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BACKGROUND: Immune checkpoint inhibitors have revolutionized cancer treatment. However, they are associated with a unique spectrum of side effects, called immune-related adverse events (irAEs), which can cause significant morbidity and quickly progress to severe or life-threatening events if not treated promptly. Identifying predictive biomarkers for irAEs before immunotherapy initiation is therefore a critical area of research. Polymorphisms within the T-cell receptor beta (TCRB) variable (TRBV) gene have been implicated in autoimmune disease and may be mechanistically linked to irAEs. However, the repetitive nature of the TCRB locus and incomplete genome assembly has hampered the evaluation of TRBV polymorphisms in the past. PATIENTS AND METHODS: We used a novel method for long-amplicon next generation sequencing of rearranged TCRB chains from peripheral blood total RNA to evaluate the link between TRBV polymorphisms and irAEs in patients treated with immunotherapy for cancer. We employed multiplex PCR to create amplicons spanning the three beta chain complementarity-determining regions (CDR) regions to enable detection of polymorphism within the germline-encoded framework and CDR1 and CDR2 regions in addition to CDR3 profiling. Resultant amplicons were sequenced via the Ion Torrent and TRBV allele profiles constructed for each individual was correlated with irAE annotations to identify haplotypes associated with severe irAEs (≥ grade 3). RESULTS: Our study included 81 patients who had irAEs when treated with immunotherapy for cancer. By using principal component analysis of the 81 TRBV allele profiles followed by k-means clustering, we identified six major TRBV haplotypes. Strikingly, we found that one-third of this cohort possessed a TRBV allele haplotype that appeared to be protective against severe irAEs. CONCLUSION: The data suggest that long-amplicon TCRB repertoire sequencing can potentially identify TRBV haplotype groups that correlate with the risk of severe irAEs. Germline-encoded TRBV polymorphisms may serve as a predictive biomarker of severe irAEs.
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Enfermedades Autoinmunes , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Humanos , Inhibidores de Puntos de Control Inmunológico , Inmunoterapia/efectos adversos , Receptores de Antígenos de Linfocitos TRESUMEN
Purpose: Patients with non-infectious complications have worse clinical outcomes in common variable immunodeficiency (CVID) than those with infections-only. Non-infectious complications are associated with gut microbiome aberrations, but there are no reductionist animal models that emulate CVID. Our aim in this study was to uncover potential microbiome roles in the development of non-infectious complications in CVID. Methods: We examined fecal whole genome shotgun sequencing from patients CVID, and non-infectious complications, infections-only, and their household controls. We also performed Fecal Microbiota transplant from CVID patients to Germ-Free Mice. Results: We found potentially pathogenic microbes Streptococcus parasanguinis and Erysipelatoclostridium ramosum were enriched in gut microbiomes of CVID patients with non-infectious complications. In contrast, Fusicatenibacter saccharivorans and Anaerostipes hadrus, known to suppress inflammation and promote healthy metabolism, were enriched in gut microbiomes of infections-only CVID patients. Fecal microbiota transplant from non-infectious complications, infections-only, and their household controls into germ-free mice revealed gut dysbiosis patterns in recipients from CVID patients with non-infectious complications, but not infections-only CVID, or household controls recipients. Conclusion: Our findings provide a proof of concept that fecal microbiota transplant from CVID patients with non-infectious complications to Germ-Free mice recapitulates microbiome alterations observed in the donors.
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OBJECTIVES: To identify the etiology of peripheral eosinophilia in a large pediatric population and to develop a diagnostic algorithm to help guide diagnosis and management of peripheral eosinophilia in the outpatient pediatric population. STUDY DESIGN: We performed a retrospective chart review of children presenting to Texas Children's Hospital in Houston with peripheral eosinophilia between January 1, 2011 and December 31, 2019. Eosinophilia was classified as mild (absolute eosinophil count [AEC] >500 and <1500 cells/µL), moderate (AEC >1500 and <4500 cells/µL), or severe (AEC >4500 cells/µL). Demographic information and diagnostic workup data were collected. RESULTS: A total of 771 patients aged <18 years were evaluated. The most common cause of eosinophilia was allergy (n = 357; 46%), with atopy (n = 296) and drug reaction (n = 54) the most common subcauses. This was followed by unknown etiology (n = 274; 36%), infectious causes (n = 72; 9%), and eosinophilic disorders (n = 47; 6%). Many patients with an unknown cause (n = 202; 74%) had limited or no follow-up testing. CONCLUSIONS: More information on the etiology of pediatric eosinophilia and workup data could help identify the causes. This study provides important information on the evaluation of eosinophilia in the US pediatric population, including a diagnostic algorithm to guide primary care pediatricians.
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Eosinofilia , Hipersensibilidad , Humanos , Niño , Eosinófilos , Estudios Retrospectivos , Eosinofilia/diagnóstico , Eosinofilia/etiología , Recuento de Leucocitos , Hipersensibilidad/complicacionesRESUMEN
BACKGROUND: Despite immunoglobulin replacement (IgRT) therapy, some patients with primary antibody deficiency (PAD) continue to develop respiratory infections. Recurrent and severe respiratory infections, particularly pneumonia, can lead to significant morbidity and mortality. Therefore, we sought to determine the risk factors of developing pneumonia in PAD patients, already receiving IgRT. METHODS: We evaluated clinical and laboratory features of PAD patients enrolled in the US Immune Deficiency Network (USIDNET) registry by April 2017. Patients were included if they met the following criteria: (1) PAD diagnosis (common variable immunodeficiency (CVID), agammaglobulinemia, hypogammaglobinemia, and specific antibody deficiency (SAD) and (2) available data on infections before and after IgRT. Patients were excluded if they were not receiving IgRT, or if no pre/post infections data were available. Descriptive and multivariable logistic regression analyses were used to identify factors associated with pneumonia post-IgRT. RESULTS: A total of 1232 patients met the inclusion criteria. Following IgRT, 218 patients (17.7%) were reported to have at least one pneumonia episode. Using multivariate logistic regression analysis, we found a statistically significant increased risk of pneumonia in patients with asthma (OR: 2.55, 95% CI (1.69-3.85), p < 0.001) bronchiectasis (OR: 3.94, 95% CI (2.29-6.80), p < 0.001), interstitial lung disease (ILD) (OR: 3.28, 95%CI (1.43-7.56), p < 0.005), splenomegaly (OR: 2.02, 95%CI (1.08-3.76), p < 0.027), allergies (OR: 2.44, 95% CI [1.44-4.13], p = 0.001), and patients who were not on immunosuppressives (OR: 1.61; 95%CI [1.06-2.46]; p = 0.027). For every 50 unit increase in IgA, the odds of reporting pneumonia post IgRT decreased (OR: 0.86, 95% CI [0.73-1.02], p = 0.062). Infectious organisms were reported in 35 of 218 patients who reported pneumonia after IgRT. Haemophilus influenzae was the most frequently reported (n = 11, 31.43%), followed by Streptococcus pneumoniae (n = 7, 20.00%). CONCLUSION: Our findings suggest PAD patients with chronic and structural lung disease, splenomegaly, and allergies were associated with persistent pneumonia. However, our study is limited by the cross-sectional nature of the USIDNET database and limited longitudinal data. Further studies are warranted to identify susceptible causes and explore targeted solutions for prevention and associated morbidity and mortality. CLINICAL IMPLICATIONS: Patients with primary antibody deficiency with structural lung disease, allergies, and splenomegaly are associated with persistent pneumonia post-IgRT.
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Inmunodeficiencia Variable Común , Hipersensibilidad , Síndromes de Inmunodeficiencia , Enfermedades Pulmonares Intersticiales , Neumonía , Enfermedades de Inmunodeficiencia Primaria , Infecciones del Sistema Respiratorio , Humanos , Esplenomegalia/complicaciones , Estudios Transversales , Síndromes de Inmunodeficiencia/diagnóstico , Síndromes de Inmunodeficiencia/epidemiología , Síndromes de Inmunodeficiencia/complicaciones , Neumonía/diagnóstico , Neumonía/epidemiología , Neumonía/etiología , Inmunodeficiencia Variable Común/diagnóstico , Inmunodeficiencia Variable Común/epidemiología , Inmunodeficiencia Variable Común/complicaciones , Inmunización Pasiva/efectos adversos , Enfermedades Pulmonares Intersticiales/complicaciones , Inmunoglobulinas/uso terapéutico , Factores de Riesgo , Infecciones del Sistema Respiratorio/etiología , Hipersensibilidad/complicaciones , Enfermedades de Inmunodeficiencia Primaria/diagnóstico , Enfermedades de Inmunodeficiencia Primaria/epidemiologíaRESUMEN
The efficacy of dupilumab in pediatric patients with severe eczema presenting in the setting of elevated immunoglobulin E (IgE) levels and recurrent bacterial skin infections is not well-understood. Here we present the case of a child with elevated IgE levels in whom dupilumab treatment led to remarkable control of his eczema and recurrent skin infections. We also review the use of dupilumab in other patients with molecularly proven cases of hyper IgE (HIGE) syndrome. Our case supports the notion that dupilumab may have a seminal application in treating severe eczema that occurs in the setting of elevated IgE levels and recurrent bacterial skin infections.
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The need to identify biomarkers to predict immunotherapy response for rare cancers has been long overdue. We aimed to study this in our paper, 'Radiomics analysis for predicting pembrolizumab response in patients with advanced rare cancers'. In this response to the Letter to the Editor by Cunha et al, we explain and discuss the reasons behind choosing LASSO (Least Absolute Shrinkage and Selection Operator) and XGBoost (eXtreme Gradient Boosting) with LOOCV (Leave-One-Out Cross-Validation) as the feature selection and classifier method, respectively for our radiomics models. Also, we highlight what care was taken to avoid any overfitting on the models. Further, we checked for the multicollinearity of the features. Additionally, we performed 10-fold cross-validation instead of LOOCV to see the predictive performance of our radiomics models.
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Estudios Retrospectivos , HumanosRESUMEN
The pioneer transcription factor (TF) PU.1 controls hematopoietic cell fate by decompacting stem cell heterochromatin and allowing nonpioneer TFs to enter otherwise inaccessible genomic sites. PU.1 deficiency fatally arrests lymphopoiesis and myelopoiesis in mice, but human congenital PU.1 disorders have not previously been described. We studied six unrelated agammaglobulinemic patients, each harboring a heterozygous mutation (four de novo, two unphased) of SPI1, the gene encoding PU.1. Affected patients lacked circulating B cells and possessed few conventional dendritic cells. Introducing disease-similar SPI1 mutations into human hematopoietic stem and progenitor cells impaired early in vitro B cell and myeloid cell differentiation. Patient SPI1 mutations encoded destabilized PU.1 proteins unable to nuclear localize or bind target DNA. In PU.1-haploinsufficient pro-B cell lines, euchromatin was less accessible to nonpioneer TFs critical for B cell development, and gene expression patterns associated with the pro- to pre-B cell transition were undermined. Our findings molecularly describe a novel form of agammaglobulinemia and underscore PU.1's critical, dose-dependent role as a hematopoietic euchromatin gatekeeper.
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Agammaglobulinemia/genética , Cromatina/genética , Proteínas Proto-Oncogénicas/genética , Transactivadores/genética , Adolescente , Adulto , Linfocitos B/fisiología , Diferenciación Celular/genética , Línea Celular , Niño , Preescolar , Células Dendríticas/fisiología , Femenino , Regulación del Desarrollo de la Expresión Génica/genética , Células HEK293 , Hematopoyesis/genética , Células Madre Hematopoyéticas/fisiología , Humanos , Lactante , Linfopoyesis/genética , Masculino , Mutación/genética , Células Precursoras de Linfocitos B/fisiología , Células Madre/fisiología , Adulto JovenRESUMEN
BACKGROUND: We present a radiomics-based model for predicting response to pembrolizumab in patients with advanced rare cancers. METHODS: The study included 57 patients with advanced rare cancers who were enrolled in our phase II clinical trial of pembrolizumab. Tumor response was evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and immune-related RECIST (irRECIST). Patients were categorized as 20 "controlled disease" (stable disease, partial response, or complete response) or 37 progressive disease). We used 3D-slicer to segment target lesions on standard-of-care, pretreatment contrast enhanced CT scans. We extracted 610 features (10 histogram-based features and 600 second-order texture features) from each volume of interest. Least absolute shrinkage and selection operator logistic regression was used to detect the most discriminatory features. Selected features were used to create a classification model, using XGBoost, for the prediction of tumor response to pembrolizumab. Leave-one-out cross-validation was performed to assess model performance. FINDINGS: The 10 most relevant radiomics features were selected; XGBoost-based classification successfully differentiated between controlled disease (complete response, partial response, stable disease) and progressive disease with high accuracy, sensitivity, and specificity in patients assessed by RECIST (94.7%, 97.3%, and 90%, respectively; p<0.001) and in patients assessed by irRECIST (94.7%, 93.9%, and 95.8%, respectively; p<0.001). Additionally, the common features of the RECIST and irRECIST groups also highly predicted pembrolizumab response with accuracy, sensitivity, specificity, and p value of 94.7%, 97%, 90%, p<0.001% and 96%, 96%, 95%, p<0.001, respectively. CONCLUSION: Our radiomics-based signature identified imaging differences that predicted pembrolizumab response in patients with advanced rare cancer. INTERPRETATION: Our radiomics-based signature identified imaging differences that predicted pembrolizumab response in patients with advanced rare cancer.
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias/diagnóstico por imagen , Neoplasias/tratamiento farmacológico , Interpretación de Imagen Radiográfica Asistida por Computador , Enfermedades Raras/diagnóstico por imagen , Enfermedades Raras/tratamiento farmacológico , Tomografía Computarizada por Rayos X , Adulto , Anciano , Anticuerpos Monoclonales Humanizados/efectos adversos , Antineoplásicos Inmunológicos/efectos adversos , Toma de Decisiones Clínicas , Ensayos Clínicos Fase II como Asunto , Progresión de la Enfermedad , Femenino , Humanos , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Masculino , Persona de Mediana Edad , Selección de Paciente , Valor Predictivo de las Pruebas , Criterios de Evaluación de Respuesta en Tumores Sólidos , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , Factores de Tiempo , Resultado del Tratamiento , Adulto JovenRESUMEN
Fatigue is the most prevalent symptom of cancer and its treatments. Changes in the intestinal microbiome have been identified in chronic fatigue syndrome and other neuropsychiatric disorders, and cancer patients. However, the association between intestinal microbiome and fatigue in patients with advanced cancers has not been evaluated. Understanding the connection between intestinal microbiome and fatigue will provide interventional and therapeutic opportunities to manipulate the microbiome to improve fatigue and other patients' reported outcomes. In this project, we aimed to identify associations between microbiome composition and fatigue in advanced cancer patients. In this cross-sectional observational study at a tertiary cancer care center, we included 88 patients with advanced, metastatic, unresectable cancers who were in a washout period from chemotherapy. We measured fatigue using the MD Anderson Symptom Inventory-Immunotherapy fatigue score, and used 16srRNA to analyze intestinal microbiome. Using correlation analysis we found that Eubacterium hallii was negatively associated with fatigue severity scores (r = - 0.30, p = 0.005), whereas Cosenzaea was positively associated with fatigue scores (r = 0.33, p = 0.0002). We identified microbial species that exhibit distinct composition between high-fatigued and low-fatigued cancer patients. Further studies are warranted to investigate whether modulating the microbiome reduces cancer patients' fatigue severity and improves their quality of life.
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Fatiga/etiología , Fatiga/microbiología , Microbioma Gastrointestinal , Neoplasias/complicaciones , Adulto , Anciano , Bacterias/clasificación , Biodiversidad , Femenino , Humanos , Inmunoterapia , Masculino , Persona de Mediana Edad , Neoplasias/terapia , Filogenia , Análisis de Componente Principal , Estadísticas no Paramétricas , Adulto JovenRESUMEN
Introduction: For maximum utility of molecular characterization by next-generation sequencing (NGS) and better understanding of tumor microenvironment with immune correlates analysis, biopsy specimens must yield adequate tumor tissue, and sequential biopsy specimens should sample a consistent site. We developed a web-based lesion selection tool (LST) that enables management and tracking of the biopsy specimen collections. Methods: Of 145 patients, the LST was used for 88 patients; the other 57 served as controls. We evaluated consistency of the lesion biopsied in longitudinal collections, number of cores obtained, and cores with adequate tumor cellularity for NGS. The Fisher exact test and Wilcoxon rank sum test were used to identify differences between the groups. Results: The analysis included 30 of 88 (34%) patients in the LST group and 52 of 57 (91%) in the control group. The LST workflow ensured 100% consistency in the lesions biopsied compared with 75% in the control group in longitudinal collections and increased the proportion of patients in whom at least five cores were collected per biopsy. Conclusions: The novel LST platform facilitates coordination, performance, and management of longitudinal biopsy specimens. Use of the LST enables sampling of the designated lesion consistently, which is likely to accurately inform us the effect of the treatment on tumor microenvironment and evolution of resistant pathways. Such studies are important translational component of any clinical trials and research as they guide the development of next line of therapy, which has significant effect on clinical utility. However, validation of this approach in a larger study is warranted.
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Soft-tissue sarcomas associated with eosinophilia are rare, with limited cases reported in adults, and even fewer in the pediatric population. In this report, we highlight the importance of malignancy in the differential of hypereosinophilia in an adolescent. A 17-year-old boy presented with incidental findings of multiple bilateral pulmonary nodules on chest computed tomography (CT), and hypereosinophilia (absolute eosinophilic count [AEC] 7029 cells/mm3, hypereosinophilia defined as AEC >1500 cells/mm3). Lung biopsy showed high-grade metastatic sarcoma. A positron emission tomography-computed tomography (PET-CT) demonstrated a 7.9-cm mass in the left thigh, with biopsy revealing dedifferentiated liposarcoma. Subsequently, the patient was diagnosed with liposarcoma, with lung, mediastinal, and brain metastases. He completed six cycles of ifosfamide/doxorubicin, followed by surgical resection of primary thigh tumor and brain lesion. Given widely metastatic disease, he received palliative chemotherapy, and later transitioned to hospice. The patient died of respiratory failure from malignant pleural effusions. In conclusion, this case demonstrates the importance of a having a broad differential for hypereosinophilia, including malignancy, to expedite the diagnosis and initiate appropriate management promptly.
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Rubella virus (RuV) has recently been found in association with granulomatous inflammation of the skin and several internal organs in patients with inborn errors of immunity (IEI). The cellular tropism and molecular mechanisms of RuV persistence and pathogenesis in select immunocompromised hosts are not clear. We provide clinical, immunological, virological, and histological data on a cohort of 28 patients with a broad spectrum of IEI and RuV-associated granulomas in skin and nine extracutaneous tissues to further delineate this relationship. Combined immunodeficiency was the most frequent diagnosis (67.8%) among patients. Patients with previously undocumented conditions, i.e., humoral immunodeficiencies, a secondary immunodeficiency, and a defect of innate immunity were identified as being susceptible to RuV-associated granulomas. Hematopoietic cell transplantation was the most successful treatment in this case series resulting in granuloma resolution; steroids, and TNF-α and IL-1R inhibitors were moderately effective. In addition to M2 macrophages, neutrophils were identified by immunohistochemical analysis as a novel cell type infected with RuV. Four patterns of RuV-associated granulomatous inflammation were classified based on the structural organization of granulomas and identity and location of cell types harboring RuV antigen. Identification of conditions that increase susceptibility to RuV-associated granulomas combined with structural characterization of the granulomas may lead to a better understanding of the pathogenesis of RuV-associated granulomas and discover new targets for therapeutic interventions.
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Granuloma/inmunología , Inflamación/inmunología , Macrófagos/inmunología , Neutrófilos/inmunología , Virus de la Rubéola/fisiología , Rubéola (Sarampión Alemán)/inmunología , Anciano , Antígenos Virales/metabolismo , Estudios de Cohortes , Citocinas/metabolismo , Susceptibilidad a Enfermedades , Femenino , Enfermedades Genéticas Congénitas , Trasplante de Células Madre Hematopoyéticas , Humanos , Inmunohistoquímica , Síndromes de Inmunodeficiencia , Masculino , Persona de Mediana Edad , Receptores de Interleucina-1/antagonistas & inhibidores , Rubéola (Sarampión Alemán)/complicaciones , Células Th2/inmunología , Factor de Necrosis Tumoral alfa/antagonistas & inhibidoresRESUMEN
Tumor exists as a complex network of structures with an ability to evolve and evade the host immune surveillance mechanism. The immune milieu which includes macrophages, dendritic cells, natural killer cells, neutrophils, mast cells, B cells, and T cells is found in the core, the invasive margin, or the adjacent stromal or lymphoid component of the tumor. The immune infiltrate is heterogeneous and varies within a patient and between patients of the same tumor histology. The location, density, functionality, and the crosstalk between the immune cells in the tumor microenvironment influence the nature of immune response, prognosis, and treatment outcomes in cancer patients. Therefore, an understanding of the characteristics of the immune cells and their role in tumor immune surveillance is of paramount importance to identify immune targets and to develop novel immune therapeutics in the war against cancer. In this chapter, we provide an overview of the individual components of the human immune system and the translational relevance of predictive biomarkers.
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Neoplasias , Microambiente Tumoral , Humanos , Vigilancia Inmunológica , Células Asesinas Naturales , Neoplasias/terapia , NeutrófilosRESUMEN
With the advent of immunotherapeutic agents, durable and dramatic responses have been observed in several hard-to-treat malignancies, outlining a roadmap to conquering cancer. Immune checkpoint inhibitors (ICPi) are a class of immunotherapeutic agents that attack the tumor cells by reinvigorating the suppressed immune system. However, the unbridled T-cell activity disrupts the immune homeostasis and induces a unique spectrum of side effects called immune-related adverse events (irAEs) in a significant proportion of patients. These irAEs are distinct from the side effects produced by traditional chemotherapeutic agents. Although majority of irAEs are manageable with corticosteroids and other immunosuppressive agents, life-threatening and fatal events have been reported. In the absence of predictive biomarkers to identify patients at risk for irAEs and standardized approach to detect, report, and treat irAEs, management of irAEs has been challenging to the patients, caregivers and the healthcare providers alike. With increasing use of ICPis for treatment of various cancers, the incidence of irAEs will undoubtedly increase. There is a compelling need to develop measures to effectively manage irAEs, both in the community settings and in cancer centers alike. To this end, in this paper, we propose several strategies, such as providing patient education, harmonizing irAE management guidelines, standardizing reporting of irAEs, optimizing the choice of immunosuppressive agents, conducting preclinical, clinical and translational studies to better understand irAEs, including high-risk patients, incorporating diagnostic tools to personalize irAE management using wireless technology and digital health, providing a platform to hear the missing patient's voice, and sharing evolving data to improve the management of irAEs.
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Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/tratamiento farmacológico , Inmunoterapia/métodos , HumanosRESUMEN
Cancer cells can evade immune surveillance in the body. However, immune checkpoint inhibitors can interrupt this evasion and enhance the antitumor activity of T cells. Other mechanisms for promoting antitumor T-cell function are the targeting of costimulatory molecules expressed on the surface of T cells, such as 4-1BB, OX40, inducible T-cell costimulator and glucocorticoid-induced tumor necrosis factor receptor. In addition, CD40 targets the modulation of the activation of antigen-presenting cells, which ultimately leads to T-cell activation. Agonists of these costimulatory molecules have demonstrated promising results in preclinical and early-phase trials and are now being tested in ongoing clinical trials. In addition, researchers are conducting trials of combinations of such immune modulators with checkpoint blockade, radiotherapy and cytotoxic chemotherapeutic drugs in patients with advanced tumors. This review gives a comprehensive picture of the current knowledge of T-cell agonists based on their use in recent and ongoing clinical trials.
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Inmunoterapia/métodos , Neoplasias/tratamiento farmacológico , Linfocitos T/inmunología , HumanosRESUMEN
X-linked lymphoproliferative disease (XLP1) is a rare primary immunodeficiency characterized by EBV-triggered immune dysregulation, lymphoproliferation, dysgammaglobulinemia, and lymphoma. Early childhood mortality from overwhelming inflammation is expected in most patients. The only curative therapy is hematopoietic stem cell transplant (HSCT); however, whether to perform HSCT on an asymptomatic patient remains debatable. This uncertainty arises because the natural history of XLP1 patients without transplantation is not clear. In this case report, we present the natural history of XLP1 in a 43-year-old male patient who did not receive HSCT. We also review the literature on untransplanted XLP1 patients who lived into mid-adulthood. Despite surviving childhood presentations that are typically fatal, we found that these rare patients remain susceptible to manifestations of XLP1 decades later.
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Tumor exists as a complex network of structures with an ability to evolve and evade the host immune surveillance mechanism. The immune milieu which includes macrophages, dendritic cells, natural killer cells, neutrophils, mast cells, B cells, and T cells are found in the core, the invasive margin, or the adjacent stromal or lymphoid component of the tumor. The immune infiltrate is heterogeneous and varies within a patient and between patients of the same tumor histology. The location, density, functionality, and cross-talk between the immune cells in the tumor microenvironment influence the nature of immune response, prognosis, and treatment outcomes in cancer patients. Therefore, an understanding of the characteristics of the immune cells and their role in tumor immune surveillance is of paramount importance to identify immune targets and to develop novel immune therapeutics in the war against cancer. In this chapter, we provide an overview of the individual components of the human immune system and the translational relevance of predictive biomarkers.