RESUMEN
BACKGROUND: Patients with squamous non-small-cell lung cancer that is refractory to multiple treatments have poor outcomes. We assessed the activity of nivolumab, a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, for patients with advanced, refractory, squamous non-small-cell lung cancer. METHODS: We did this phase 2, single-arm trial at 27 sites (academic, hospital, and private cancer centres) in France, Germany, Italy, and USA. Patients who had received two or more previous treatments received intravenous nivolumab (3 mg/kg) every 2 weeks until progression or unacceptable toxic effects. The primary endpoint was the proportion of patients with a confirmed objective response as assessed by an independent radiology review committee. We included all treated patients in the analyses. This study is registered with ClinicalTrials.gov, number NCT01721759. FINDINGS: Between Nov 16, 2012, and July 22, 2013, we enrolled and treated 117 patients. 17 (14·5%, 95% CI 8·7-22·2) of 117 patients had an objective response as assessed by an independent radiology review committee. Median time to response was 3·3 months (IQR 2·2-4·8), and median duration of response was not reached (95% CI 8·31-not applicable); 13 (77%) of 17 of responses were ongoing at the time of analysis. 30 (26%) of 117 patients had stable disease (median duration 6·0 months, 95% CI 4·7-10·9). 20 (17%) of 117 patients reported grade 3-4 treatment-related adverse events, including: fatigue (five [4%] of 117 patients), pneumonitis (four [3%]), and diarrhoea (three [3%]). There were two treatment-associated deaths caused by pneumonia and ischaemic stroke that occurred in patients with multiple comorbidities in the setting of progressive disease. INTERPRETATION: Nivolumab has clinically meaningful activity and a manageable safety profile in previously treated patients with advanced, refractory, squamous non-small cell lung cancer. These data support the assessment of nivolumab in randomised, controlled, phase 3 studies of first-line and second-line treatment. FUNDING: Bristol-Myers Squibb.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Anciano , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/patología , Comorbilidad , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Esquema de Medicación , Europa (Continente) , Femenino , Humanos , Infusiones Intravenosas , Estimación de Kaplan-Meier , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Terapia Molecular Dirigida , Nivolumab , Receptor de Muerte Celular Programada 1/metabolismo , Factores de Riesgo , Transducción de Señal/efectos de los fármacos , Factores de Tiempo , Resultado del Tratamiento , Estados UnidosRESUMEN
Neuroblastoma (NB) is a common, highly lethal pediatric cancer, with treatment failures largely attributable to the emergence of chemoresistance. The pro-survival Bcl2 homology (BH) proteins critically regulate apoptosis, and may represent important therapeutic targets for restoring drug sensitivity in NB. We used a human NB tumor tissue microarray to survey the expression of pro-survival BH proteins Mcl1 and Bcl2, and correlated expression to clinical prognostic factors and survival. Primary NB tumors heterogeneously expressed Mcl1 or Bcl2, with high expression correlating to high-risk phenotype. Co-expression is infrequent (11%), but correlates to reduced survival. Using RNA interference, we investigated the functional relevance of Mcl1 and Bcl2 in high-risk NB cell lines (SK-N-AS, IMR-5, NLF). Mcl1 knockdown induced apoptosis in all NB cell lines, while Bcl2 knockdown inhibited only NLF, suggesting functional heterogeneity. Finally, we determined the relevance of Mcl1 in resistance to conventional chemotherapy (etoposide, doxorubicin) and small molecule Bcl2-family antagonists (ABT-737 and AT-101). Mcl1 silencing augmented sensitivity to chemotherapeutics 2- to 300-fold, while Bcl2 silencing did not, even in Bcl2-sensitive NLF cells. Resistance to ABT-737, which targets Bcl2/-w/-x, was overcome by Mcl1 knockdown. AT-101, which also neutralizes Mcl1, had single-agent cytotoxicity, further augmented by Mcl1 knockdown. In conclusion, Mcl1 appears a predominant pro-survival protein contributing to chemoresistance in NB, and Mcl1 inactivation may represent a novel therapeutic strategy. Optimization of compounds with higher Mcl1 affinity, or combination with additional Mcl1 antagonists, may enhance the clinical utility of this approach.
Asunto(s)
Neuroblastoma/genética , Neuroblastoma/terapia , Proteínas Proto-Oncogénicas c-bcl-2/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-bcl-2/genética , Compuestos de Bifenilo/farmacología , Línea Celular Tumoral , Proliferación Celular , Terapia Combinada , Regulación hacia Abajo , Silenciador del Gen , Gosipol/análogos & derivados , Gosipol/farmacología , Humanos , Microscopía de Contraste de Fase , Proteína 1 de la Secuencia de Leucemia de Células Mieloides , Neuroblastoma/tratamiento farmacológico , Nitrofenoles/farmacología , Piperazinas/farmacología , Proteínas Proto-Oncogénicas c-bcl-2/biosíntesis , Interferencia de ARN , Sulfonamidas/farmacología , TransfecciónRESUMEN
Malignant rhabdoid tumor has traditionally been defined by its histologic phenotype. However, genetic investigations of malignant rhabdoid tumor have revealed a characteristic loss of or mutation in the INI1 gene on chromosome 22q. The occurrence and significance of soft tissue tumors meeting genetic criteria for malignant rhabdoid tumor but with an undifferentiated non-rhabdoid histology is poorly characterized. Seventeen undifferentiated sarcomas, lacking rhabdoid histology were identified either through the surgical pathology files of The Children's Hospital of Philadelphia (1980-2005) or in consultation. Immunohistochemistry for the INI1 protein showed a loss of nuclear expression within tumor cells in five of these cases. On histologic review, these five tumors had a featureless sheet-like architecture; four were small round blue cell tumors, and one showed focal spindling. Although they had variably prominent nucleoli, classic rhabdoid morphologic features were not identified in any of these cases at primary presentation. Additional immunohistochemistry showed a polyphenotypic profile. Four of the five tumors showed genetic abnormalities involving the INI1 gene by a combination of fluorescent in situ hybridization, reverse transcription-polymerase chain reaction, and/or mutational analysis. Patient ages ranged from 1 week to 5 years. Four patients were male, and one was female. Sites included two neck tumors, two extremity tumors, and one paraspinal tumor. Two patients are alive and well over 15 years from the time of diagnosis; the remaining four are alive and well but with less than 2 years follow-up. Thus, alterations of the INI1 gene with consequent loss of expression identified a population of undifferentiated sarcomas lacking classic rhabdoid morphology in young patients, with evidence of favorable survival. Whether these undifferentiated sarcomas represent a clinicopathologic entity distinct from classic malignant rhabdoid tumor requires further investigation.
Asunto(s)
Proteínas Cromosómicas no Histona/genética , Proteínas de Unión al ADN/genética , Sarcoma/genética , Sarcoma/patología , Neoplasias de los Tejidos Blandos/genética , Neoplasias de los Tejidos Blandos/patología , Factores de Transcripción/genética , Adolescente , Adulto , Edad de Inicio , Niño , Preescolar , Proteínas Cromosómicas no Histona/metabolismo , Terapia Combinada , Análisis Mutacional de ADN , Proteínas de Unión al ADN/metabolismo , Femenino , Expresión Génica , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Lactante , Recién Nacido , Masculino , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Proteína SMARCB1 , Sarcoma/terapia , Neoplasias de los Tejidos Blandos/terapia , Factores de Transcripción/metabolismo , Resultado del TratamientoRESUMEN
We describe a patient with chronic granulomatous disease and receiving immunosuppressive therapy for refractory granulomatous colitis who developed fatal fulminant pneumonia, with Trichosporon pullulans isolated from multiple sites. This case highlights potential difficulties in treating chronic granulomatous disease colitis with high dose immunosuppressants and suggests that T. pullulans may represent an opportunistic organism with high morbidity and mortality in such patients.
Asunto(s)
Enfermedad Granulomatosa Crónica/complicaciones , Inmunosupresores/uso terapéutico , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Micosis/complicaciones , Neumonía/complicaciones , Trichosporon/aislamiento & purificación , Adulto , Resultado Fatal , Humanos , Inmunosupresores/administración & dosificación , Enfermedades Inflamatorias del Intestino/complicaciones , Masculino , Micosis/microbiología , Neumonía/microbiologíaRESUMEN
Local drug delivery has become an important treatment modality for the prevention of thrombotic events following coronary angioplasty. In this study, we investigate the ability of liposomes bearing surface conjugated linear Arg-Gly-Asp (RGD) peptide (GSSSGRGDSPA) moieties to target and bind activated platelets, and the effect of such RGD-modified liposomes on platelet activation and aggregation. The binding of RGD-liposomes to human platelets was assessed by fluorescence microscopy, phase contrast microscopy and flow cytometry. The effect of RGD-modified liposomes on platelet activation and aggregation was investigated in vitro, with and without platelet agonists. RGD-liposomes were found to bind activated platelets at levels significantly greater than the control RGE-liposomes. The RGD-liposomes did not exhibit any statistically significant effect on platelet activation or aggregation. The results demonstrate the ability of the RGD-modified liposomes to target and bind activated platelets without causing significant platelet aggregation and suggests a feasible way for the development of a platelet-targeted anti-thrombogenic drug delivery system. Furthermore, the approach can be extended to the development of liposomes for other vascular targets, for application in drug delivery or gene therapy.
Asunto(s)
Plaquetas/metabolismo , Sistemas de Liberación de Medicamentos , Oligopéptidos/farmacocinética , Activación Plaquetaria , Humanos , Liposomas , Oligopéptidos/uso terapéutico , Agregación Plaquetaria , Complejo GPIIb-IIIa de Glicoproteína Plaquetaria/metabolismo , Unión Proteica , Enfermedades Vasculares/sangre , Enfermedades Vasculares/tratamiento farmacológicoRESUMEN
Cardiovascular disease processes such as atherosclerosis, restenosis, and inflammation are typically localized to discrete regions of the vasculature, affording great opportunity for targeted pharmacological treatment. Liposomes are potentially advantageous targeted drug carriers for such intravascular applications. To facilitate their use as drug delivery vehicles, we have considered three components of liposome design: (i) identification of candidate cell surface receptors for targeting; (ii) identification of ligands that maintain binding specificity and affinity; and (iii) prevention of rapid nonspecific clearance of liposomes into the reticuloendothelial organs. In this report, we describe our work in developing liposomal surface modifications that address both targeting and clearance. An arginine-glycine-aspartic acid (RGD) containing peptide was used as a model ligand to target liposomes to the integrin GPIIb-IIIa on activated platelets. Additionally, oligodextran surfactants incorporated into liposomes provided insight into the effect of vesicle perturbations on liposome clearance, and the importance of molecular geometry in designing oligosaccharide surface modifications. Together these studies demonstrate the feasibility of using peptides to guide liposomes to desired receptors, and illustrate the influence of vesicle stability on liposome interactions in vivo. Furthermore, they underscore the importance of simultaneously considering both targeting specificity and vesicle longevity in the design of effective targeted drug delivery systems.