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1.
Oncotarget ; 7(29): 46120-46126, 2016 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-27323861

RESUMO

In order to select a suitable combination of cancer cell lines as an appropriate source of antigens for dendritic cell-based immunotherapy of ovarian cancer, we analyzed the expression level of 21 tumor associated antigens (BIRC5, CA125, CEA, DDX43, EPCAM, FOLR1, Her-2/neu, MAGE-A1, MAGE-A2, MAGE-A3, MAGE-A4, MAGE-A6, MAGE-A10, MAGE-A12, MUC-1, NY-ESO-1, PRAME, p53, TPBG, TRT, WT1) in 4 established ovarian cancer cell lines and in primary tumor cells isolated from the high-grade serous epithelial ovarian cancer tissue. More than 90% of tumor samples expressed very high levels of CA125, FOLR1, EPCAM and MUC-1 and elevated levels of Her-2/neu, similarly to OVCAR-3 cell line. The combination of OV-90 and OVCAR-3 cell lines showed the highest overlap with patients' samples in the TAA expression profile.


Assuntos
Antígenos de Neoplasias/análise , Biomarcadores Tumorais/análise , Neoplasias Epiteliais e Glandulares/imunologia , Neoplasias Ovarianas/imunologia , Transcriptoma , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Epitelial do Ovário , Linhagem Celular Tumoral , Feminino , Perfilação da Expressão Gênica , Humanos , Pessoa de Meia-Idade , Células Tumorais Cultivadas
2.
Oncotarget ; 6(20): 18192-205, 2015 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-26078335

RESUMO

PURPOSE: We conducted an open-label, single-arm Phase I/II clinical trial in metastatic CRPC (mCRPC) patients eligible for docetaxel combined with treatment with autologous mature dendritic cells (DCs) pulsed with killed LNCaP prostate cancer cells (DCVAC/PCa). The primary and secondary endpoints were safety and immune responses, respectively. Overall survival (OS), followed as a part of the safety evaluation, was compared to the predicted OS according to the Halabi and MSKCC nomograms. EXPERIMENTAL DESIGN: Twenty-five patients with progressive mCRPC were enrolled. Treatment comprised of initial 7 days administration of metronomic cyclophosphamide 50 mg p.o. DCVAC/PCa treatment consisted of a median twelve doses of 1 × 107 dendritic cells per dose injected s.c. (Aldara creme was applied at the site of injection) during a one-year period. The initial 2 doses of DCVAC/PCa were administered at a 2-week interval, followed by the administration of docetaxel (75 mg/m2) and prednisone (5 mg twice daily) given every 3 weeks until toxicity or intolerance was observed. The DCVAC/PCa was then injected every 6 weeks up to the maximum number of doses manufactured from one leukapheresis. RESULTS: No serious DCVAC/PCa-related adverse events have been reported. The median OS was 19 months, whereas the predicted median OS was 11.8 months with the Halabi nomogram and 13 months with the MSKCC nomogram. Kaplan-Meier analyses showed that patients had a lower risk of death compared with both MSKCC (Hazard Ratio 0.26, 95% CI: 0.13-0.51) and Halabi (Hazard Ratio 0.33, 95% CI: 0.17-0.63) predictions. We observed a significant decrease in Tregs in the peripheral blood. The long-term administration of DCVAC/PCa led to the induction and maintenance of PSA specific T cells. We did not identify any immunological parameter that significantly correlated with better OS. CONCLUSIONS: In patients with mCRPC, the combined chemoimmunotherapy with DCVAC/PCa and docetaxel was safe and resulted in longer than expected survival. Concomitant chemotherapy did not preclude the induction of specific anti-tumor cytotoxic T cells.


Assuntos
Adenocarcinoma/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Imunoterapia/métodos , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Adenocarcinoma/imunologia , Adenocarcinoma/mortalidade , Adenocarcinoma/secundário , Administração Metronômica , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Alquilantes/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Quimioterapia Adjuvante , Ciclofosfamida/administração & dosagem , Células Dendríticas/imunologia , Células Dendríticas/transplante , Docetaxel , Humanos , Imunoterapia/efeitos adversos , Imunoterapia/mortalidade , Estimativa de Kaplan-Meier , Linfócitos do Interstício Tumoral/imunologia , Masculino , Pessoa de Meia-Idade , Nomogramas , Prednisona/administração & dosagem , Modelos de Riscos Proporcionais , Neoplasias de Próstata Resistentes à Castração/imunologia , Neoplasias de Próstata Resistentes à Castração/mortalidade , Neoplasias de Próstata Resistentes à Castração/patologia , Fatores de Risco , Subpopulações de Linfócitos T/imunologia , Taxoides/administração & dosagem , Fatores de Tempo , Resultado do Tratamento
3.
Clin Immunol ; 153(1): 49-55, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24709112

RESUMO

OBJECTIVE: Dendritic cells (DCs) play an important role in pathogenesis of autoimmunity, including type 1 diabetes (T1D). In this study, we investigated DC subpopulations and their responses to TLR stimulation in T1D patients and their relatives. METHODS: We analyzed the frequency of myeloid (mDCs) and plasmacytoid DCs (pDCs) in 97 T1D patients (69 onset, 28 long-term), 67 first-degree relatives, and 64 controls. We additionally tested the IFN-alpha production by pDCs upon stimulation with TLR 7, 8 and 9 agonists. RESULTS: A lower number of mDCs and pDCs were found in T1D patients and their relatives. Of all the tested TLR ligands, only stimulation with CpG 2216 induced IFN-alpha production that was the highest in T1D relatives, except of autoantibody-negative relatives bearing the protective haplotypes. CONCLUSION: Our data demonstrate disturbances in DC number and function expressed most significantly in T1D relatives and point to a potential role of TLR9-induced IFN-alpha production in T1D development.


Assuntos
Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/metabolismo , Interferon-alfa/biossíntese , Receptor Toll-Like 9/metabolismo , Adolescente , Adulto , Contagem de Células , Criança , Pré-Escolar , Família , Feminino , Humanos , Interferon-alfa/sangue , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Ligantes , Masculino , Oligodesoxirribonucleotídeos/farmacologia , Adulto Jovem
4.
Int J Cancer ; 132(5): 1070-9, 2013 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-22865582

RESUMO

The type of immune cells that are present within the tumor microenvironment can play a crucial role in the survival of patients. However, little is known about the dynamics of the tumor-infiltrating immune cells during disease progression. We studied the immune cells that infiltrated the tumor tissues of ovarian cancer patients at different stages of disease. The early stages of development of ovarian carcinomas were characterized by a strong Th17 immune response, whereas in stage II patients, recruitment of high numbers of Th1 cells was observed. In disseminated tumors (Stages III-IV), we detected a dominant population of Helios(+) activated regulatory T cells (Tregs) along with high numbers of monocytes/macrophages and myeloid dendritic cells (mDCs). Tumor-infiltrating Tregs had markedly lower expression of CCR4 than circulating Tregs, and the numbers of tumor-infiltrating Tregs significantly correlated with the levels of CCL22 in ovarian tumor cell culture supernatants, suggesting their recruitment via a CCR4/CCL22 interaction. CCL22 was mainly produced by tumor cells, monocytes/macrophages and mDCs in the primary ovarian tumors, and its expression markedly increased in response to IFNγ. Taken together, the specific recruitment of Tregs, probably triggered by inflammatory stimuli, leads to a significant immune suppression in the advanced stages of ovarian cancer.


Assuntos
Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/patologia , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/patologia , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/patologia , Processos de Crescimento Celular/imunologia , Linhagem Celular Tumoral , Quimiocina CCL22/imunologia , Quimiocina CCL22/metabolismo , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Progressão da Doença , Feminino , Humanos , Interferon gama/imunologia , Interferon gama/metabolismo , Linfócitos do Interstício Tumoral/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Pessoa de Meia-Idade , Monócitos/imunologia , Monócitos/metabolismo , Neoplasias Ovarianas/metabolismo , Receptores CCR4/imunologia , Receptores CCR4/metabolismo , Linfócitos T Reguladores/metabolismo , Células Th17/metabolismo , Microambiente Tumoral/imunologia
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