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1.
Cancer Immunol Res ; 1(5): 340-50, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24777970

RESUMO

Vaccination of patients with ovarian cancer with overlapping long peptides (OLP) from cancer-testis antigen NY-ESO-1 and poly-ICLC in Montanide-ISA-51 (Montanide) was found to consistently induce integrated immune responses (antibody, CD4(+), and CD8(+) T cells). Using detailed methods, we investigated the respective effects of poly-ICLC and Montanide adjuvant on pre- and postvaccine NY-ESO-1-specific CD4(+) T cells, because of their central function for induction and maintenance of both antibody and CD8(+) T cells. Polyclonal NY-ESO-1-specific CD4(+) T-cell lines were generated from 12 patients using CD154-based selection of precursors before and after vaccination with (i) OLP alone, (ii) OLP in Montanide, or (iii) OLP and poly-ICLC in Montanide. Kinetics, quantification, fine specificity, avidity, and cytokine-producing pattern were analyzed in depth and compared between vaccine cohorts. Vaccination with OLP alone did not elicit CD4(+) T-cell responses; it suppressed high-avidity CD4(+) T-cell precursors that recognized naturally processed NY-ESO-1 protein before vaccination. Emulsification of OLP in Montanide was required for the expansion of high-avidity NY-ESO-1-specific CD4(+) T-cell precursors. Poly-ICLC significantly enhanced CD4(+) Th1 responses while suppressing the induction of interleukin (IL)-4-producing Th2 and IL-9-producing Th9 cells. In summary, Montanide and poly-ICLC had distinct and cooperative effects for the induction of NY-ESO-1-specific Th1 cells and integrated immune responses by OLP vaccination. These results support the use of admixing poly-ICLC in Montanide adjuvant to rapidly induce antitumor type I immune responses by OLP from self/tumor antigens in human cancer vaccines.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Vacinas Anticâncer/administração & dosagem , Carboximetilcelulose Sódica/análogos & derivados , Manitol/análogos & derivados , Ácidos Oleicos/administração & dosagem , Peptídeos/imunologia , Poli I-C/administração & dosagem , Polilisina/análogos & derivados , Antígenos de Neoplasias/imunologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Ligante de CD40/biossíntese , Ligante de CD40/imunologia , Vacinas Anticâncer/imunologia , Carboximetilcelulose Sódica/administração & dosagem , Epitopos de Linfócito T/imunologia , Humanos , Manitol/administração & dosagem , Manitol/imunologia , Proteínas de Membrana/imunologia , Ácidos Oleicos/imunologia , Poli I-C/imunologia , Polilisina/administração & dosagem , Polilisina/imunologia
2.
Clin Cancer Res ; 18(23): 6497-508, 2012 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-23032745

RESUMO

PURPOSE: Long peptides are efficiently presented to both CD4(+) and CD8(+) T cells after intracellular processing by antigen-presenting cells. To investigate the safety and in vivo immunogenicity of synthetic overlapping long peptides (OLP) from a human tumor self-antigen, we conducted a phase I clinical trial with OLP from cancer-testis antigen NY-ESO-1 in various adjuvant combinations. EXPERIMENTAL DESIGN: Twenty-eight patients with advanced ovarian cancer in second or third remission were enrolled sequentially in three cohorts and received at least one vaccination. Patients in Cohort 1 (n = 4) received 1.0 mg OLP, Cohort 2 (n = 13) received OLP in Montanide-ISA-51, and Cohort 3 (n = 11) received OLP + 1.4 mg Poly-ICLC in Montanide-ISA-51 on weeks 1, 4, 7, 10, and 13. Humoral and cellular responses were evaluated by standardized immunomonitoring techniques (ELISA, ELISPOT assay, intracellular cytokine staining, and tetramer staining). RESULTS: The vaccine was generally well tolerated with injection site reactions and fatigue that resolved. NY-ESO-1-specific antibody and CD8(+) T cells were undetectable after vaccination with OLP alone, but were found in 6 of 13 (46%) and 8 of 13 (62%) patients, respectively, after vaccination with OLP+Montanide, and in 10 of 11 (91%) and 10 of 11 (91%) patients, respectively, after vaccination with OLP+Montanide+Poly-ICLC. NY-ESO-1-specific CD4(+) T cells were detected in all patients with greater frequency and polyclonality when Montanide-ISA-51 was used for vaccination. Inclusion of Poly-ICLC as an adjuvant further accelerated the induction of NY-ESO-1-specific immune responses. CONCLUSIONS: The current study shows that NY-ESO-1 OLP vaccine is safe and rapidly induces consistent integrated immune responses (antibody, CD8(+) and CD4(+)) in nearly all vaccinated patients when given with appropriate adjuvants.


Assuntos
Antígenos de Neoplasias/imunologia , Autoantígenos/imunologia , Vacinas Anticâncer/imunologia , Carboximetilcelulose Sódica/análogos & derivados , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/terapia , Peptídeos/imunologia , Poli I-C/imunologia , Polilisina/análogos & derivados , Adulto , Idoso , Anticorpos/imunologia , Antígenos de Neoplasias/química , Autoantígenos/química , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Vacinas Anticâncer/administração & dosagem , Vacinas Anticâncer/efeitos adversos , Feminino , Seguimentos , Humanos , Imunidade Humoral , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Ovarianas/patologia , Polilisina/imunologia , Linfócitos T Reguladores/imunologia , Resultado do Tratamento , Vacinas de Subunidades Antigênicas/administração & dosagem , Vacinas de Subunidades Antigênicas/efeitos adversos , Vacinas de Subunidades Antigênicas/imunologia
3.
Laryngoscope ; 121(2): 446-50, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21271604

RESUMO

OBJECTIVE: The irrigation of the upper third of the nasal fossa is supplied by the anterior ethmoidal artery. We describe a surgical technique to deal with epistaxis due to anterior ethmoidal artery bleeding. PATIENTS AND METHODS: From January 2006 to March 2010 transcaruncular coagulation of the anterior ethmoidal artery was done on nine patients with epistaxis of the upper third of the nasal fossa. RESULTS: The procedure was successful on all cases. No bleeding relapse, major complications, or nasal or orbital sequelae were present in any of the patients. DISCUSSION/CONCLUSIONS: Transcaruncular electrocoagulation of the anterior ethmoidal artery is a safe and effective technique to deal with upper third nasal fossa bleeding.


Assuntos
Eletrocoagulação/métodos , Epistaxe/cirurgia , Seio Etmoidal/irrigação sanguínea , Adulto , Idoso , Idoso de 80 Anos ou mais , Artérias/cirurgia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
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