RESUMEN
Lung cancer is notoriously known for its predisposition to metastasize to the bones. Diagnostic tools, including positron emission tomography coupled with computed tomography, offer increased sensitivity in detecting bone infiltration. Management strategies encompass a multidisciplinary approach, including pharmacological pain management, anti-resorptive therapy, radiotherapy, interventional techniques, and surgery. This article provides an in-depth analysis of the incidence and distribution of bone metastases, skeletal-related events (SRE), diagnostic imaging techniques, and contemporary therapeutic strategies to prevent SRE. Systemic anticancer therapy and pain management, although crucial for treating BM, are not discussed in this article.
Le cancer du poumon est notoirement connu pour sa prédisposition à métastaser dans les os. Les outils diagnostiques, notamment la tomographie par émission de positrons couplée à la tomodensitométrie, offrent une sensibilité accrue pour détecter l'infiltration osseuse. Les stratégies de prise en charge englobent une approche multidisciplinaire, comprenant le traitement médicamenteux de la douleur, la thérapie antirésorptive, la radiothérapie, les techniques interventionnelles ainsi que la chirurgie. Cet article propose une analyse approfondie de l'incidence et de la distribution des métastases osseuses (MO), des événements liés au squelette (SRE), des techniques d'imagerie diagnostique et des stratégies thérapeutiques contemporaines pour prévenir les SRE. Le traitement systémique anticancéreux et la gestion de la douleur, bien que cruciaux pour traiter les MO, ne sont pas discutés dans cet article.
Asunto(s)
Neoplasias Óseas , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/patología , Carcinoma de Pulmón de Células no Pequeñas/terapia , Carcinoma de Pulmón de Células no Pequeñas/secundario , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Óseas/secundario , Neoplasias Óseas/terapia , Manejo del Dolor/métodos , Tomografía Computarizada por Rayos X/métodosRESUMEN
Precision medicine is playing an increasingly crucial role in the treatment of prostate cancer. By tailoring treatments to the unique characteristics of patients and their tumors, this approach enables more targeted and personalized care, ultimately improving patient survival. In this article, we discuss the targeted therapies that have recently changed the management of this cancer.
La médecine de précision joue un rôle de plus en plus crucial dans le traitement du cancer de la prostate. En adaptant les traitements aux caractéristiques individuelles des patients et de leurs tumeurs, cette approche permet une prise en charge plus ciblée et personnalisée, contribuant ainsi à améliorer la survie des patients. Dans cet article, nous abordons les traitements ciblés qui ont récemment transformé la prise en charge de ce cancer.
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Medicina de Precisión , Neoplasias de la Próstata , Masculino , Humanos , Neoplasias de la Próstata/diagnóstico , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/terapia , Terapia Molecular Dirigida , Cuidados PaliativosRESUMEN
The past year has brought several innovations in medical oncology, opening up promising new options for many solid tumors, both localized and metastatic. Immunotherapy, a real spearhead of emerging therapies in metastatic diseases, is seeing its use extend to adjuvant and neoadjuvant modalities, particularly in colon and lung cancers. 2022 also sees a great deal of focus on targeted therapies, as well as on antibody-drug conjugates, which creates new standards in both breast and lung cancers. Here we present the major advances in solid tumors.
L'année écoulée a apporté son lot d'innovations en oncologie médicale, ouvrant de nouvelles options prometteuses pour bon nombre de tumeurs solides, qu'elles soient localisées ou métastatiques. L'immunothérapie, véritable fer de lance des thérapies émergentes dans les maladies métastatiques, voit son usage s'étendre à des modalités adjuvantes et néoadjuvantes, notamment dans les cancers du côlon et du poumon. 2022 donne également la part belle aux thérapies ciblées mais aussi aux conjuguées anticorps-médicaments qui apportent de nouveaux standards tant pour les cancers du sein que du poumon. Nous vous présentons ici les avancées majeures concernant les tumeurs solides.
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Neoplasias Pulmonares , Oncología Médica , Humanos , Inmunoterapia , Terapia Neoadyuvante , Neoplasias Pulmonares/terapiaRESUMEN
In recent years, new therapeutic strategies for non-small cell lung cancer (NSCLC) have been developed, stemming from a better understanding of oncogenic signaling pathways. The analysis of the alterations of genes involved in NSCLC oncogenesis is now an integral part of the diagnostic approach and opens the way to so-called "targeted" therapies. In this article, we will share the latest therapeutic advances by focusing on alterations of HER2, MET, EGFR and KRAS genes, for which new dedicated treatments have become available.
Au cours de ces dernières années, de nouvelles stratégies thérapeutiques pour le cancer du poumon non à petites cellules (CPNPC) se sont développées, découlant d'une meilleure compréhension des voies de signalisation oncogéniques. L'analyse des altérations de gènes impliqués dans le développement de ce sous-type de maladie oncologique fait désormais partie intégrante de la démarche diagnostique et ouvre la voie à des thérapies dites « ciblées ¼. Nous partagerons dans cet article les dernières avancées thérapeutiques en nous intéressant aux altérations des gènes HER2, MET, EGFR et KRAS, pour lesquelles de nouveaux traitements dédiés sont disponibles.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , MutaciónRESUMEN
Human health is recently affected by several factors in which food contamination is one of the most dangerous elements that damage directly on our bodies. In this study, we provided a novel approach for the rapid detection of Salmonella sp. at the molecular level using the response of Saccharomyces cerevisiae's vacuoles. First, an augmentation of vacuoles intensity was observed by confocal microscopy after treating Salmonella strains with yeast cells. Second, the vacuolar enzymes were isolated and then analyzed by two-dimensional electrophoresis for the screening of specific biomarkers. After that, various recombinant yeasts containing exclusive biomarkers were constructed by fusing these biomarkers with several fluorescent proteins. Finally, the recombinant strains showed the ability to detect Salmonella strains specifically by appropriate fluorescent signals from 20 CFU/mL after 15 Min of exposure.
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Técnicas de Tipificación Bacteriana , Bioensayo , Proteínas Fúngicas , Saccharomyces cerevisiae , Salmonella , Vacuolas , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Vacuolas/genética , Vacuolas/metabolismo , Vacuolas/microbiologíaRESUMEN
BACKGROUND: Joubert syndrome is a genetically heterogeneous autosomal recessive ciliopathy characterized by the combination of hypoplasia/aplasia of the cerebellar vermis, thickened and elongated superior cerebellar peduncles and a deep interpeduncular fossa, known as "molar tooth sign" associated with hypotonia, respiratory control disturbances and abnormal eye movements. To date, pathogenic variants in over 35 genes are known to cause autosomal recessive Joubert Syndrome, while one gene is associated with X-linked recessive inheritance. CASE PRESENTATION: We describe here a non-consanguineous Vietnamese family with Joubert syndrome, a fetus and 10-year-old developmentally delayed boy. Ultrasonography showed ventriculomegaly at 26 + 6 weeks of gestation in the fetus. The 10-year-old-boy was diagnosed with cerebral palsy of unknown origin. Clinical physical examination at the age of 10, he showed clinical features of Joubert syndrome including typical facial dysmorphism, ataxia, severe psychomotor delay, oculomotor apraxia and molar tooth sign on brain MRI. Whole exome sequencing analysis identified a novel compound heterozygous c.725A > G p.Asn242Ser and c.313-3 T > G p.Lys105Valfs*16 TMEM67 variant in the proband and the affected fetus. These two variants were inherited from each parent and confirmed by Sanger sequencing. The variant c.725A > G p.Asn242Ser was previously documented in patients with JS, the novel splice-site c.313-3 T > G p.Lys105Valfs*16 TMEM67 variant produced an aberrant transcript with the loss of four nucleotides of exon 03. CONCLUSION: This study confirms the diagnosis of Joubert syndrome in a Vietnamese family and expands the mutational spectrum of TMEM67 sequence variations. We also highlight the importance of molecular approaches to unravel underlying mechanisms of human genetic disorders. Early precise diagnosis could help provide further accurate genetic counseling for recurrence-risk assessment, future diagnostic option, management as well as treatment guidance for rare disorders.
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Anomalías Múltiples/genética , Cerebelo/anomalías , Anomalías del Ojo/genética , Predisposición Genética a la Enfermedad , Enfermedades Renales Quísticas/genética , Proteínas de la Membrana/genética , Retina/anomalías , Anomalías Múltiples/diagnóstico , Anomalías Múltiples/fisiopatología , Adulto , Cerebelo/fisiopatología , Niño , Exones/genética , Anomalías del Ojo/diagnóstico , Anomalías del Ojo/fisiopatología , Femenino , Humanos , Enfermedades Renales Quísticas/diagnóstico , Enfermedades Renales Quísticas/fisiopatología , Imagen por Resonancia Magnética , Masculino , Mutación/genética , Linaje , Isoformas de Proteínas/genética , Retina/metabolismo , Retina/patología , Retina/fisiopatología , Vietnam , Secuenciación del ExomaRESUMEN
BACKGROUND AIMS: Several studies report on Good Manufacturing Process (GMP)-compliant manufacturing protocols for the ex vivo expansion of tumor-infiltrating lymphocytes (TILs) for the treatment of patients with refractory melanoma and other solid malignancies. Further opportunities for improvements in terms of ergonomy and operating time have been identified. METHODS: To enable GMP-compliant TILs production for adoptive cell therapy needs, a simple automated and reproducible protocol for TILs manufacturing with the use of a closed system was developed and implemented at the authors' institution. RESULTS: This protocol enabled significant operating time reduction during TILs expansion while allowing the generation of high-quality TILs products. CONCLUSIONS: A simplified and efficient method of TILs expansion will enable the broadening of individualized tumor therapy and will increase patients' access to state-of-the-art TILs adoptive cell therapy treatment.
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Técnicas de Cultivo de Célula/métodos , Hospitales , Linfocitos Infiltrantes de Tumor/citología , Automatización , Recuento de Células , Proliferación Celular , Criopreservación , Femenino , Humanos , Cinética , Fenotipo , Control de CalidadRESUMEN
Cell blocking (CB) technique has been widely applied in many studies since the last century. In our research, this technique was mostly used to study the enhancement of the vacuolar response-based system that could detect Shigella sp. and Salmonella sp. investigated in previous studies. The recombinant yeast cells were blocked by mixing with agarose gel on a 96-wells plate, then storing this plate in -80 °C before using. The optimal conditions for the new system, such as agarose concentration, maximum storage time, were also established. Finally, the efficiency of the vacuolar response-based system was improved, and this system could be used as a portable detector for the foodborne pathogen.
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Fluorometría/métodos , Saccharomyces cerevisiae/metabolismo , Salmonella/aislamiento & purificación , Shigella/aislamiento & purificación , Colorantes Fluorescentes/análisis , Microbiología de Alimentos/métodos , Enfermedades Transmitidas por los Alimentos/microbiología , Salmonella/química , Shigella/química , Vacuolas/química , Vacuolas/microbiologíaRESUMEN
Small cell lung cancer is a recalcitrant malignancy with 5-year survival rates of less than 20%. In the majority of cases, patients have metastatic disease at diagnosis despite the new screening method by low-dose CT-scan. The high throughput sequencing has deepened our understanding of its biology. While the treatment of localized disease has changed little, the arrival of immune checkpoint inhibitors have revolutionized the management of extensive disease. At the same time, new strategies involving certain potential genetic targets are being analyzed on a large scale that could become valuable therapeutic alternatives in the future. Radiation therapy remains a very useful therapeutic modality in all stages of the disease. This article aims to review the epidemiology, molecular pathology, management and innovative therapies in small-cell lung cancer.
Le cancer pulmonaire à petites cellules (CPPC) est une tumeur récalcitrante avec une survie à 5 ans de moins de 20â %. Il est fréquemment découvert à un stade métastatique malgré le nouveau dépistage par computed tomography scan low-dose. Le séquençage à haut débit a permis d'approfondir notre compréhension de sa biologie. Bien que le traitement du CPPC localisé ait peu évolué, l'immunothérapie par inhibiteurs des points de contrôle a révolutionné la prise en charge de la maladie métastatique. Parallèlement, de nouvelles stratégies impliquant certaines cibles génétiques potentielles sont en cours d'évaluation et pourraient se révéler précieuses à l'avenir. La radiothérapie reste très utile à tous les stades de la maladie. Cet article passe en revue l'épidémiologie, la pathologie moléculaire, la prise en charge et les thérapies novatrices dans le CPPC.
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Neoplasias Pulmonares/terapia , Carcinoma Pulmonar de Células Pequeñas/terapia , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/radioterapia , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Carcinoma Pulmonar de Células Pequeñas/radioterapia , Tasa de SupervivenciaRESUMEN
Lung cancer is the leading cause of cancer related deaths worldwide. Since the advent of immunotherapy, survival has significantly improved. Though encouraging treatment results, initially only some patients used to benefit significantly and specifically from immunotherapy administered alone. Recently, different combinations of immunotherapy treatments with cytotoxic chemotherapy and anti-angiogenic treatments were tested in order to improve the results. Six immunotherapy treatment strategies are currently approved in Switzerland for the treatment of advanced lung cancer, either in first or later line of treatment, alone or in combination with other cytotoxic treatments. In this paper we will review the results of the latest clinical trials testing immunotherapy that led to change of the standard of care for non-small cell lung cancer, and will mention the latest perspectives of the treatment for locally advanced cancers and for small cell lung cancer.
Le carcinome pulmonaire représente la première cause de mortalité par cancer dans le monde. Ces dernières années, depuis l'avènement de l'immunothérapie, la survie a été significativement améliorée. Malgré des résultats encourageants, seule une minorité de patients bénéficiaient spécifiquement et significativement du traitement par immunothérapie administré en monothérapie. Récemment, plusieurs combinaisons entre différents traitements d'immunothérapie ou avec d'autres traitements cytotoxiques et anti-angiogéniques ont été testées en vue d'améliorer ces résultats. Six stratégies d'immunothérapie sont maintenant approuvées en Suisse pour le traitement du cancer pulmonaire avancé, en première ligne ou en ligne tardive, en monothérapie ou en association avec d'autres traitements cytotoxiques. Cet article se propose de passer en revue les résultats des dernières études cliniques qui ont changé les standards thérapeutiques, testant l'immunothérapie dans le traitement du carcinome pulmonaire non à petites cellules de stade avancé, et évoquer les perspectives pour les tumeurs précoces et le cancer à petites cellules.
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Carcinoma de Pulmón de Células no Pequeñas , Inmunoterapia , Neoplasias Pulmonares , Carcinoma de Pulmón de Células no Pequeñas/terapia , Humanos , Neoplasias Pulmonares/terapia , SuizaRESUMEN
Aging of the population results in an increase of the incidence of cancer and bone metastases. The proximal femur is one of the most frequent locations of bone metastases. A pathological fracture has a major impact on the quality of life and potentially on survival. In case of impending fracture, prophylactic fixation is therefore strongly recommended. The management of metastases of the proximal femur depends on multiple parameters, life expectancy and fracture risk being the most important ones. If survival is estimated to be less than 6 weeks, surgery is generally not indicated. Beyond 6 weeks, surgical indication essentially depends on location of the metastases on the proximal femur and the presence of a fracture.
L'augmentation de l'espérance de vie s'accompagne d'une croissance de l'incidence des cancers et des métastases osseuses. Le fémur proximal est un des sites les plus fréquents de métastases osseuses. Une fracture pathologique dans cette localisation a un impact majeur sur la qualité de vie et potentiellement sur la survie du patient. Un traitement chirurgical prophylactique est ainsi recommandé en cas de risque de fracture imminente. La prise en charge des métastases fémorales proximales se décide en fonction de multiples paramètres, dont la survie théorique et le risque de fracture sont les plus importants. Si la survie est estimée à moins de 6 semaines, une chirurgie n'est en général pas indiquée. Au-delà, l'indication chirurgicale dépend essentiellement de la localisation des lésions et de la présence d'une fracture associée.
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Neoplasias Óseas , Fracturas Espontáneas , Neoplasias Óseas/secundario , Neoplasias Óseas/cirugía , Fémur , Humanos , Calidad de Vida , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
PURPOSE OF REVIEW: Recent advances in nanotechnology have addressed some of the issues related to lack of selectivity and nonspecific toxicities associated with conventional chemotherapy. Nanoparticles are therapeutic carriers that can be fine tuned for specific application and for passive or active tumor targeting. RECENT FINDINGS: Although the nanoparticle field is rapidly expanding, there are to date only six nanoparticle-based drug delivery platforms and two antibody-drug conjugates that are clinically approved for cancer therapy. Here, we review the clinical data of liposomal anthracyclines, nanoparticle formulations of paclitaxel and trastuzumab emtansine. We then briefly comment on efficacy and safety issues of nanoparticles, as well as on the next-generation nanoparticles for cancer therapy. SUMMARY: The emerging development of cancer nanotechnology offers the opportunity of reinvestigating the potential of cytotoxic agents, improving tumor targeting and drug delivery, leading to better safety profile and antitumor activity. Adding specificity to nanoparticles may allow personalization of cancer therapy using chemotherapy.
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Paclitaxel Unido a Albúmina/administración & dosificación , Anticuerpos Monoclonales Humanizados/administración & dosificación , Antineoplásicos Fitogénicos/administración & dosificación , Portadores de Fármacos/química , Maitansina/análogos & derivados , Nanopartículas/química , Neoplasias/tratamiento farmacológico , Paclitaxel/administración & dosificación , Ado-Trastuzumab Emtansina , Albúminas , Humanos , Maitansina/administración & dosificación , Nanotecnología , TrastuzumabRESUMEN
Despite being essential for spatial cell division control, the mechanisms governing spindle positioning remain incompletely understood. In the Caenorhabditis elegans one-cell stage embryo, the spindle becomes asymmetrically positioned during anaphase through the action of as-yet unidentified cortical force generators that pull on astral microtubules and that depend on two G alpha proteins and associated proteins. We performed spindle-severing experiments following temporally restricted gene inactivation and drug exposure, and established that microtubule dynamics and dynein are both required for generating efficient pulling forces. We found that the G alpha-associated proteins GPR-1/2 and LIN-5 interact in vivo with LIS-1, a component of the dynein complex. Moreover, we discovered that the LIN-5, GPR-1/2 and the G alpha proteins promote the presence of the dynein complex at the cell cortex. Our findings suggest a mechanism by which the G alpha proteins enable GPR-1/2 and LIN-5 recruitment to the cortex, thus ensuring the presence of cortical dynein. Together with microtubule dynamics, this allows pulling forces to be exerted and proper cell division to be achieved.
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Caenorhabditis elegans , Polaridad Celular , Dineínas/metabolismo , Subunidades alfa de la Proteína de Unión al GTP/metabolismo , Huso Acromático/fisiología , Animales , Proteínas de Caenorhabditis elegans/metabolismo , Proteínas de Ciclo Celular/metabolismo , Microtúbulos/fisiologíaRESUMEN
The blood-brain barrier (BBB) is a brain protection structure that restricts drug delivery from the blood to the central nervous system. Thus, we developed a novel drug carrier using yeast vacuoles to overcome this problem. The purpose of this study was to assess the drug transportability of yeast vacuoles using a human cerebral microvascular endothelial cell line (hCMEC/D3) cell monolayer. Here, we used daunorubicin (DNR) as a microtubule-targeting agent with the ability to disaggregate pre-formed fibrils and prevent Tau fibrillization. An in vitro model was developed by culturing hCMEC/D3 cells on Transwell inserts in EBM-2 endothelial basal medium until the cells formed a monolayer. Next, nano-sized yeast vacuoles were loaded with DNR, and the signals inside and outside the hMEC/D3 cell monolayer were detected using the GloMax® Explorer fluorometer. DNR penetrated the cell monolayer and was regulated by endocytosis via receptor-mediated macropinocytosis on the surface of the cell. Confocal imaging showed a significant increase in intracellular DNR fluorescence when the cells were treated with the vacuole-encapsulated drug. These results indicate that the drug penetrated the hCMEC/D3 cell monolayer via encapsulation into the vacuoles. Overall, yeast-derived vacuoles are promising candidates as drug carriers to the brain.
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Saccharomyces cerevisiae , Vacuolas , Humanos , Células Endoteliales/metabolismo , Línea Celular , Barrera HematoencefálicaRESUMEN
A 40-year-old patient with cT4cN1M0 squamous cell lung cancer of the upper right lobe received preoperative induction chemotherapy. Systemic induction treatment failed to reverse tumour growth with the addition of conventional radiotherapy (RT). A salvage lattice RT boost of 12 Gy was administered immediately to increase the dose to the tumour. Conventional RT was resumed at the planned dose of 60 Gy. The tumour shrank rapidly, and the patient was surged. The postoperative pathology remained ypT0ypN0 status.
RESUMEN
Staphylococcus aureus is a common pathogen that causes health care-related and community-associated infections. In this study, we provide a novel system that can recognize and kill S. aureus bacteria. The system is specifically based on a combination of the phage display library technique and yeast vacuoles. A phage clone displaying a peptide capable of specific binding to a whole S. aureus cell was selected from a 12-mer phage peptide library. The peptide sequence was SVPLNSWSIFPR. The selected phage's ability to bind specifically with S. aureus was confirmed using an enzyme-linked immunosorbent assay, and the chosen peptide was then synthesized. The results showed that the synthesized peptides displayed high affinity with S. aureus but low binding ability with other strains, including Gram-negative and Gram-positive bacteria such as Salmonella sp., Shigella spp., Escherichia coli, and Corynebacterium glutamicum. In addition, yeast vacuoles were used as a drug carrier by encapsulating daptomycin, a lipopeptide antibiotic used to treat Gram-positive bacterial infections. The expression of specific peptides at the encapsulated vacuole membrane created an efficient system that can specifically recognize and kill S. aureus bacteria. IMPORTANCE The phage display method was used to select peptides with high affinity and specificity for S. aureus, and these peptides were then induced to be expressed on the surface of yeast vacuoles. These surface-modified vacuoles can act as drug carriers, with drugs such as the lipopeptide antibiotic daptomycin loaded inside. An advantage of using yeast vacuoles as a drug carrier is that they can be easily produced through yeast culture, making the approach cost-effective and suitable for large-scale production and potential implementation in clinical settings. This novel approach offers a promising way to specifically target and eliminate S. aureus that could ultimately lead to improved treatment of bacterial infections and reduced risk of antibiotic resistance.
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Daptomicina , Infecciones Estafilocócicas , Humanos , Staphylococcus aureus , Saccharomyces cerevisiae , Vacuolas , Péptidos/farmacología , Infecciones Estafilocócicas/microbiología , Antibacterianos/farmacologíaRESUMEN
Currently, ascorbic acid (AA) is widely used as a skin whitening material, but, AA, an unstable hydrophilic molecule, cannot penetrate the skin easily, due to the hydrophobic character of the stratum corneum. Therefore, we conjugated AA with hydrated zinc oxide-an inorganic matrix with positive surface charge, to improve the stability of AA. The metal-conjugated-ascorbic acid (ZnAA) was then combined with yeast vacuole through the vacuolar membrane proteins that relate to metal transportation to create an enhanced vacuole that contained ZnAA. The characteristics of vacuole with ZnAA (ZnAA_Vac) were next examined by various tests that included X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), Field emission scanning electron microscopy (FE-SEM), and energy-dispersive X-ray (EDX) analysis. Furthermore, the ability of ZnAA_Vac to degrade melanin was confirmed in both melanoma cell line B16F10, and the artificial human skin MelanoDerm. The results showed that ZnAA_Vac possessed a higher depigmenting effect than the wild-type vacuole or ascorbic acid by reducing 75% of melanin color. Interestingly, ZnAA_Vac was found to be harmless, and did not cause any cytotoxicity to the cells. Overall, ZnAA_Vac is expected to provide a robust, harmless, and effective whitening agent for the skin.
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Nanopartículas del Metal , Nanopartículas , Óxido de Zinc , Humanos , Óxido de Zinc/farmacología , Óxido de Zinc/química , Ácido Ascórbico/farmacología , Ácido Ascórbico/química , Melaninas , Vacuolas/metabolismo , Espectroscopía Infrarroja por Transformada de Fourier , Nanopartículas del Metal/química , Difracción de Rayos X , Antibacterianos/químicaRESUMEN
The success of cancer immunotherapy depends in part on the strength of antigen recognition by T cells. Here, we characterize the T cell receptor (TCR) functional (antigen sensitivity) and structural (monomeric pMHC-TCR off-rates) avidities of 371 CD8 T cell clones specific for neoantigens, tumor-associated antigens (TAAs) or viral antigens isolated from tumors or blood of patients and healthy donors. T cells from tumors exhibit stronger functional and structural avidity than their blood counterparts. Relative to TAA, neoantigen-specific T cells are of higher structural avidity and, consistently, are preferentially detected in tumors. Effective tumor infiltration in mice models is associated with high structural avidity and CXCR3 expression. Based on TCR biophysicochemical properties, we derive and apply an in silico model predicting TCR structural avidity and validate the enrichment in high avidity T cells in patients' tumors. These observations indicate a direct relationship between neoantigen recognition, T cell functionality and tumor infiltration. These results delineate a rational approach to identify potent T cells for personalized cancer immunotherapy.
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Melanoma , Animales , Ratones , Melanoma/metabolismo , Linfocitos T CD8-positivos , Receptores de Antígenos de Linfocitos T/metabolismo , Antígenos de Neoplasias , Células Clonales/metabolismoRESUMEN
The identification of patient-specific tumor antigens is complicated by the low frequency of T cells specific for each tumor antigen. Here we describe NeoScreen, a method that enables the sensitive identification of rare tumor (neo)antigens and of cognate T cell receptors (TCRs) expressed by tumor-infiltrating lymphocytes. T cells transduced with tumor antigen-specific TCRs identified by NeoScreen mediate regression of established tumors in patient-derived xenograft mice.
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Neoplasias , Receptores de Antígenos de Linfocitos T , Animales , Antígenos de Neoplasias/genética , Linfocitos T CD8-positivos , Humanos , Linfocitos Infiltrantes de Tumor , Ratones , Neoplasias/genética , Neoplasias/terapia , Receptores de Antígenos de Linfocitos T/genética , Linfocitos TRESUMEN
INTRODUCTION: For patients with corticosteroid (CS)-refractory immune checkpoint inhibitor-related cholangiohepatitis (irCH), no consensus exists regarding treatment, and outcomes remain poor. We evaluated the possibility of personalized treatment according to the patient's cytokine profile and the immunohistopathologic assessment of the predominant immune infiltrate type of liver tissue. METHODS: NSCLCs with CS-refractory irCH were analyzed by immunohistochemistry of liver biopsy specimen, serum cytokine panel, and assessment of peripheral blood mononuclear cell immune cell monitoring by mass cytometry. RESULTS: A total of three consecutive patients with irCH were identified. We found a predominant T-cell infiltrate and an interferon-gamma or T helper 1 proinflammatory cytokine profile. Here, we report for the first time that a T-cell-targeted therapy with the interleukin (IL)-6 receptor-neutralizing antibody tocilizumab, which inhibits signaling downstream of interferon-gamma and several other Janus kinase-dependent cytokines, is an effective single cytokine-directed therapy for CS-refractory irCH. Three patients with severe, CS-refractory irCH who were treated with tocilizumab were found to have persistent clinical and biological remission. CONCLUSIONS: Dysregulation of the IL-6/T-cell axis may contribute to the pathogenesis of CS-refractory irCH. Our observations suggest that IL-6 blockade seems to have promise in the treatment of CS-refractory irCH. The results from our three patients need to be confirmed in a larger patient population.