RESUMEN
BACKGROUND: Immune checkpoint inhibitors (ICIs) improve survival outcomes in metastatic melanoma and non-small cell lung cancer (NSCLC). Preclinical evidence suggests that overexpression of cyclo-oxygenase-2 (COX2) in tumors facilitates immune evasion through prostaglandin E2 production and that COX inhibition synergizes with ICIs to promote antitumor T-cell activation. This study investigates whether concurrent COX inhibitor (COXi) use during ICI treatment compared with ICI alone is associated with improved time-to-progression (TTP), objective response rate (ORR) and overall survival (OS) in patients with metastatic melanoma and NSCLC. METHODS: We retrospectively reviewed 90 metastatic melanoma and 37 metastatic NSCLC patients, treated with ICI between 2011 and 2019. Differences in TTP and OS by ICI+COXi versus ICI alone were compared using Kaplan-Meier and Cox regression. Interaction between ICI+COXi versus ICI alone and pretreatment neutrophil-lymphocyte ratio (NLR) was examined. Independent radiology review per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 was performed. RESULTS: For patients with melanoma, median TTP was significantly prolonged in ICI+COXi versus ICI alone (245 vs 100.5 days, p=0.002). On multivariate analysis, ICI+COXi associated with increased TTP (HR 0.36, 95% CI 0.2 to 0.66, p=0.001), adjusted for age, pretreatment NLR, and gender. For NSCLC patients, ICI+COXi also associated with increased TTP compared with ICI alone on multivariate analysis (HR 0.45; 95% CI 0.21 to 0.97; p=0.042) adjusted for age. ORR at 6 months was significantly higher in patients who received ICI+COXi compared with ICI alone in both melanoma (58.6% vs 19.2%, p=0.0005) and NSCLC (73.7% vs 33.3%, p=0.036) cohorts. In the melanoma cohort, high pretreatment NLR (>5) associated with decreased TTP (HR 3.21, 95% CI 1.64 to 6.3; p=0.0007); however, ICI+COXi significantly associated with increased TTP in high NLR (>5) patients (HR 0.08, 95% CI 0.03 to 0.25), but not in low NLR (≤5) patients (HR 0.65, 95% CI 0.32 to 1.32). Similar outcomes were found in an adjusted melanoma cohort after RECIST review. CONCLUSIONS: Our study suggests that COXi use concurrently with ICI significantly associated with longer TTP and improved ORR at 6 months in patients with metastatic melanoma and NSCLC compared with ICI alone. Furthermore, COXi use appears to reverse the negative prognostic effect of a high NLR by prolonging TTP in patients with melanoma.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Inhibidores de la Ciclooxigenasa/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inmunoterapia/métodos , Melanoma/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Inhibidores de la Ciclooxigenasa/farmacología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Análisis de SupervivenciaRESUMEN
Given the rapidly expanding library of disease biomarkers and targeting agents, the number of unique targeted nanoparticles is growing exponentially. The high variability and expense of animal testing often makes it unfeasible to examine this large number of nanoparticles in vivo. This often leads to the investigation of a single formulation that performed best in vitro. However, nanoparticle performance in vivo depends on many variables, many of which cannot be adequately assessed with cell-based assays. To address this issue, we developed a lanthanide-doped nanoparticle method that allows quantitative comparison of multiple targeted nanoparticles simultaneously. Specifically, superparamagnetic iron oxide (SPIO) nanoparticles with different targeting ligands were created, each with a unique lanthanide dopant. Following the simultaneous injection of the various SPIO compositions into tumor-bearing mice, inductively coupled plasma mass spectroscopy was used to quantitatively and orthogonally assess the concentration of each SPIO composition in serial blood and resected tumor samples.
Asunto(s)
Proteínas del Choque Térmico HSP47/metabolismo , Integrina alfa5/metabolismo , Neoplasias Hepáticas/terapia , Nanopartículas del Metal/uso terapéutico , Terapia Molecular Dirigida , Receptor ErbB-2/metabolismo , Secuencia de Aminoácidos , Animales , Anticuerpos/química , Anticuerpos/metabolismo , Línea Celular Tumoral , Compuestos Férricos/química , Expresión Génica , Proteínas del Choque Térmico HSP47/genética , Células Estrelladas Hepáticas/efectos de los fármacos , Células Estrelladas Hepáticas/metabolismo , Células Estrelladas Hepáticas/patología , Inyecciones Intralesiones , Integrina alfa5/genética , Elementos de la Serie de los Lantanoides/química , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Nanopartículas del Metal/química , Ratones , Ratones Desnudos , Datos de Secuencia Molecular , Péptidos/química , Péptidos/metabolismo , Ratas , Receptor ErbB-2/genética , Espectrofotometría Atómica , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Recent advances in material science and chemistry have led to the development of nanoparticles with diverse physicochemical properties, e.g. size, charge, shape, and surface chemistry. Evaluating which physicochemical properties are best for imaging and therapeutic studies is challenging not only because of the multitude of samples to evaluate, but also because of the large experimental variability associated with in vivo studies (e.g. differences in tumor size, injected dose, subject weight, etc.). To address this issue, we have developed a lanthanide-doped nanoparticle system and analytical method that allows for the quantitative comparison of multiple nanoparticle compositions simultaneously. Specifically, superparamagnetic iron oxide (SPIO) with a range of different sizes and charges were synthesized, each with a unique lanthanide dopant. Following the simultaneous injection of the various SPIO compositions into tumor-bearing mice, inductively coupled plasma mass spectroscopy (ICP-MS) was used to quantitatively and orthogonally assess the concentration of each SPIO composition in serial blood samples and the resected tumor and organs. The method proved generalizable to other nanoparticle platforms, including dendrimers, liposomes, and polymersomes. This approach provides a simple, cost-effective, and non-radiative method to quantitatively compare tumor localization, biodistribution, and blood clearance of more than 10 nanoparticle compositions simultaneously, removing subject-to-subject variability.
Asunto(s)
Elementos de la Serie de los Lantanoides/sangre , Elementos de la Serie de los Lantanoides/farmacocinética , Nanopartículas/química , Espectrofotometría Atómica/métodos , Animales , Dextranos/sangre , Dextranos/farmacocinética , Luz , Nanopartículas de Magnetita , Ratones , Células 3T3 NIH , Nanopartículas/ultraestructura , Tamaño de la Partícula , Reproducibilidad de los Resultados , Dispersión de Radiación , Espectrometría por Rayos X , Electricidad Estática , Propiedades de Superficie , Distribución TisularRESUMEN
A wide variety of nanoparticle platforms are being developed for the diagnosis and treatment of malignancy. While many of these are passively targeted or rely on receptor-ligand interactions, metabolically directed nanoparticles provide a complementary approach. It is known that both primary and secondary events in tumorigenesis alter the metabolic profile of developing and metastatic cancers. One highly conserved metabolic phenotype is a state of up-regulated glycolysis and reduced use of oxidative phosphorylation, even when oxygen tension is not limiting. This metabolic shift, termed the Warburg effect, creates a "hostile" tumor microenvironment with increased levels of lactic acid and low extracellular pH. In order to exploit this phenomenon and improve the delivery of nanoparticle platforms to a wide variety of tumors, a pH-responsive iron oxide nanoparticle was designed. Specifically, glycol chitosan (GC), a water-soluble polymer with pH-titratable charge, was conjugated to the surface of superparamagnetic iron oxide nanoparticles (SPIO) to generate a T(2)*-weighted MR contrast agent that responds to alterations in its surrounding pH. Compared to control nanoparticles that lack pH sensitivity, these GC-SPIO nanoparticles demonstrated potent pH-dependent cellular association and MR contrast in vitro. In murine tumor models, GC-SPIO also generated robust T(2)*-weighted contrast, which correlated with increased delivery of the agent to the tumor site, measured quantitatively by inductively coupled plasma mass spectrometry. Importantly, the increased delivery of GC-SPIO nanoparticles cannot be solely attributed to the commonly observed enhanced permeability and retention effect since these nanoparticles have similar physical properties and blood circulation times as control agents.
Asunto(s)
Dextranos/química , Aumento de la Imagen/métodos , Imagen por Resonancia Magnética/métodos , Nanopartículas de Magnetita/química , Neoplasias de los Tejidos Blandos/química , Neoplasias de los Tejidos Blandos/patología , Animales , Línea Celular Tumoral , Medios de Contraste/química , Concentración de Iones de Hidrógeno , Ratones , Ratones DesnudosRESUMEN
Group II introns are multidomain ribozymes that catalyze their own removal from pre-mRNA. The nucleophile for the first cleavage step is the 2'OH of a specific adenosine within domain 6 (D6), called the branch site. Mechanistic parallels and limited secondary structural similarity with the eukaryotic spliceosome lead many to speculate that the two systems have a common ancestry. We have elucidated structural features of the branch site region and the importance of the internal loop to branch site conformation within D6 of the ai5gamma Group II intron by NMR and fluorescence spectroscopy. Fluorescence experiments in which 2-aminopurine was substituted for the branch site adenosine suggest that the branch site base is exposed to solvent and that this position is enhanced by Mg2+ or Ca2+. Upfield NMR chemical shifts of imino protons of the two uridine residues flanking the branch site adenosine, and an n --> n + 2 NOE between them, suggest a stacked intrahelical conformation of the two uridines. In contrast, results of NMR and 2-aminopurine fluorescence spectra of a mutated D6 from which the internal loop had been deleted suggest a less exposed position of the branch site adenosine, which is likely to form a G-A base pair with the opposing 3'G. These findings describe a model in which the branch site adenosine of D6 is in an extrahelical position, surrounded by two intrahelical bases. The internal loop and divalent metal ions facilitate this motif.