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Eur J Cancer ; 64: 167-74, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27428073


BACKGROUND: Autologous tumour lysate dendritic cell vaccine (ADC) has T-cell stimulatory capacity and, therefore, potential antitumour activity. We designed a phase II randomised trial of ADC + best supportive care (BSC) (experimental arm [EA]) compared with BSC (control arm [CA]), in pre-treated metastatic colorectal cancer (mCRC) patients. PATIENTS AND METHODS: Patients with progressive mCRC, at least to two chemotherapy regimens and Eastern Cooperative Oncology Group performance status (ECOG PS) 0-2, were randomised to EA versus CA. Stratification criteria: ECOG PS (0-1 versus 2) and lactate dehydrogenase (ULN). EA was administered subcutaneously till progressive disease. Primary end-point was progression-free survival (PFS) at 4 months. RESULTS: Fifty-two patients were included (28 EA/24 CA). An interim analysis recommended early termination for futility. No objective radiological response was observed in EA. Median PFS in EA was 2.7 months (95% confidence interval [CI], 2.3-3.2 months) versus 2.3 months (95% CI, 2.1-2.5 months) in CA (p = 0.628). Median overall survival (OS) was 6.2 months (95% CI, 4.4-7.9 months) in EA versus 4.7 months (95% CI, 2.3-7 months) in CA (p = 0.41). No ADC-related adverse events were reported. Immunization induces tumour-specific T-cell response in 21 of 25 (84%) patients. Responder patients have an OS of 7.3 months (95% CI, 5.2-9.4 months) versus 3.8 months (95% CI, 0.6-6.9 months) in non-responders; p = 0.026). CONCLUSION: Our randomised clinical trial comparing ADC + BSC versus BSC in mCRC demonstrates that ADC generates a tumour-specific immune response but not benefit on PFS and OS. Our results do not support the use of ADC alone, in a phase III trial.

Vacinas Anticâncer/administração & dosagem , Neoplasias Colorretais/terapia , Células Dendríticas/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Vacinas Anticâncer/imunologia , Linhagem Celular Tumoral , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/patologia , Neoplasias Colorretais/secundário , Feminino , Humanos , Imunoterapia/métodos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Análise de Sobrevida
Int J Gynecol Cancer ; 25(1): 12-7, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25365589


OBJECTIVE: Current evidence suggests that the presence of tumor-initiating cells (TICs) in epithelial ovarian cancer (EOC) has a role in chemoresistance and relapse. Surface markers such as CD44(+)/CD24(-), CD117(+), and CD133(+) expression have been reported as potential markers for TICs related to ovarian cancer and tumorigenic cell lines. In this study, we have investigated if spheroid forms are TIC specific or whether they can also be produced by somatic stem cells from healthy tissue in vitro. In addition, we also investigated the specificity of surface markers to identify TICs from papillary serous EOC patients. METHODS: Cells were obtained from fresh tumors from 10 chemotherapy-naive patients with EOC, and cells from ovarian and tubal epithelium were obtained from 5 healthy menopausal women undergoing surgery for benign pathology and cultured in standard and in selective medium. Cells forming nonadherent spheroids were considered TICs, and the adherent cells were considered as non-TIC-like. Percentages of CD24(+), CD44(+), CD117(+), CD133(+), and vascular endothelial growth factor receptor (VEGF-R)(+) cell surface markers were analyzed by flow cytometry. RESULTS: Four of 10 EOC cell tissues were excluded from the study. Tumor cells cultured in selective medium developed spheroid forms after 1 to 7 weeks in 5 of 6 EOC patients. No spheroid forms were observed in cultures of cells from healthy women. Unlike previously published data, low levels of CD24(+), CD44(+), CD117(+), and VEGF-R(+) expression were observed in spheroid cells, whereas expression of CD133(+) was moderate but higher in adherent cells from papillary serous EOC cells in comparison with adherent cells from controls. CONCLUSIONS: Papillary serous EOC contains TICs that form spheroids with low expression of CD44(+), CD24(+), CD117(+) and VEGF-R(+). Further research is required to find specific surface markers to identify papillary serous TICs.

Cistadenocarcinoma Seroso/patologia , Recidiva Local de Neoplasia/patologia , Células-Tronco Neoplásicas/patologia , Neoplasias Ovarianas/patologia , Ovário/patologia , Esferoides Celulares/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD/metabolismo , Biomarcadores Tumorais/metabolismo , Estudos de Casos e Controles , Células Cultivadas , Cistadenocarcinoma Seroso/metabolismo , Feminino , Citometria de Fluxo , Seguimentos , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/metabolismo , Estadiamento de Neoplasias , Células-Tronco Neoplásicas/metabolismo , Neoplasias Ovarianas/metabolismo , Ovário/metabolismo , Projetos Piloto , Prognóstico , Esferoides Celulares/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo
PLoS One ; 9(11): e113090, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25402503


OBJECTIVE: CD5 plays a crucial role in autoimmunity and is a well-established genetic risk factor of developing RA. Recently, evidence of positive selection has been provided for the CD5 Pro224-Val471 haplotype in East Asian populations. The aim of the present work was to further analyze the functional relevance of non-synonymous CD5 polymorphisms conforming the ancestral and the newly derived haplotypes (Pro224-Ala471 and Pro224-Val471, respectively) as well as to investigate the potential role of CD5 on the development of SLE and/or SLE nephritis. METHODS: The CD5 SNPs rs2241002 (C/T; Pro224Leu) and rs2229177 (C/T; Ala471Val) were genotyped using TaqMan allelic discrimination assays in a total of 1,324 controls and 681 SLE patients of Spanish origin. In vitro analysis of CD3-mediated T cell proliferative and cytokine response profiles of healthy volunteers homozygous for the above mentioned CD5 haplotypes were also analyzed. RESULTS: T-cell proliferation and cytokine release were significantly increased showing a bias towards to a Th2 profile after CD3 cross-linking of peripheral mononuclear cells from healthy individuals homozygous for the ancestral Pro224-Ala471 (CC) haplotype, compared to the more recently derived Pro224-Val471 (CT). The same allelic combination was statistically associated with Lupus nephritis. CONCLUSION: The ancestral Ala471 CD5 allele confers lymphocyte hyper-responsiveness to TCR/CD3 cross-linking and is associated with nephritis in SLE patients.

Antígenos CD5/genética , Haplótipos/genética , Lúpus Eritematoso Sistêmico/genética , Nefrite Lúpica/etiologia , Ativação Linfocitária/imunologia , Polimorfismo Genético/genética , Linfócitos T/imunologia , Alelos , Autoimunidade/imunologia , Estudos de Casos e Controles , Predisposição Genética para Doença , Genótipo , Humanos , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/imunologia , Nefrite Lúpica/diagnóstico
FEBS Lett ; 588(17): 2805-13, 2014 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-24945728


CD6 is a lymphocyte glycoprotein receptor that physically associates with the antigen-specific receptor complex at the center of the immunological synapse, where it interacts with its ligand CD166/ALCAM. The present work reports the carbohydrate-dependent interaction of CD6 and CD166/ALCAM with Galectin-1 and -3, two well-known soluble mammalian lectins. Both galectins interfered with superantigen-induced T cell proliferation and cell adhesion phenomena mediated by the CD6-CD166/ALCAM pair, while CD6 expression protected cells from galectin-induced apoptosis. The results suggest that interaction of Galectin-1 and -3 with CD6 and CD166/ALCAM might modulate some relevant aspects of T cell physiology.

Molécula de Adesão de Leucócito Ativado/metabolismo , Antígenos CD/metabolismo , Antígenos de Diferenciação de Linfócitos T/metabolismo , Galectina 1/metabolismo , Galectina 3/metabolismo , Apoptose , Linfócitos B/citologia , Metabolismo dos Carboidratos , Adesão Celular , Membrana Celular/metabolismo , Células Dendríticas/imunologia , Humanos , Ligação Proteica , Superantígenos/imunologia , Linfócitos T/citologia , Linfócitos T/imunologia