidly improves asthma control in predominantly anti-IL5/IL5R pretreated Austrian real-life severe asthmatics.

Dupilumab is a monoclonal antibody against the IL‐4 receptor alpha which has shown efficacy in T2 high severe asthmatics in phase 3 randomized controlled trials. The purpose of this real‐life study is to demonstrate the real‐life effectiveness of dupilumab in Austrian severe asthma patients. We retrospectively analyzed all patients receiving dupilumab at our severe asthma clinic. Thirteen patients have so far received dupilumab at our center. The primary outcome, asthma control questionnaire 6‐item scale at 2 weeks, improved by 0.57 points (p = .014), which is statistically and clinically significant. Similarly, the asthma control test at 4 weeks improved by 3.91 points (p = .024), also statistically and clinically significant. Improvements in forced expiratory volume in 1 s at 2 weeks were neither statistically, nor clinically significant. Improvements at 4 weeks (+220 ml, p = .041), and 3 months (+229 ml, p = .006), were statistically significant and clinically borderline significant. No severe adverse events or hypereosinophilia were observed. No adverse events led to treatment discontinuation. Most patients (85%) had previously received monoclonal antibody treatment for severe asthma. Previous monoclonal antibody treatment had been discontinued in these patients due to a lack of clinical response. Dupilumab is effective and safe in Austrian real‐life severe asthmatics. It provides a possible treatment strategy for T2 high severe asthmatics who do not qualify for anti‐immunoglobulin E or anti‐IL5/IL5R monoclonal antibody treatments or do not adequately respond to these.

Baseline Plasma Inflammatory Profile Is Associated With Response to Neoadjuvant Chemotherapy in Patients With Pancreatic Adenocarcinoma.

Despite its increased application in pancreatic ductal adenocarcinoma (PDAC), complete response to neoadjuvant therapy (NAT) is rare. Given the critical role of host immunity in regulating cancer, we sought to correlate baseline inflammatory profiles to significant response to NAT. PDAC patients receiving NAT were classified as responders (R) or nonresponders (NR) by carbohydrate antigen 19-9 response, pathologic tumor size, and lymph node status in the resected specimen. Baseline (treatment-naive) plasma was analyzed to determine levels of 27 inflammatory mediators. Logistic regression was used to correlate individual mediators with response. Network analysis and Pearson correlation maps were derived to determine baseline inflammatory mediator profiles. Forty patients (20R and 20NR) met study criteria. The R showed significantly higher overall survival (59.4 vs. 21.25 mo, P=0.002) and disease-free survival (50.97 vs. 10.60 mo, P=0.005), compared with NR. soluble interleukin-2 receptor alpha was a significant predictor of no response to NAT (P=0.045). Analysis of inflammatory profiles using the Pearson heat map analysis followed by network analysis depicted increased inflammatory network complexity in NR compared with R (1.69 vs. 1), signifying a more robust baseline inflammatory status of NR. A panel of inflammatory mediators identified by logistic regression and Fischer score analysis was used to create a potential decision tree to predict NAT response. We demonstrate that baseline inflammatory profiles are associated with response to NAT in PDAC, and that an upregulated inflammatory status is associated with a poor response to NAT. Further analysis into the role of inflammatory mediators as predictors of chemotherapy response is warranted.

IL‐13/IL4Rα Signaling Increases Tension in Human Circular and Longitudinal Esophageal Smooth Muscle Through Distinct Molecular Pathways: Potential Contribution to Reduced Esophageal Distensibility in EoE

Introduction Reduced esophageal distensibility (ED) in EoE has been attributed largely to fibrosis, but inflammatory cell infiltration and increased tension in esophageal smooth muscle (ESM) also might contribute to reduced ED. EoE is a type 2 immune disease in which type 2 cytokines IL-4 and IL-13 signal through the IL-4 receptor alpha (IL4Rα), activating Janus kinases (JAKs) that in turn activate STAT6. Dupilumab, a monoclonal antibody against IL4Rα, can improve ED in EoE patients, but it is unclear whether this is due to effects on fibrosis, inflammatory cells, or ESM tension. To explore how IL4Rα signaling might affect ESM tension, we treated ESM cells with IL-13 and selective inhibitors of STAT6 (AS1517499, 600 nM) or JAK1/2 (ruxolitinib, 100 ng/ml). Since ESM tension is induced by phosphorylation of myosin light chains through PKC and ROCK pathways, we also studied effects of selective inhibitors of PKC (calphostin C, 500 nM) and ROCK (Y-27632, 10 µM) on ESM tension. Methods Using 1 circular (C) and 1 longitudinal (L) telomerase-expressing ESM cell lines generated from muscularis propria of a human organ donor, cell contraction was assessed in the attached gel contraction model. Gels containing equal numbers of ESM cells were cultured for 48 hours with and without IL-13 (50 ng/ml), during which ESM tension developed; contraction was initiated by releasing the gel from the sides of the culture plate. Histamine (100 µM), a contraction mediator, was added immediately prior to release in some studies. Contraction was assessed by measuring gel surface area over 24 hours using Image J. Gel contraction studies were repeated in the presence of pathway inhibitors. Results In non-treated cells, gel sizes of CESM were significant smaller at all time points than those of LESM (p<0.001). Compared to non-treated controls, IL-13 significantly reduced gel size in both CESM and LESM (Figures 1&2). Also compared to non-treated controls, IL-13-treatment resulted in smaller gel sizes at all time points following histamine stimulation in both CESM and LESM (p<0.05). In LESM, IL-13-induced reductions in gel size were significantly inhibited by ruxolitinib, calphostin C, and Y-27632, but not by AS1517499 (Figure 2). In CESM, these IL-13-induced reductions were significantly inhibited by ruxolitinib and calphostin C, but not by Y-27632 or AS1517499 (Figure 1). Conclusions CESM generates more baseline tension that LESM. IL-13 increases tension and enhances the contractile response to histamine in both CESM and LESM. In LESM, both the PKC and ROCK pathways contribute to IL-13-mediated increases in tension whereas in CESM, only the PKC pathway contributes to this effect. These findings demonstrate distinct molecular pathways whereby IL-13 contributes to LESM and CESM tension, and suggest that IL-13-induced ESM tension may contribute to the reduced ED of EoE.

In vivo targeting of lentiviral vectors pseudotyped with the Tupaia paramyxovirus H glycoprotein bearing a cell-specific ligand

Despite their exceptional capacity for transgene delivery ex vivo, lentiviral (LV) vectors have been slow to demonstrate clinical utility in the context of in vivo applications. Unresolved safety concerns related to broad LV vector tropism have limited LV vectors to ex vivo applications. Here, we report on a novel LV vector-pseudotyping strategy involving envelope glycoproteins of Tupaia paramyxovirus (TPMV) engineered to specifically target human cell-surface receptors. LV vectors pseudotyped with the TPMV hemagglutinin (H) protein bearing the interleukin (IL)-13 ligand in concert with the TPMV fusion (F) protein allowed efficient transduction of cells expressing the human IL-13 receptor alpha 2 (IL-13Rα2). Immunodeficient mice bearing orthotopically implanted human IL-13Rα2 expressing NCI-H1299 non-small cell lung cancer cells were injected intravenously with a single dose of LV vector pseudotyped with the TPMV H-IL-13 glycoprotein. Vector biodistribution was monitored using bioluminescence imaging of firefly luciferase transgene expression, revealing specific transduction of tumor tissue. A quantitative droplet digital PCR (ddPCR) analysis of lung tissue samples revealed a >15-fold increase in the tumor transduction in mice treated with LV vectors displaying IL-13 relative to those without IL-13. Our results show that TPMV envelope glycoproteins can be equipped with ligands to develop targeted LV vectors for in vivo applications.

Il4ra-independent vaginal eosinophil accumulation following helminth infection exacerbates epithelial ulcerative pathology of HSV-2 infection

SummaryHow helminths influence the pathogenesis of sexually transmitted viral infections is not comprehensively understood. Here, we show that an acute helminth infection (Nippostrongylus brasiliensis [Nb]) induced a type 2 immune profile in the female genital tract (FGT). This leads to heightened epithelial ulceration and pathology in subsequent herpes simplex virus (HSV)-2 infection. This was IL-5-dependent but IL-4 receptor alpha (Il4ra) independent, associated with increased FGT eosinophils, raised vaginal IL-33, and enhanced epithelial necrosis. Vaginal eosinophil accumulation was promoted by IL-33 induction following targeted vaginal epithelium damage from a papain challenge. Inhibition of IL-33 protected against Nb-exacerbated HSV-2 pathology. Eosinophil depletion reduced IL-33 release and HSV-2 ulceration in Nb-infected mice. These findings demonstrate that Nb-initiated FGT eosinophil recruitment promotes an eosinophil, IL-33, and IL-5 inflammatory circuit that enhances vaginal epithelial necrosis and pathology following HSV-2 infection. These findings identify a mechanistic framework as to how helminth infections can exacerbate viral-induced vaginal pathology.

A molecular subtype of colorectal cancers initiates independently of epidermal growth factor receptor and has an accelerated growth rate mediated by IL10-dependent anergy.

Although epidermal growth factor receptor (EGFR)-targeted therapies are approved for colorectal cancer (CRC) treatment, only 15% of CRC patients respond to EGFR inhibition. Here, we show that colorectal cancers (CRC) can initiate and grow faster through an EGFR-independent mechanism, irrespective of the presence of EGFR, in two different mouse models using tissue-specific ablation of Egfr. The growth benefit in the absence of EGFR is also independent of Kras status. An EGFR-independent gene expression signature, also observed in human CRCs, revealed that anergy-inducing genes are overexpressed in EGFR-independent polyps, suggesting increased infiltration of anergic lymphocytes promotes an accelerated growth rate that is partially caused by escape from cell-mediated immune responses. Many genes in the EGFR-independent gene expression signature are downstream targets of interleukin 10 receptor alpha (IL10RA). We further show that IL10 is detectable in serum from mice with EGFR-independent colon polyps. Using organoids in vitro and Src ablation in vivo, we show that IL10 contributes to growth of EGFR-independent CRCs, potentially mediated by the well-documented role of SRC in IL10 signaling. Based on these data, we show that the combination of an EGFR inhibitor with an anti-IL10 neutralizing antibody results in decreased cell proliferation in organoids and in decreased polyp size in pre-clinical models harboring EGFR-independent CRCs, providing a new therapeutic intervention for CRCs resistant to EGFR inhibitor therapies.

High Expression of Interleukin-3 Receptor Alpha Chain (CD123) Predicts Favorable Outcome in Pediatric B-Cell Acute Lymphoblastic Leukemia Lacking Prognosis-Defining Genomic Aberrations.

BackgroundAberrant expression of CD123 (IL-3Rα) was observed in various hematological malignancies including acute lymphoblastic leukemia (ALL), which is the most common malignancy in childhood. Although widely used for minimal residual disease (MRD) monitoring, the prognostic value of CD123 has not been fully characterized in pediatric B-ALL. This retrospective study aims to evaluate the association between the CD123 expression of leukemic blasts and the outcomes of the pediatric B-ALL patients.MethodsA total of 976 pediatric B-ALL, including 328 treated with CCLG-ALL-2008 protocol and 648 treated with CCCG-ALL-2015 protocol, were recruited in this retrospective study. CD123 expression was evaluated by flow cytometry. Patients with >50, 20–50, or <20% of CD123 expressing blasts were grouped into CD123high, CD123low, and CD123neg, respectively. The correlation between CD123 expression and the patients’ clinical characteristics, overall survival (OS), event-free survival (EFS), and relapse-free survival (RFS) were studied statistically.ResultsOf 976 pediatric B-ALL, 53.4% from the CCLG-ALL-2008 cohort and 49.2% from the CCCG-ALL-2015 cohort were CD123high. In the CCLG-ALL-2008 cohort, CD123high was significantly associated with chromosome hyperdiploidy (p < 0.0001), risk stratification (p = 0.004), and high survival rate (p = 0.005). By comparing clinical outcomes, patients with CD123high displayed favorable prognosis, with a significantly better OS (p = 0.005), EFS (p = 0.017), and RFS (p = 0.045), as compared to patients with CD123low and CD123neg. The prognostic value of CD123 expression was subsequently confirmed in the CCCG-ALL-2015 cohort. Univariate and multivariate cox regression model analysis showed that high CD123 expression was independently associated with favorable EFS (OR: 0.528; 95% CI: 0.327 to 0.853; p = 0.009) in this cohort. In patients without prognosis-defining genomic abnormalities, high CD123 expression strongly indicated superior survival rates and was identified as an independent prognosis factor for EFS and RFS in both cohorts.ConclusionsA group of B-ALL lacks prognosis-defining genomic aberrations, which proposes a challenge in risk stratification. Our findings revealed that high CD123 expression of leukemic blasts was associated with favorable clinical outcomes in pediatric B-ALL and CD123 could serve as a promising prognosis predictor, especially in patients without prognosis-defining genetic aberrations.

Dupilumab: new opportunities for the treatment of asthma and chronic rhinosinusitis with nasal polyps

Airway inflammation plays a crucial role in the development of asthma and chronic rhinosinusitis with nasal polyps (CRSwNP). The severity of inflammation influences the clinical picture of the disease and, most importantly, the effectiveness of therapy. To date, the growth in the incidence rate of asthma and CRSwNP is still high and the effectiveness of existing therapy for severe asthma, especially associated with CRSwNP, is unsatisfactory. Therefore, the aim is to investigate novel diagnostic tools and therapies. The emergence of biologics that target specific inflammatory pathways is a promising step forward to achieve control of severe uncontrolled asthma and recurrent CRSwNP. Dupilumab is one of recently introduced monoclonal antibodies, which has shown significant advances in the treatment of asthma and CRSwNP. Dupilumab is a fully human monoclonal antibody targeted to interleukin-4 receptor alpha subunit (IL-4R) that is a receptor for both IL-4 and IL-13. Thus, it helps to inhibit cytokine T2-signaling (IL-4 and IL-13), since the IL-4/IL-13/STAT6 signaling pathway plays a crucial role in T2-inflammation. In Russia, dupilumab is currently approved as a treatment for atopic dermatitis (in children over 6 years of age), asthma (in children over 12 years of age) and severe CRSwNP in adults. This article summarizes the main data on dupilumab and its efficacy in patients with asthma and CRSwNP and presents a relevant case report.

Interleukin-2 receptor alpha as a biomarker for nonalcoholic fatty liver disease diagnosis.

Two recent studies in the adult and pediatric Nonalcoholic Steatohepatitis-Clinical Research Network (NASH-CRN) cohorts have shown that soluble interleukin-2 receptor alpha (IL2RA) levels increased with fibrosis severity. However, no hepatic study has been conducted in Asian morbidly obese patients who underwent bariatric surgery. In this study, we proposed IL2RA as a biomarker for nonalcoholic fatty liver disease (NAFLD) diagnosis and performed immunohistochemistry (IHC) staining of IL2RA. This prospective cohort study enrolled 123 morbidly obese patients who underwent bariatric surgery at Taipei Medical University Hospital from October 2016 to June 2018. During bariatric surgery, all patients underwent a wedge liver biopsy under laparoscopic guidance. The diagnoses of NASH and liver fibrosis were made histologically. In IHC of IL2RA, the number of lymphocytes with IL2RA immunoreactivity was counted in five high-power fields (×400, total: 1.19 mm2). Among the 123 patients, the mean age was 35.5 years, mean body mass index (BMI) was 40.6 kg/m2, 87 (70.7%) were female, 25 (20.7%) had diabetes mellitus, and 57 (46.3%; 11 with non-NAFLD and 46 with steatosis) and 66 (53.7%) were included in the non-NASH and NASH groups, respectively. The NASH group had higher IHC of IL2RA than the non-NASH group. In multivariate analysis, IHC of IL2RA (odds ratio, 1.025; 95% confidence interval, 1.006-1.045; p = 0.011) and alanine aminotransferase (ALT; odds ratio, 1.045; 95% confidence interval, 1.018-1.073; p = 0.001) were the independent factors associated with NASH. The area under the receiver operating curve of IL2RA IHC for NASH was 0.627 at the cutoff value of 82 (p = 0.0113). IL2RA is significantly associated with NASH in morbidly obese patients and would be a useful biomarker for NASH diagnosis.

Early and Long-Term Effects of Dupilumab Treatment on Circulating T-Cell Functions in Patients with Moderate-to-Severe Atopic Dermatitis

Dupilumab, a mAb targeting IL-4 receptor alpha (IL-4Rα), markedly improves disease severity in patients with atopic dermatitis. However, the effect of IL-4Rα blockade on dynamics of circulating skin-homing T cells, which are crucial players in the pathologic mechanism of atopic dermatitis, has not been studied yet. In addition, it remains unknown whether dupilumab treatment induces long-lasting T- and B-cell polarization. Therefore, we studied the short- and long-term effects of dupilumab treatment on IL-4Rα expression and T-cell cytokine production within total and skin-homing (cutaneous lymphocyte antigen+/CCR4+) subpopulations in patients with moderate-to-severe atopic dermatitis. Dupilumab treatment completely blocked IL-4Rα expression and signal transducer and activator of transcription 6 phosphorylation in CD19+ B cells and CD4+ T cells within 2 hours of administration and through week 52. Although no change in the proportion of skin-homing T-cell subsets was found, dupilumab treatment significantly decreased the percentage of proliferating (Ki67+) and T helper type 2 and T helper type 22 cytokine-producing skin-homing CD4+ T cells at week 4. No evidence of general T helper type cell skewing following a year of dupilumab treatment was found. In summary, dupilumab treatment rapidly and stably inhibited IL-4Rα, which was accompanied by a strong early functional immunological effect specifically on skin-homing T cells without affecting overall T helper type cell skewing in the long term.

Heterodimeric IL-15 in Cancer Immunotherapy.

Simple SummaryThe rapidly expanding field of cancer immunotherapy uses diverse technologies, including cytokines, T cells, and antibody administration, with the aim to induce effective immune responses leading to tumor control. Interleukin-15 (IL-15), a cytokine discovered in 1994, supports the homeostasis of cytotoxic immune cells and shows promise as an anti-tumor agent. Many studies have elucidated IL-15 synthesis, regulation and biological function and explored its therapeutic efficacy in preclinical cancer models. Escherichia coli-derived single-chain IL-15 was tested in the first in-human trial in cancer patients. Its effects were limited by the biology of IL-15, which in vivo comprises a complex of the IL-15 chain with the IL-15 receptor alpha (IL-15Rα) chain, together forming the IL-15 heterodimer (hetIL-15). Currently, single-chain IL-15 and several heterodimeric IL-15:IL-15Rα variants (hetIL-15, N-803 and RLI) are being tested in clinical trials. This review presents a summary of contemporary preclinical and clinical research on IL-15.Immunotherapy has emerged as a valuable strategy for the treatment of many cancer types. Interleukin-15 (IL-15) promotes the growth and function of cytotoxic CD8+ T and natural killer (NK) cells. It also enhances leukocyte trafficking and stimulates tumor-infiltrating lymphocytes expansion and activity. Bioactive IL-15 is produced in the body as a heterodimeric cytokine, comprising the IL-15 and the so-called IL-15 receptor alpha chain that are together termed “heterodimeric IL-15” (hetIL-15). hetIL-15, closely resembling the natural form of the cytokine produced in vivo, and IL-15:IL-15Rα complex variants, such as hetIL-15Fc, N-803 and RLI, are the currently available IL-15 agents. These molecules have showed favorable pharmacokinetics and biological function in vivo in comparison to single-chain recombinant IL-15. Preclinical animal studies have supported their anti-tumor activity, suggesting IL-15 as a general method to convert “cold” tumors into “hot”, by promoting tumor lymphocyte infiltration. In clinical trials, IL-15-based therapies are overall well-tolerated and result in the expansion and activation of NK and memory CD8+ T cells. Combinations with other immunotherapies are being investigated to improve the anti-tumor efficacy of IL-15 agents in the clinic.

IL-15/IL-15Rα Heterodimeric Complex as Cancer Immunotherapy in Murine Breast Cancer Models.

Interleukin 15 (IL-15) has been evaluated as a potential treatment for solid tumors in clinical trials, but the effectiveness of systemic IL-15 administration as a monotherapy has not been realized. IL-15 receptor alpha (IL-15Rα) can stabilize IL-15 and enhance its bioactivity. The goal of this study was to examine the activity of IL-15/IL-15Rα complex (IL-15cx) to CD8+ T cells and evaluate its potential efficacy in murine breast cancer models. The antitumor efficacy was studied in mouse mammary carcinoma models (Her2/neu transgenic and 4T1-luc mammary cancers) treated with systemic recombinant protein with/without the depletion of myeloid-derived suppressor cells or intra-tumoral gene electrotransfer (GET). IL-15cx shows superior in vivo bioactivity to expand CD8 T cells in comparison to an equimolar single chain IL-15. T-bet is partially involved in CD8 T cell expansion ex vivo and in vivo due to IL-15 or IL-15cx. Intraperitoneal administration of IL-15cx results in a moderate inhibition of breast cancer growth that is associated with an increase in the frequency of cytotoxic CD8 T cells and the improvement of their function. The depletion of myeloid-derived suppressor cells (MDSCs) has no impact on mouse breast cancer growth. IL-15cx treatment diminishes MDSCs in murine tumors. However, it also antagonizes the effects of anti-Gr-1 depleting antibodies. Intratumoral GET with plasmid IL-15/IL-15Rα leads to a long-term survival benefit in 4T1 mammary carcinoma model. An early increase of local cytotoxic cells correlates with GET treatment and an increase of long-term memory T cells results from animals with complete tumor regression. Systemic and local administration of IL-15cx shows two distinct therapeutic responses, a moderate tumor growth inhibition or heterogeneous tumor regressions with survival improvement. Further studies are warranted to improve the efficacy of IL-15cx as an immunotherapy for breast cancer.