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BACKGROUND: NHS-IL12 is a first-in-class, recombinant fusion protein composed of the human monoclonal antibody NHS76 (binds exposed DNA/histones at sites of intratumoral necrosis) fused to 2 IL-12 heterodimers. The maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of NHS-IL12 monotherapy given subcutaneously (SC) every 4 weeks was previously reported. The study was expanded to include a high-exposure cohort with NHS-IL12 SC every 2 weeks (q2w). METHODS: This single-arm, phase I trial evaluated NHS-IL12 12 µg/kg SC q2w or 16.8µg/kg SC q2w in patients with metastatic solid tumors. The primary endpoint was safety. RESULTS: Using a 3+3 design, 13 patients with advanced cancer were enrolled and 12 were dose-limiting toxicity (DLT) evaluable. There was 1 DLT (Grade 3 aspartate transaminase/alanine transaminase [AST/ALT] elevation). Other grade 3 toxicities included: flu-like symptoms 1/13 (8%), decreased absolute lymphocyte count (ALC) 1/13 (8%), decreased white blood cell count (WBC) 1/13 (8%), but most adverse events reported were low grade and self-limiting grade. Fifty percent of evaluable patients (6/12) experienced stable disease (SD) with 42% (5/12) developing progressive disease (PD) at the first restaging. CONCLUSION: Biweekly NHS-IL12 was well tolerated in this small phase I study. Additional studies incorporating NHS-IL12 with other immunomodulating agents are underway. (ClinicalTrials.gov Identifier: NCT01417546).
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Segunda Neoplasia Primária , Neoplasias , Humanos , Medicina Estatal , Interleucina-12/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Proteínas Recombinantes de Fusão/uso terapêuticoRESUMO
BACKGROUND: Triple negative breast cancer (TNBC) is an aggressive breast cancer for which there is currently no targeted therapy. Tumor-infiltrating B-cells (TIB) have been observed in tumor tissues of TNBC patients, but their functional role is unclear. IgG4 is one of four antibody subclasses of IgG expressed and secreted by B cells. Unlike other IgG isotypes, IgG4 has an immunosuppressive function and is induced by Th2-type cytokines. In cancers such as melanoma, IgG4 has been linked with advanced disease and poor patient survival. Therefore, we sought to determine if IgG4 + B cells are present and determine the mechanisms driving isotype switching in TNBC. METHODS: We performed co-culture assays to examine expression of Th2 cytokines by TNBC cells with and without the presence of B cells. We also performed in vitro class switching experiments with peripheral B cells with and without co-culture with TNBC cells in the presence or absence of an IL-10 blocking antibody. We examined expression of CD20+ TIB, IgG4 and Th2 cytokines by immunohistochemistry in 152 TNBC samples. Statistical analysis was done using Log-Rank and Cox-proportional hazards tests. RESULTS: Our findings indicate that B cells interact with TNBC to drive chronic inflammatory responses through increased expression of inflammatory cytokines including the TH2 cytokines IL-4 and IL-10. In vitro class switching studies show that interactions between TNBC cell lines and B cells drive isotype switching to the IgG4 isotype in an IL-10 dependent manner. In patient tissues, expression of IgG4 correlates with CD20 and tumor expression of IL-10. Both IgG4 and tumor IL-10 are associated to shorter recurrence free survival (RFS) and overall survival (OS) in TNBC. In a multi-variant analysis, IL-10 was associated with poor outcomes indicating that tumor IL-10 may drive immune escape. CONCLUSIONS: These findings indicate that interactions between TIB and TNBC results in activation of chronic inflammatory signals such as IL-10 and IL-4 that drive class switching to an IgG4 + subtype which may suppress antibody driven immune responses. The presence of IgG4 + B cells may serve as a biomarker for poor prognosis.
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Neoplasias de Mama Triplo Negativas , Formação de Anticorpos , Comunicação Celular , Linhagem Celular Tumoral , Humanos , Switching de Imunoglobulina , Imunoglobulina G/metabolismo , Interleucina-10/metabolismo , Neoplasias de Mama Triplo Negativas/genética , Regulação para CimaRESUMO
BACKGROUND: Routine cytology of biliary stricture brushings obtained during endoscopic retrograde cholangiopancreatography (ERCP) has suboptimal sensitivity for malignancy. We compared the individual and combined ability of cytology, fluorescence in situ hybridization (FISH) analysis and PCR-based mutation profiling (MP) to detect malignancy in standard biliary brushings. METHODS: We performed a prospective study of patients undergoing ERCP using histology or 1 year follow-up to determine patient outcomes. MP was performed on free-DNA from biliary brushing specimens using normally discarded supernatant fluid. MP examined KRAS point mutations and tumor suppressor gene associated loss of heterozygosity mutations at 10 genomic loci. FISH examined chromosome specific gains or losses. RESULTS: A total of 101 patients were included in final analysis and 69% had malignancy. Cytology had 26% sensitivity and 100% specificity for malignancy. Using either FISH or MP in combination with cytology increased sensitivity to 44% and 56%, respectively. The combination of all 3 tests (cytology, FISH, and MP) had the highest sensitivity for malignancy (66%). There was no difference in the specificity of cytology, FISH or MP testing when examined alone or in combination. MP improved diagnostic yield of each procedure from 22% to 100%; FISH improved yield to 90%. MP detected 21 malignancies beyond that identified by cytology; FISH detected an additional 13. The combination of FISH and MP testing detected an additional 28 malignancies. CONCLUSIONS: Both MP and FISH are complimentary molecular tests that can significantly increase detection of biliary malignancies when used in combination with routine cytology of standard biliary brush specimens.
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Neoplasias do Sistema Biliar/diagnóstico , Colangiopancreatografia Retrógrada Endoscópica , Colestase/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias do Sistema Biliar/genética , Sistema Livre de Células , Citodiagnóstico , Feminino , Humanos , Hibridização in Situ Fluorescente , Masculino , Pessoa de Meia-Idade , Mutação , Reação em Cadeia da Polimerase , Estudos Prospectivos , Sensibilidade e EspecificidadeRESUMO
BACKGROUND: Pediatric acute liver failure (PALF) is a public heath burden, often requiring prolonged hospitalization and liver transplantation. Hepatic encephalopathy (HE) is a complication of PALF with limited diagnostic tools to predict outcomes. Serum neurological markers (neuron-specific enolase, S100ß, and myelin basic protein) can be elevated in traumatic or ischemic brain injury. We hypothesized that these neuromarkers would be associated with the development of HE in PALF. METHODS: PALF study participants enrolled between May 2012 and December 2014 by 12 participating centers were the subjects of this analysis. Daily HE assessments were determined by study investigators. Neurological and inflammatory markers were measured using enzyme-linked immunosorbent assay and MILLIPLEX techniques, respectively. To model encephalopathy, these markers were log2 transformed and individually examined for association with HE using a generalized linear mixed model with a logit link and random intercept. RESULTS: Eighty-two children had neurological and inflammatory marker levels and HE assessments recorded, with the majority having assessments for 3 days during their illness. An indeterminate diagnosis (29%) was most common and the median age was 2.9 years. Significant associations were observed for HE with S100ß (odds ratio 1.16, 95% confidence interval [1.03-1.29], Pâ=â0.04) and IL-6 (odds ratio 1.24 [1.11-1.38], Pâ=â0.006). CONCLUSIONS: Serum S100ß and IL-6 are associated with HE in children with PALF. Measuring these markers may assist in assessing neurological injury in PALF, impacting clinical decisions.
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Encefalopatia Hepática/sangue , Falência Hepática Aguda/sangue , Adolescente , Biomarcadores/sangue , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Encefalopatia Hepática/etiologia , Humanos , Lactente , Recém-Nascido , Interleucina-6/sangue , Falência Hepática Aguda/complicações , Masculino , Subunidade beta da Proteína Ligante de Cálcio S100/sangue , Índice de Gravidade de DoençaRESUMO
BACKGROUND & AIMS: It is a challenge to detect malignancies in biliary strictures. Various sampling methods are available to increase diagnostic yield, but these require additional procedure time and expertise. We evaluated the combined accuracy of fluorescence in situ hybridization (FISH) and polymerase chain reaction-based DNA mutation profiling (MP) of specimens collected using standard brush techniques. METHODS: We performed a prospective study of 107 consecutive patients treated for biliary strictures by endoscopic retrograde cholangiopancreatography from June 2012 through June 2014. We performed routine cytology and FISH analyses on cells collected by standard brush techniques, and analyzed supernatants for point mutations in KRAS and loss-of-heterozygosity mutations in tumor-suppressor genes at 10 loci (MP analysis was performed at Interpace Diagnostics). Strictures were determined to be nonmalignant based on repeat image analysis or laboratory test results 12 months after the procedure. Malignant strictures were identified based on subsequent biopsy or cytology analyses, pathology analyses of samples collected during surgery, or death from biliary malignancy. We determined the sensitivity and specificity with which FISH and MP analyses detected malignancies using the exact binomial test. RESULTS: Our final analysis included 100 patients; 41% had biliary malignancies. Cytology analysis identified patients with malignancies with 32% sensitivity and 100% specificity. Addition of FISH or MP results to cytology results increased the sensitivity of detection to 51% (P < .01) without reducing specificity. The combination of cytology, MP, and FISH analyses detected malignancies with 73% sensitivity (P < .001). FISH identified an additional 9 of the 28 malignancies not detected by cytology analysis, and MP identified an additional 8 malignancies. FISH and MP together identified 17 of the 28 malignancies not detected by cytology analysis. CONCLUSIONS: Addition of FISH and mutation analyses to cytology analysis significantly increased the level of sensitivity with which we detected malignancy in biliary strictures, with 100% specificity. These techniques can be performed using standard brush samples collected during endoscopic retrograde cholangiopancreatography, with mutations detected in free DNA in supernatant fluid of samples. The tests are complementary and therefore should be used sequentially in the diagnostic evaluation of biliary strictures.
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Neoplasias do Sistema Biliar/diagnóstico , Colestase Extra-Hepática/etiologia , Constrição Patológica/etiologia , Técnicas de Genotipagem , Hibridização in Situ Fluorescente , Técnicas de Diagnóstico Molecular/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias do Sistema Biliar/patologia , Colestase Extra-Hepática/patologia , Constrição Patológica/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Estudos Prospectivos , Sensibilidade e EspecificidadeRESUMO
OBJECTIVE: To evaluate energy expenditure in a cohort of children with severe traumatic brain injury. DESIGN: A prospective observational study. SETTING: A pediatric neurotrauma center within a tertiary care institution. PATIENTS: Mechanically ventilated children admitted with severe traumatic brain injury (Glasgow Coma Scale < 9) with a weight more than 10 kg were eligible for study. A subset of children was co-enrolled in a phase 3 study of early therapeutic hypothermia. All children were treated with a comprehensive neurotrauma protocol that included sedation, neuromuscular blockade, temperature control, antiseizure prophylaxis, and a tiered-based system for treating intracranial hypertension. INTERVENTIONS: Within the first week after injury, indirect calorimetry measurements were performed daily when the patient's condition permitted. MEASUREMENTS AND MAIN RESULTS: Data from 13 children were analyzed (with a total of 32 assessments). Measured energy expenditure obtained from indirect calorimetry was compared with predicted resting energy expenditure calculated from Harris-Benedict equation. Overall, measured energy expenditure/predicted resting energy expenditure averaged 70.2% ± 3.8%. Seven measurements obtained while children were hypothermic did not differ from normothermic values (75% ± 4.5% vs 68.9% ± 4.7%, respectively, p = 0.273). Furthermore, children with favorable neurologic outcome at 6 months did not differ from children with unfavorable outcome (76.4% ± 6% vs 64.7% ± 4.7% for the unfavorable outcome, p = 0.13). CONCLUSIONS: Contrary to previous work from several decades ago that suggested severe pediatric traumatic brain injury is associated with a hypermetabolic response (measured energy expenditure/predicted resting energy expenditure > 110%), our data suggest that contemporary neurocritical care practices may blunt such a response. Understanding the metabolic requirements of children with severe traumatic brain injury is the first step in development of rational nutritional support goals that might lead to improvements in outcome.
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Lesões Encefálicas/metabolismo , Metabolismo Energético/fisiologia , Adolescente , Lesões Encefálicas/terapia , Calorimetria Indireta , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Estudos Prospectivos , Respiração Artificial , Atenção Terciária à SaúdeRESUMO
BACKGROUND: The aim of this study is to determine the utility of non-invasive bedside neuromonitoring, including cerebral regional oxygen saturation (rSO2) measured by near-infrared spectroscopy and serum biomarkers, in identifying children at risk from adverse neurological outcome after heart surgery. METHODS: Prospective observational study including 39 consecutive children undergoing heart surgery with cardiopulmonary bypass (CPB) and normal neurologic exam prior to surgery. Cerebral rSO2 was measured at baseline (prior to surgery) and then continuously during surgery and for the first 16 h post-operatively. Neuromarkers [neuron-specific enolase (NSE), S100ß, glial fibrillary acidic protein (GFAP), and brain-derived neurotrophic factor (BDNF)] were measured in serum at baseline, immediately after CPB and at 16 h post-operatively. Adverse neurological outcome was defined as an abnormal pediatric cerebral performance category (PCPC) scale score at 12 months after surgery. RESULTS: Sixteen children (41 %) had an abnormal PCPC scale score at the 12-month evaluation after surgery. In children with unfavorable neurological outcomes, mean cerebral rSO2 values were lower and the area-under-the-curve below a threshold of 40 and 20% below baseline were also increased. No significant differences were found in serum neuromarkers between groups at the time points that were assessed. CONCLUSIONS: Bedside determination of cerebral rSO2 may have some utility in identifying children at risk for adverse neurological outcome after heart surgery in children. Additional studies that are sufficiently powered to control for the many covariates in this patient population will be required to fully interrogate this important question. The role of serum neuromarkers in the immediate post-operative period do not appear to be helpful in this question, though more thorough interrogation of delayed periods may ultimately demonstrate some utility in answering this question.
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Encéfalo/fisiopatologia , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Ponte Cardiopulmonar/efeitos adversos , Monitorização Neurofisiológica/métodos , Complicações Pós-Operatórias/diagnóstico , Biomarcadores/sangue , Encéfalo/metabolismo , Humanos , Lactente , Monitorização Neurofisiológica Intraoperatória/métodos , Oximetria , Oxigênio/metabolismo , Prognóstico , Espectroscopia de Luz Próxima ao Infravermelho , Resultado do TratamentoRESUMO
BACKGROUND: With the rapid adoption of immunotherapy for the treatment of cancer comes the pressing need for readily accessible biomarkers to guide immunotherapeutic strategies and offer insights into outcomes with specific treatments. Regular sampling of solid tumour tissues outside of melanoma for immune monitoring is not often feasible; conversely, routine, frequent interrogation of circulating immune biomarkers is entirely possible. As immunotherapies and immune checkpoint inhibitors, in particular, are more widely used in first-line, neoadjuvant, and metastatic settings, the discovery and validation of peripheral immune biomarkers are urgently needed across solid tumour types for improved prediction and prognostication of clinical outcomes in response to immunotherapy, as well as elucidation of mechanistic underpinnings of the intervention. Careful experimental design, encompassing both retrospective and prospective studies, is required in such biomarker identification studies, and concerted efforts are essential for their advancement into clinical settings. CONCLUSION: In this review, we summarize shared immune features between the tumour microenvironment and systemic circulation, evaluate exploratory peripheral immune biomarker studies, and discuss associations between candidate biomarkers with clinical outcomes. We also consider integration of multiple peripheral immune parameters for better prediction and prognostication and discuss considerations in study design to further evaluate the clinical utility of candidate peripheral immune biomarkers for immunotherapy of solid tumours. HIGHLIGHTS: Peripheral immune biomarkers are critical for improved prediction and prognostication of clinical outcomes for patients with solid tumours treated with immune checkpoint inhibition. Candidate peripheral biomarkers, such as cytokines, soluble factors, and immune cells, have potential as biomarkers to guide immunotherapy of solid tumours. Multiple peripheral immune parameters may be integrated to improve prediction and prognostication. The potential of peripheral immune biomarkers to guide immunotherapy of solid tumours requires critical work in biomarker discovery, validation, and standardization.
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Biomarcadores Tumorais , Inibidores de Checkpoint Imunológico , Neoplasias , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias/imunologia , Neoplasias/tratamento farmacológico , Neoplasias/terapia , Biomarcadores Tumorais/sangue , Imunoterapia/métodos , Microambiente Tumoral/imunologiaRESUMO
BACKGROUND: Acute brain dysfunction during sepsis, which manifests as delirium or coma, is common and is associated with multiple adverse outcomes, including longer periods of mechanical ventilation, prolonged hospital stays, and increased mortality. Delirium and coma during sepsis may be manifestations of alteration in systemic metabolism. Because access to brain mitochondria is a limiting factor, measurement of peripheral platelet bioenergetics offers a potential opportunity to understand metabolic changes associated with acute brain dysfunction during sepsis. RESEARCH QUESTION: Are altered platelet mitochondrial bioenergetics associated with acute brain dysfunction during sepsis? STUDY DESIGN AND METHODS: We assessed participants with critical illness in the ICU for the presence of delirium or coma via validated assessment measures. Blood samples were collected and processed to isolate and measure platelet mitochondrial oxygen consumption. We used Seahorse extracellular flux to measure directly baseline, proton leak, maximal oxygen consumption rate, and extracellular acidification rate. We calculated adenosine triphosphate-linked, spare respiratory capacity, and nonmitochondrial oxygen consumption rate from the measured values. RESULTS: Maximum oxygen consumption was highest in patients with coma, as was spare respiratory capacity and extracellular acidification rate in unadjusted analysis. After adjusting for age, sedation, modified Sequential Organ Failure Assessment score without the neurologic component, and preexisting cognitive function, increased spare respiratory capacity remained associated with coma. Delirium was not associated with any platelet mitochondrial bioenergetics. INTERPRETATION: In this single-center exploratory prospective cohort study, we found that increased platelet mitochondrial spare respiratory capacity was associated with coma in patients with sepsis. Future studies powered to determine any relationship between delirium and mitochondrial respiration bioenergetics are needed.
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[This corrects the article DOI: 10.3389/fped.2024.1340385.].
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Introduction: Hospitalized children diagnosed with SARS-CoV-2-related conditions are at risk for new or persistent symptoms and functional impairments. Our objective was to analyze post-hospital symptoms, healthcare utilization, and outcomes of children previously hospitalized and diagnosed with acute SARS-CoV-2 infection or Multisystem Inflammatory Syndrome in Children (MIS-C). Methods: Prospective, multicenter electronic survey of parents of children <18 years of age surviving hospitalization from 12 U.S. centers between January 2020 and July 2021. The primary outcome was a parent report of child recovery status at the time of the survey (recovered vs. not recovered). Secondary outcomes included new or persistent symptoms, readmissions, and health-related quality of life. Multivariable backward stepwise logistic regression was performed for the association of patient, disease, laboratory, and treatment variables with recovered status. Results: The children [n = 79; 30 (38.0%) female] with acute SARS-CoV-2 (75.7%) or MIS-C (24.3%) had a median age of 6.5 years (interquartile range 2.0-13.0) and 51 (64.6%) had a preexisting condition. Fifty children (63.3%) required critical care. One-third [23/79 (29.1%)] were not recovered at follow-up [43 (31, 54) months post-discharge]. Admission C-reactive protein levels were higher in children not recovered vs. recovered [5.7 (1.3, 25.1) vs. 1.3 (0.4, 6.3)â mg/dl, p = 0.02]. At follow-up, 67% overall had new or persistent symptoms. The most common symptoms were fatigue (37%), weakness (25%), and headache (24%), all with frequencies higher in children not recovered. Forty percent had at least one return emergency visit and 24% had a hospital readmission. Recovered status was associated with better total HRQOL [87 (77, 95) vs. 77 (51, 83), p = 0.01]. In multivariable analysis, lower admission C-reactive protein [odds ratio 0.90 (95% confidence interval 0.82, 0.99)] and higher admission lymphocyte count [1.001 (1.0002, 1.002)] were associated with recovered status. Conclusions: Children considered recovered by their parents following hospitalization with SARS-CoV-2-related conditions had less symptom frequency and better HRQOL than those reported as not recovered. Increased inflammation and lower lymphocyte count on hospital admission may help to identify children needing longitudinal, multidisciplinary care. Clinical Trial Registration: ClinicalTrials.gov (NCT04379089).
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Chemotherapy and immune checkpoint inhibitors have a role in the post-neoadjuvant setting in patients with triple-negative breast cancer (TNBC). However, the effects of nivolumab, a checkpoint inhibitor, capecitabine, or the combination in changing peripheral immunoscore (PIS) remains unclear. This open-label randomized phase II OXEL study (NCT03487666) aimed to assess the immunologic effects of nivolumab, capecitabine, or the combination in terms of the change in PIS (primary endpoint). Secondary endpoints included the presence of ctDNA, toxicity, clinical outcomes at 2-years and association of ctDNA and PIS with clinical outcomes. Forty-five women with TNBC and residual invasive disease after standard neoadjuvant chemotherapy were randomized to nivolumab, capecitabine, or the combination. Here we show that a combination of nivolumab plus capecitabine leads to a greater increase in PIS from baseline to week 6 (91%) compared with nivolumab (47%) or capecitabine (53%) alone (log-rank p = 0.08), meeting the pre-specified primary endpoint. In addition, the presence of circulating tumor DNA (ctDNA) is associated with disease recurrence, with no new safety signals in the combination arm. Our results provide efficacy and safety data on this combination in TNBC and support further development of PIS and ctDNA analyses to identify patients at high risk of recurrence.
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Nivolumabe , Neoplasias de Mama Triplo Negativas , Humanos , Feminino , Capecitabina/efeitos adversos , Nivolumabe/uso terapêutico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Recidiva Local de Neoplasia/patologia , Terapia Neoadjuvante , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
Tumor biopsy is often not available or difficult to obtain in patients with solid tumors. Investigation of the peripheral immune system allows for in-depth and dynamic profiling of patient immune response prior to and over the course of treatment and disease. Phosphoflow cytometry is a flow cytometryâbased method to detect levels of phosphorylated proteins in single cells. This method can be applied to peripheral immune cells to determine responsiveness of signaling pathways in specific immune subsets to cytokine stimulation, improving on simply defining numbers of populations of cells based on cell surface markers. Here, we review studies using phosphoflow cytometry to (a) investigate signaling pathways in cancer patients' peripheral immune cells compared with healthy donors, (b) compare immune cell function in peripheral immune cells with the tumor microenvironment, (c) determine the effects of agents on the immune system, and (d) predict cancer patient response to treatment and outcome. In addition, we explore the use and potential of phosphoflow cytometry in preclinical cancer models. We believe this review is the first to provide a comprehensive summary of how phosphoflow cytometry can be applied in the field of cancer immunology, and demonstrates that this approach holds promise in exploring the mechanisms of response or resistance to immunotherapy both prior to and during the course of treatment. Additionally, it can help identify potential therapeutic avenues that can restore normal immune cell function and improve cancer patient outcome.
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Imunoterapia , Neoplasias , Humanos , Neoplasias/terapia , Biópsia , Citocinas , Transdução de Sinais , Microambiente TumoralRESUMO
The immunocytokine NHS-IL12 delivers IL-12 to the tumor microenvironment by targeting DNA/histones in necrotic areas. The first-in-human clinical trial administered NHS-IL12 subcutaneously in 59 patients treated every four weeks (Q4W), with a maximum tolerated dose of 16.8 mcg/kg. The phase I study was expanded to include a high-exposure cohort that received bi-weekly treatment (Q2W) with two dose levels of NHS-IL12: 12.0 mcg/kg and 16.8 mcg/kg. Here, patients given NHS-IL12 were analyzed both prior to and early after treatment for effects on 10 serum soluble analytes, complete blood counts, and 158 peripheral immune subsets. Higher levels of immune activation were seen with a dose of 16.8 mcg/kg versus 12.0 mcg/kg in patients in the high-exposure cohort, as evidenced by greater increases in serum IFNγ, TNFα, and soluble PD-1, and greater increases in frequencies of peripheral ki67+ mature natural killer (NK), CD8+T, and NKT cells. Greater immune activation was also seen in the Q2W versus Q4W cohort, as demonstrated by greater increases in pro-inflammatory serum analytes, ki67+ CD8+ T, NK, and NKT cells, intermediate monocytes, and a greater decrease in CD73+ T cells. Specific immune analytes at baseline including lower levels of monocytes and plasmacytoid dendritic cells, and early changes after treatment such as an increase in refined NK cell subsets and total CD8+ T cells, associated with better clinical response. These findings may help to guide future schedule and dosing regimens of clinical studies of NHS-IL12 as monotherapy and in combination therapies.
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Neoplasias , Medicina Estatal , Humanos , Antígeno Ki-67 , Interleucina-12 , Neoplasias/tratamento farmacológico , Células Matadoras Naturais , Microambiente TumoralRESUMO
Chemotherapy and immune checkpoint inhibitors have a role in the post-neoadjuvant setting in patients with triple-negative breast cancer (TNBC). However, the effects of nivolumab, a checkpoint inhibitor, capecitabine, or the combination in changing peripheral immunoscore (PIS) remains unclear. This open-label randomized phase II OXEL study (NCT03487666) aimed to assess the immunologic effects of nivolumab, capecitabine, or the combination in terms of the change in PIS (primary endpoint). Secondary endpoints include the presence of ctDNA, toxicity, clinical outcomes at 2-years and association of ctDNA and PIS with clinical outcomes. Forty-five women with TNBC and residual invasive disease after standard neoadjuvant chemotherapy were randomized to nivolumab, capecitabine, or the combination. Here we show that a combination of nivolumab plus capecitabine leads to a greater increase in PIS from baseline to week 6 (91%) compared with nivolumab (47%) or capecitabine (53%) alone (log-rank p = 0.08), meeting the pre-specified primary endpoint. In addition, the presence of circulating tumor DNA (ctDNA) was associated with disease recurrence, with no new safety signals in the combination arm. Our results provide efficacy and safety data on this combination in TNBC and support further development of PIS and ctDNA analyses to identify patients at high risk of recurrence.
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PURPOSE: Bintrafusp alfa is a bifunctional agent consisting of an anti-human PD-L1 antibody linked to two TGFßRII. It is designed to act both as a checkpoint inhibitor and to 'trap' TGFß in the tumor microenvironment. Phase I and II clinical studies demonstrated clinical activity in patients with a range of human papillomavirus (HPV)-associated cancers. The purpose of the studies reported here was the interrogation of various aspects of the peripheral immunome in patients with HPV-associated cancers, both prior to and early in the treatment regimen of bintrafusp alfa to better understand the mode of action of the agent and to help define which patients are more likely to benefit from bintrafusp alfa treatment. PATIENTS AND METHODS: The peripheral immunome of patients (n=65) with HPV+ malignancies was analyzed both prior to treatment with bintrafusp alfa and day 14 post-treatment for levels and changes in (1) 158 different immune cell subsets, (2) multiple plasma soluble factors including analytes reflecting immune stimulatory and inhibitory status, (3) complete blood counts, and in a subset of patients (4) TCR diversity and (5) HPV-specific T-cell responses. RESULTS: Interrogation of the peripheral immunome prior to bintrafusp alfa treatment revealed several factors that associated with clinical response, including (1) higher levels of sCD27:sCD40L ratios, (2) lower levels of TGFß1 and 12 additional factors associated with tumor mesenchymalization, and (3) higher CD8+ T cell:MDSC ratios. Analysis at 2 weeks post bintrafusp alfa revealed that eventual clinical responders had fewer increases in IL-8 levels and the neutrophil to lymphocyte ratio, and higher levels of HPV-16 specific CD8+ T cells. This study also provided information concerning differences in the peripheral immunome for patients who were naïve versus refractory to prior checkpoint inhibition therapy. While preliminary, two multivariate models developed predicted clinical benefit with 76%-91% accuracy. CONCLUSIONS: These studies add insight into the mechanism of action of bintrafusp alfa and provide evidence that the interrogation of both cellular and soluble components of the peripheral immunome of patients with HPV-associated malignancies, either prior to or early in the therapeutic regimen, can provide information as to which patients are more likely to benefit with bintrafusp alfa therapy.
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Alphapapillomavirus , Neoplasias , Infecções por Papillomavirus , Linfócitos T CD8-Positivos/patologia , Humanos , Fatores Imunológicos/uso terapêutico , Neoplasias/tratamento farmacológico , Papillomaviridae , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/tratamento farmacológico , Infecções por Papillomavirus/patologia , Microambiente TumoralRESUMO
BACKGROUND: Metformin may have anticancer effects that are independent of its hypoglycemic effects. Retrospective studies have shown that metformin use is associated with decreased incidence of prostate cancer and prostate cancer-specific mortality. Preclinical studies suggesting additive anticancer effects of combining metformin and bicalutamide prompted this clinical trial (NCT02614859). METHODS: This open-label, randomized, phase 2 trial enrolled non-diabetic patients with biochemically recurrent prostate cancer, a PSADT of 3-9 months, BMI > 25 and normal testosterone. Patients were randomized 1:2 to observation for an initial 8 weeks (Arm A) or metformin 1000 mg twice daily (Arm B). Bicalutamide 50 mg/day was added after 8 weeks to both arms. The primary objective was to evaluate the number of patients with undetectable PSA ( < 0.2 ng/mL) at the end of 32 weeks. Immune correlatives were assessed as exploratory endpoints. RESULTS: A total of 29 patients were enrolled from March 2015 to January 2020. No difference was seen between the 2 arms in the proportion of patients with undetectable PSA. Modest PSA decrease ranging from 4% to 24% were seen in 40.0% (95% CI: 19.1-64.0%) of patients with metformin monotherapy, compared to 11.1% (95% CI: 0.3-48.3%) in the observation arm. Metformin monotherapy reduced PD-1+ NK cells, and increased NKG2D+ NK cells. The combination of metformin and bicalutamide led to greater reductions in PD-1 expressing NK, CD4+ T, and CD8+ T-cell subsets compared to bicalutamide alone. The trial was stopped early due to predicted inability to achieve its primary endpoint. CONCLUSIONS: Although metformin plus bicalutamide was well tolerated, there was no improvement in rates of achieving undetectable PSA at 32 weeks. Metformin monotherapy induced modest PSA declines in 40% of patients after 8 weeks. Metformin, given alone and in combination with bicalutamide, displayed immune modifying effects, primarily within NK and T cells subsets. TRIAL REGISTRATION: Trial Registration Number: NCT02614859.
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Metformina , Neoplasias da Próstata , Masculino , Humanos , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/induzido quimicamente , Antígeno Prostático Específico , Metformina/uso terapêutico , Sobrepeso , Estudos Retrospectivos , Receptor de Morte Celular Programada 1/uso terapêutico , Compostos de Tosil/efeitos adversos , Anilidas/efeitos adversos , Nitrilas , Antagonistas de Androgênios/efeitos adversos , Obesidade/complicaçõesRESUMO
While vaccines directed against the SARS-CoV-2 spike protein will have varying degrees of effectiveness in preventing SARS-CoV-2 infections, the severity of infection will be determined by multiple host factors including the ability of immune cells to lyse virus-infected cells. This review will discuss the complexity of both adaptive and innate immunomes and how a flow-based assay can detect up to 158 distinct cell subsets in the periphery. This assay has been employed to show the effect of age on differences in specific immune cell subsets, and the differences in the immunome between healthy donors and age-matched cancer patients. Also reviewed are the numerous soluble factors, in addition to cytokines, that may vary in the pathogenesis of SARS-CoV-2 infections and may also be employed to help define the effectiveness of a given vaccine or other antiviral agents. Various steroids have been employed in the management of autoimmune adverse events in cancer patients receiving immunotherapeutics and may be employed in the management of SARS-CoV-2 infections. The influence of steroids on multiple immune cells subsets will also be discussed.
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Imunidade Adaptativa/imunologia , Linfócitos B/imunologia , COVID-19/imunologia , Células Dendríticas/imunologia , Imunidade Inata/imunologia , Células Matadoras Naturais/imunologia , Neoplasias/imunologia , Linfócitos T/imunologia , Fatores Etários , Antígeno B7-H1/imunologia , Ligante de CD40/imunologia , COVID-19/prevenção & controle , Vacinas contra COVID-19/uso terapêutico , Citocinas/imunologia , Suscetibilidade a Doenças , Glucocorticoides/uso terapêutico , Granzimas/imunologia , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Imunossenescência/imunologia , Células Supressoras Mieloides/imunologia , Neoplasias/tratamento farmacológico , Receptor de Morte Celular Programada 1/imunologia , Proteoma , SARS-CoV-2 , Índice de Gravidade de Doença , Subpopulações de Linfócitos T/imunologia , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/imunologiaRESUMO
INTRODUCTION: Focused and expanded mutation panels were assessed for the incremental utility of using an expanded panel in combination with microRNA risk classification. METHODS: Molecular results were reviewed for patients who underwent either a focused mutation panel (ThyGenX®) or an expanded mutation panel (ThyGeNEXT®) for strong and weak oncogenic driver mutations and fusions. microRNA results (ThyraMIR®) predictive of malignancy, including strong positive results highly specific for malignancy, were examined. RESULTS: Results of 12 993 consecutive patients were reviewed (focused panel = 8619, expanded panel = 4374). The expanded panel increased detection of strong drivers by 8% (P < .001), with BRAFV600E and TERT promoters being the most common. Strong drivers were highly correlated with positive microRNA results of which 90% were strongly positive. The expanded panel increased detection of coexisting drivers by 4% (P < .001), with TERT being the most common partner often paired with RAS. It increased the detection of weak drivers, with RAS and GNAS being the most common. 49% of nodules with weak drivers had positive microRNA results of which 33% were strongly positive. The expanded panel also decreased the number of nodules lacking mutations and fusions by 15% (P < .001), with 8% of nodules having positive microRNA results of which 22% were strongly positive. CONCLUSIONS: Using expanded mutation panels that include less common mutations and fusions can offer increased utility when used in combination with microRNA classification, which helps to identify high risk of malignancy in the cases where risk is otherwise uncertain due to the presence of only weak drivers or the absence of all drivers.
Assuntos
MicroRNAs/genética , Neoplasias da Glândula Tireoide/diagnóstico , Neoplasias da Glândula Tireoide/genética , Nódulo da Glândula Tireoide/genética , Biópsia por Agulha Fina/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Técnicas de Diagnóstico Molecular , Proteínas Proto-Oncogênicas B-raf/genética , Telomerase/genética , Neoplasias da Glândula Tireoide/patologia , Nódulo da Glândula Tireoide/patologiaRESUMO
BACKGROUND: The risk-benefit calculation for corticosteroid administration in the management of COVID-19 is complex and urgently requires data to inform the decision. The neutrophil-to-lymphocyte ratio (NLR) is a marker of systemic inflammation associated with poor prognosis in both COVID-19 and cancer. Investigating NLR as an inflammatory marker and lymphocyte levels as a critical component of antiviral immunity may inform the dilemma of reducing toxic hyperinflammation while still maintaining effective antiviral responses. METHODS: We performed a retrospective analysis of NLR, absolute neutrophil counts (ANCs) and absolute lymphocyte counts (ALCs) in patients with cancer enrolled in immunotherapy trials who received moderate-dose to high-dose corticosteroids. We compared paired presteroid and available poststeroid initiation values daily during week 1 and again on day 14 using the Wilcoxon signed-rank test. Associated immune subsets by flow cytometry were included where available. RESULTS: Patients (n=48) with a variety of solid tumors received prednisone, methylprednisolone, or dexamethasone alone or in combination in doses ranging from 20 to 190 mg/24 hours (prednisone equivalent). The median NLR prior to steroid administration was elevated at 5.0 (range: 0.9-61.2). The corresponding median ANC was 5.1 K/µL (range: 2.03-22.31 K/µL) and ALC was 1.03 K/µL (0.15-2.57 K/µL). One day after steroid administration, there was a significant transient drop in median ALC to 0.54 K/µL (p=0.0243), driving an increase in NLR (median 10.8, p=0.0306). Relative lymphopenia persisted through day 14 but was no longer statistically significant. ANC increased steadily over time, becoming significant at day 4 (median: 7.31 K/µL, p=0.0171) and remaining significantly elevated through day 14. NLR was consistently elevated after steroid initiation, significantly at days 1, 7 (median: 8.2, p=0.0272), and 14 (median: 15.0, p=0.0018). Flow cytometry data from 11 patients showed significant decreases in activated CD4 cells and effector memory CD8 cells. CONCLUSIONS: The early drop in ALC with persistent lymphopenia as well as the prolonged ANC elevation seen in response to corticosteroid administration are similar to trends associated with increased mortality in several coronavirus studies to include the current SARS-CoV-2 pandemic. The affected subsets are essential for effective antiviral immunity. This may have implications for glucocorticoid therapy for COVID-19.