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1.
J Immunother Cancer ; 11(1)2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36627144

RESUMO

Adoptive transfer of autologous tumor-specific lymphocytes represents a viable treatment method for patients with advanced malignancies. Here, we report a patient's case with metastatic hormone-refractory New York esophageal squamous cell carcinoma 1 (NY-ESO-1) expressing prostate cancer treated with in vitro expanded tumor-infiltrating lymphocytes (TILs) in conjunction with IL-2 and immune-checkpoint blockade. Complete and durable tumor remission was observed after three TIL infusions consisting of 1.4×109, 2.0×109, and 8.0×109 T cells, respectively, lasting now for more than 3.5 years. Immunological correlates to the clinical development were the decrease of tumor-driven NY-ESO-1 serum antibody and the drop of prostate-specific antigen to <0.01 µg/L. TILs were reactive against cancer-testis antigen NY-ESO-1, individual tumor mutational proteins (eg, PRPF8, TRPS1), and the androgen receptor splice variant 12.


Assuntos
Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Neoplasias da Próstata , Masculino , Humanos , Linfócitos do Interstício Tumoral , Neoplasias Esofágicas/metabolismo , Linfócitos T , Anticorpos , Neoplasias da Próstata/terapia , Neoplasias da Próstata/metabolismo , Proteínas Repressoras/metabolismo
2.
BMC Vet Res ; 17(1): 356, 2021 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-34798884

RESUMO

BACKGROUND: Bovine mastitis is an important health and cost factor in the milk industry. To elucidate whether isolated perfused bovine udders can be used to study early inflammatory events of mastitis, 1 mg of lipopolysaccharide (LPS) was instilled into quarters of 10 isolated perfused bovine udders. Three hours and 6 h after LPS instillation, tissue samples were taken from the gland cistern and base of the udder, subsequently stored in RNAlater and processed for the determination of inflammation-dependent gene regulation by real-time RT-qPCR. Gene expression analysis was performed using delta-delta Ct method. To translate mRNA results to protein, IL-1ß and IL-6 were determined in tissue homogenate by ELISA. RESULTS: The instillation of 1 mg LPS lead to an increased expression of pro-inflammatory cytokines and chemokines like TNF-α, CCL20, CXCL8 as well as of IL-1 ß, IL-6 and IL-10, lingual antimicrobial peptide (LAP) and S100A9. However, the degree of elevation differed slightly between gland cistern and udder base and markedly between 3 and 6 h after instillation, with a distinct increase in mediator expression after 6 h. IL-1ß protein increased in a time-dependent manner, whereas IL-6 was unchanged within 6 h of LPS instillation. CONCLUSION: Compared to in vivo studies with instillation of LPS into udders of living cows, a similar inflammation-dependent gene regulation profile can be mimicked in the isolated perfused bovine udder, indicating a supplementation of animal experiments.


Assuntos
Inflamação/veterinária , Lipopolissacarídeos/metabolismo , Glândulas Mamárias Animais/patologia , Mastite Bovina/patologia , Animais , Bovinos , Citocinas , Feminino , Regulação da Expressão Gênica , Técnicas In Vitro/veterinária , Lipopolissacarídeos/toxicidade , Perfusão/veterinária , Projetos Piloto
3.
Water Res ; 85: 451-7, 2015 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-26376022

RESUMO

Small polymer particles with a diameter of less than 5 mm called microplastics find their way into the environment from polymer debris and industrial production. Therefore a method is needed to identify and quantify microplastics in various environmental samples to generate reliable concentration values. Such concentration values, i.e. quantitative results, are necessary for an assessment of microplastic in environmental media. This was achieved by thermal extraction in thermogravimetric analysis (TGA), connected to a solid-phase adsorber. These adsorbers were subsequently analysed by thermal desorption gas chromatography mass spectrometry (TDS-GC-MS). In comparison to other chromatographic methods, like pyrolyse gas chromatography mass spectrometry (Py-GC-MS), the relatively high sample masses in TGA (about 200 times higher than used in Py-GC-MS) analysed here enable the measurement of complex matrices that are not homogenous on a small scale. Through the characteristic decomposition products known for every kind of polymer it is possible to identify and even to quantify polymer particles in various matrices. Polyethylene (PE), one of the most important representatives for microplastics, was chosen as an example for identification and quantification.


Assuntos
Monitoramento Ambiental/métodos , Polietileno/análise , Poluentes Químicos da Água/análise , Cromatografia Gasosa-Espectrometria de Massas
4.
Clin Cancer Res ; 18(19): 5449-59, 2012 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-22847809

RESUMO

PURPOSE: Mixed bacterial vaccine (MBV, Coley's toxins) is a historical, vaguely defined preparation of heat-inactivated Streptococcus pyogenes and Serratia marcescens used as nonspecific immunotherapy in the treatment of cancer. The mechanism of action is suspected to have an immunologic basis, yet it is poorly defined up to now. We developed a new, biochemically well defined and current good manufacturing practice-compliant MBV preparation, which has been investigated in patients with NY-ESO-1 expressing cancers. EXPERIMENTAL DESIGN: Patients received MBV subcutaneously at a starting dose of 250 EU (endotoxin units) twice a week. The MBV dose was escalated in each patient until a body temperature of 38°C to 39.5°C was induced or up to the maximum dose of 547.000 EU. Changes in serum cytokine levels were determined and immune responses to NY-ESO-1 were evaluated. Tumor response was assessed according to RECIST. RESULTS: Twelve patients were enrolled and 11 of them developed fever after the administration of MBV. Ten of 12 patients showed a consistent increase in serum IL-6 levels with the highest levels coinciding with the highest body temperature. A subgroup of patients showed increasing levels of TNF-α, IFN-γ, and IL1-ß. A patient with metastatic bladder cancer showed a partial tumor response strongly correlated with MBV-induced fever and highly elevated levels of several cytokines. CONCLUSIONS: MBV at fever-inducing dose levels can lead to a massive induction of immunoregulatory cytokines that may be involved in inducing tumor regressions. We propose to further explore the role of MBV as a potent immune modulator at higher dose levels and in conjunction with antigen-specific cancer vaccines.


Assuntos
Antígenos de Neoplasias/metabolismo , Vacinas Bacterianas/administração & dosagem , Imunoterapia , Proteínas de Membrana/metabolismo , Neoplasias , Vacinas Bacterianas/imunologia , Temperatura Corporal , Linfócitos T CD8-Positivos/metabolismo , Vacinas Anticâncer/administração & dosagem , Vacinas Anticâncer/imunologia , Humanos , Interferon gama/sangue , Interleucina-1beta/sangue , Interleucina-6/sangue , Estadiamento de Neoplasias , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Neoplasias/patologia , Serratia marcescens/imunologia , Streptococcus pyogenes/imunologia , Fator de Necrose Tumoral alfa/sangue
5.
Cancer Res ; 72(17): 4304-10, 2012 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-22738916

RESUMO

The synthetic oligodeoxynucleotide CpG 7909, which contains unmethylated cytosine/guanine (CpG) motifs, has potent immunostimulatory effects when coadministered with NY-ESO-1 peptides or recombinant NY-ESO-1 protein, resulting in an enhanced cellular and humoral immune response against the vaccine antigen. In this study, we report the development of anti-CpG-ODN antibodies in 21 of 37 patients who received CpG 7909 either alone or as a vaccine adjuvant. Specific anti-CpG immunoglobulin G (IgG) antibody titers ranged from 1:400 to 1:100,000. The anti-CpG antibodies cross-reacted with other synthetic CpG-ODNs but not with the DNA of mixed bacterial vaccine and were shown to be phosphorothioate backbone specific. Vaccine-related severe side effects observed in some patients were most likely not related to the development of anti-CpG antibodies. In addition, anti-CpG antibodies did not have negative effects on the vaccine immune response. These results show that anti-CpG antibodies develop in humans against short unmethylated CpG dinucleotide sequences after administration of CpG 7909. Our data therefore substantiate the potency of CpG 7909 to directly stimulate human B-cells and suggest that anti-CpG antibody monitoring should be a part of ongoing and planned clinical trials with CpG-ODNs.


Assuntos
Anticorpos/imunologia , Neoplasias/imunologia , Oligodesoxirribonucleotídeos/administração & dosagem , Oligodesoxirribonucleotídeos/imunologia , Adjuvantes Imunológicos/administração & dosagem , Adjuvantes Imunológicos/efeitos adversos , Especificidade de Anticorpos/imunologia , Complexo Antígeno-Anticorpo/sangue , Complexo Antígeno-Anticorpo/imunologia , Antígenos de Neoplasias/uso terapêutico , Vacinas Anticâncer , Humanos , Imunoglobulina G/imunologia , Proteínas de Membrana/uso terapêutico , Neoplasias/terapia , Oligodesoxirribonucleotídeos/efeitos adversos , Vacinas de Subunidades Antigênicas
6.
Clin Cancer Res ; 17(4): 861-70, 2011 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-21163871

RESUMO

PURPOSE: NY-ESO-1, one of the most immunogenic tumor antigens, is expressed in 15% to 25% of metastatic prostate cancers. The immunological and clinical effects of vaccination with recombinant NY-ESO-1 protein combined with CpG as adjuvant were evaluated. EXPERIMENTAL DESIGN: In a phase I clinical study, patients with advanced prostate cancer were vaccinated with recombinant NY-ESO-1 protein (100 µg) mixed with CpG 7909 (2.5 mg) every 3 weeks intradermally for 4 doses. Objectives of the study were the safety of the vaccine and changes of specific humoral and cellular immunological responses to NY-ESO-1 in relation to detectable NY-ESO-1 expression in the individual tumor. RESULTS: All 12 baseline sero-negative patients developed high-titer NY-ESO-1 antibody responses. B-cell epitope mapping identified NY-ESO-1 p91-110 to be recognized most frequently by vaccine-induced antibodies. Two patients developed significant antibody titers against the adjuvant CpG. NY-ESO-1-specific CD4+ and/or CD8+ T-cell responses were induced in 9 patients (69%). Five of these 9 patients did not express NY-ESO-1 in the autologous tumor. Postvaccine CD8+ T-cell clones recognized and lyzed HLA-matched tumor cell lines in an antigen-specific manner. CONCLUSION: Our data provide clear evidence for the capacity of NY-ESO-1 protein/CpG vaccine to induce integrated antigen-specific immune responses in vivo and to efficiently prime CD8+ T-cell responses in NY-ESO-1 antigen-negative patients. Our results may also support further clinical vaccination protocols with NY-ESO-1 protein not only focused on the treatment of existing cancer, but also to prevent further development of NY-ESO-1 positive cancers in vivo.


Assuntos
Adjuvantes Imunológicos/administração & dosagem , Antígenos de Neoplasias/administração & dosagem , Vacinas Anticâncer/administração & dosagem , Proteínas de Membrana/administração & dosagem , Oligodesoxirribonucleotídeos/administração & dosagem , Neoplasias da Próstata/terapia , Imunidade Adaptativa , Adjuvantes Imunológicos/efeitos adversos , Antígenos de Neoplasias/efeitos adversos , Antígenos de Neoplasias/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Vacinas Anticâncer/efeitos adversos , Quimioterapia Adjuvante , Humanos , Injeções Intradérmicas , Masculino , Proteínas de Membrana/efeitos adversos , Proteínas de Membrana/imunologia , Oligodesoxirribonucleotídeos/efeitos adversos , Oligodesoxirribonucleotídeos/imunologia , Neoplasias da Próstata/imunologia , Resultado do Tratamento
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