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1.
Front Immunol ; 10: 2526, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31803175

RESUMO

Background: Radiofrequency ablation (RFA) is an established treatment option for malignancies located in the liver. RFA-induced irreversible coagulation necrosis leads to the release of danger signals and cellular content. Hence, RFA may constitute an endogenous in situ tumor vaccination, stimulating innate and adaptive immune responses, including tumor-antigen specific T cells. This may explain a phenomenon termed abscopal effect, namely tumor regression in untreated lesions evidenced after distant thermal ablation or irradiation. In this study, we therefore assessed systemic and local immune responses in individual patients treated with RFA. Methods: For this prospective clinical trial, patients with liver metastasis from colorectal carcinoma (mCRC) receiving RFA and undergoing metachronous liver surgery for another lesion were recruited (n = 9) during a 5-year period. Tumor and non-malignant liver tissue samples from six patients were investigated by whole transcriptome sequencing and tandem-mass spectrometry, characterizing naturally presented HLA ligands. Tumor antigen-derived HLA-restricted peptides were selected by different predefined approaches. Further, candidate HLA ligands were manually curated. Peripheral blood mononuclear cells were stimulated in vitro with epitope candidate peptides, and functional T cell responses were assessed by intracellular cytokine staining. Immunohistochemical markers were additionally investigated in surgically resected mCRC from patients treated with (n = 9) or without RFA (n = 7). Results: In all six investigated patients, either induced immune responses and/or pre-existing T cell immunity against the selected targets were observed. Multi-cytokine responses were inter alia directed against known tumor antigens such as cyclin D1 but also against a (predicted) mutation contained in ERBB3. Immunohistochemistry did not show a relevant influx of immune cells into distant malignant lesions after RFA treatment (n = 9) as compared to the surgery only mCRC group (n = 7). Conclusions: Using an individualized approach for target selection, RFA induced and/or boosted T cell responses specific for individual tumor antigens were more frequently detectable as compared to previously published observations with well-characterized tumor antigens. However, the witnessed modest RFA-induced immunological effects alone may not be sufficient for the rejection of established tumors. Therefore, these findings warrant further clinical investigation including the assessment of RFA combination therapies e.g., with immune stimulatory agents, cancer vaccination, and/or immune checkpoint inhibitors.

2.
J Immunother Cancer ; 7(1): 307, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31730025

RESUMO

BACKGROUND: We previously showed that the bacterial lipopeptide Pam3Cys-Ser-Ser, meanwhile established as a toll-like receptor (TLR) 1/2 ligand, acts as a strong adjuvant for the induction of virus specific CD8+ T cells in mice, when covalently coupled to a synthetic peptide. CASE PRESENTATION: We now designed a new water-soluble synthetic Pam3Cys-derivative, named XS15 and characterized it in vitro by a TLR2 NF-κB luciferase reporter assay. Further, the capacity of XS15 to activate immune cells and stimulate peptide-specific CD8+ T and NK cells by 6-sulfo LacNAc+ monocytes was assessed by flow cytometry as well as cytokine induction using immunoassays. The induction of a functional immune response after vaccination of a volunteer with viral peptides was assessed by ELISpot assay and flow cytometry in peripheral blood cells and infiltrating cells at the vaccination site, as well as by immunohistochemistry and imaging. XS15 induced strong ex vivo CD8+ and TH1 CD4+ responses in a human volunteer upon a single injection of XS15 mixed to uncoupled peptides in a water-in-oil emulsion (Montanide™ ISA51 VG). A granuloma formed locally at the injection site containing highly activated functional CD4+ and CD8+ effector memory T cells. The total number of vaccine peptide-specific functional T cells was experimentally assessed and estimated to be 3.0 × 105 in the granuloma and 20.5 × 106 in peripheral blood. CONCLUSION: Thus, in one volunteer we show a granuloma forming by peptides combined with an efficient adjuvant in a water-in-oil-emulsion, inducing antigen specific T cells detectable in circulation and at the vaccination site, after one single vaccination only. The ex vivo T cell responses in peripheral blood were detectable for more than one year and could be strongly boosted by a second vaccination. Hence, XS15 is a promising adjuvant candidate for peptide vaccination, in particular for tumor peptide vaccines in a personalized setting.

3.
Genome Med ; 11(1): 28, 2019 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-31039795

RESUMO

BACKGROUND: Although mutated HLA ligands are considered ideal cancer-specific immunotherapy targets, evidence for their presentation is lacking in hepatocellular carcinomas (HCCs). Employing a unique multi-omics approach comprising a neoepitope identification pipeline, we assessed exome-derived mutations naturally presented as HLA class I ligands in HCCs. METHODS: In-depth multi-omics analyses included whole exome and transcriptome sequencing to define individual patient-specific search spaces of neoepitope candidates. Evidence for the natural presentation of mutated HLA ligands was investigated through an in silico pipeline integrating proteome and HLA ligandome profiling data. RESULTS: The approach was successfully validated in a state-of-the-art dataset from malignant melanoma, and despite multi-omics evidence for somatic mutations, mutated naturally presented HLA ligands remained elusive in HCCs. An analysis of extensive cancer datasets confirmed fundamental differences of tumor mutational burden in HCC and malignant melanoma, challenging the notion that exome-derived mutations contribute relevantly to the expectable neoepitope pool in malignancies with only few mutations. CONCLUSIONS: This study suggests that exome-derived mutated HLA ligands appear to be rarely presented in HCCs, inter alia resulting from a low mutational burden as compared to other malignancies such as malignant melanoma. Our results therefore demand widening the target scope for personalized immunotherapy beyond this limited range of mutated neoepitopes, particularly for malignancies with similar or lower mutational burden.


Assuntos
Antígenos de Neoplasias/genética , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , Transcriptoma , Idoso , Idoso de 80 Anos ou mais , Antígenos de Neoplasias/metabolismo , Carcinoma Hepatocelular/imunologia , Exoma , Feminino , Genômica/métodos , Humanos , Neoplasias Hepáticas/imunologia , Masculino , Pessoa de Meia-Idade , Taxa de Mutação
4.
J Clin Med ; 7(12)2018 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-30572653

RESUMO

BACKGROUND: Cytoreductive surgery (CRS), followed by hyperthermic intraperitoneal chemotherapy (HIPEC), combines radical surgery with abdominal heated chemotherapy, constituting a multimodal treatment approach. Since clear standards for HIPEC conduct in colorectal carcinoma (CRC) are lacking, we aimed to provide a comprehensive structured survey. Data sources and study eligibility criteria: A systematic literature search was performed in PubMed, with keywords "HIPEC" and "colorectal cancer", according to established guidelines. Articles were systematically screened, selecting 87 publications complemented by 48 publications identified through extended search for subsequent synthesis and evaluation, extracting inter alia details on used drugs, dosage, temperature, exposure times, and carrier solutions. RESULTS: Compiled publications contained 171 reports on HIPEC conduct foremost with mitomycin C and oxaliplatin, but also other drugs and drug combinations, comprising at least 60 different procedures. We hence provide an overview of interconnections between HIPEC protocols, used drugs and carrier solutions as well as their volumes. In addition, HIPEC temperatures and dosing benchmarks, as well as an estimate of in vivo resulting drug concentrations are demonstrated. CONCLUSIONS AND IMPLICATIONS: Owing to recent developments, HIPEC conduct and practices need to be reassessed. Unfortunately, imprecise and lacking reporting is frequent, which is why minimal information requirements should be established for HIPEC and the introduction of final drug concentrations for comparability reasons seems sensible.

5.
BMC Med Genet ; 19(1): 144, 2018 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-30111295

RESUMO

BACKGROUND: The PTEN-hamartoma-tumor-syndrome (PHTS) is caused by germline mutations in Phosphatase and Tensin homolog (PTEN) and predisposes to the development of several typical malignancies. Whereas PTEN mutations have been implicated in the occurrence of malignant mesotheliomas, the genetic landscape of verrucous carcinomas (VC) is largely uncharted. Both VC and malignant peritoneal mesotheliomas (MPM) are exceedingly rare and a potential link between these malignancies and PHTS has never been reported. CASE PRESENTATION: We here describe the clinical course of a PHTS patient who, in addition to a typical thyroid carcinoma at the age of 36 years, developed a highly-differentiated oral VC and an epithelioid MPM six years later. The patient with a history of occupational asbestos exposure underwent cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for MPM. The clinical diagnosis of PHTS was consequently corroborated by a germline PTEN deletion. Sequencing of tumor tissue revealed a second hit in PTEN in the thyroid carcinoma and VC, confirmed by a PTEN loss and activation of the PI3K/AKT pathway in immunohistochemistry. Furthermore, additional somatic mutations in the thyroid carcinoma as well as in the VC were detected, whereas the genetics of MPM remained unrevealing. DISCUSSION AND CONCLUSIONS: We here report the very unusual clinical course of a patient with rare tumors that have a germline mutation first hit in PTEN in common. Since this patient was exposed to asbestos and current evidence suggests molecular mechanisms that might render PHTS patients particularly susceptible to mesothelioma, we strongly recommend PHTS patients to avoid even minimal exposure.


Assuntos
Carcinoma Verrucoso/genética , Mutação em Linhagem Germinativa/genética , Neoplasias Pulmonares/genética , Mesotelioma/genética , Neoplasias Bucais/genética , PTEN Fosfo-Hidrolase/genética , Humanos , Doenças Raras
6.
Cancer Res ; 78(16): 4627-4641, 2018 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-29789417

RESUMO

Immune cell infiltrates have proven highly relevant for colorectal carcinoma prognosis, making colorectal cancer a promising candidate for immunotherapy. Because tumors interact with the immune system via HLA-presented peptide ligands, exact knowledge of the peptidome constitution is fundamental for understanding this relationship. Here, we comprehensively describe the naturally presented HLA ligandome of colorectal carcinoma and corresponding nonmalignant colon (NMC) tissue. Mass spectrometry identified 35,367 and 28,132 HLA class I ligands on colorectal carcinoma and NMC, attributable to 7,684 and 6,312 distinct source proteins, respectively. Cancer-exclusive peptides were assessed on source protein level using the Kyoto Encyclopedia of Genes and Genomes (KEGG) and protein analysis through evolutionary relationships (PANTHER), revealing pathognomonic colorectal carcinoma-associated pathways, including Wnt, TGFß, PI3K, p53, and RTK-RAS. Relative quantitation of peptide presentation on paired colorectal carcinoma and NMC tissue further identified source proteins from cancer- and infection-associated pathways to be overrepresented merely within the colorectal carcinoma ligandome. From the pool of tumor-exclusive peptides, a selected HLA-ligand subset was assessed for immunogenicity, with the majority exhibiting an existing T-cell repertoire. Overall, these data show that the HLA ligandome reflects cancer-associated pathways implicated in colorectal carcinoma oncogenesis, suggesting that alterations in tumor cell metabolism could result in cancer-specific, albeit not mutation-derived, tumor antigens. Hence, a defined pool of unique tumor peptides, attributable to complex cellular alterations that are exclusive to malignant cells, might comprise promising candidates for immunotherapeutic applications.Significance: Cancer-associated pathways are reflected in the antigenic landscape of colorectal cancer, suggesting that tumor-specific antigens do not necessarily have to be mutation-derived but may also originate from other alterations in cancer cells. Cancer Res; 78(16); 4627-41. ©2018 AACR.


Assuntos
Transformação Celular Neoplásica/genética , Neoplasias Colorretais/genética , Antígenos HLA/genética , Imunoterapia , Sequência de Aminoácidos/genética , Apresentação do Antígeno/imunologia , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/imunologia , Transformação Celular Neoplásica/imunologia , Neoplasias Colorretais/imunologia , Humanos , Ligantes , Espectrometria de Massas , Peptídeos/genética , Peptídeos/imunologia , Linfócitos T/imunologia , Linfócitos T/patologia
7.
Oncoimmunology ; 7(2): e1364827, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29308299

RESUMO

Platelets promote metastasis, among others by coating cancer cells traveling through the blood, which results in protection from NK cell immune-surveillance. The underlying mechanisms, however, remain to be fully elucidated. Here we report that platelet-coating reduces surface expression of NKG2D ligands, in particular MICA and MICB, on tumor cells, which was mirrored by enhanced release of their soluble ectodomains. Similar results were obtained upon exposure of tumor cells to platelet-releasate and can be attributed to the sheddases ADAM10 and ADAM17 that are detectable on the platelet surface and in releasate following activation and at higher levels on platelets of patients with metastasized lung cancer compared with healthy controls. Platelet-mediated NKG2DL-shedding in turn resulted in impaired "induced self" recognition by NK cells as revealed by diminished NKG2D-dependent lysis of tumor cells. Our results indicate that platelet-mediated NKG2DL-shedding may be involved in immune-evasion of (metastasizing) tumor cells from NK cell reactivity.

8.
Proc Natl Acad Sci U S A ; 114(46): E9942-E9951, 2017 11 14.
Artigo em Inglês | MEDLINE | ID: mdl-29093164

RESUMO

Immunotherapies, particularly checkpoint inhibitors, have set off a revolution in cancer therapy by releasing the power of the immune system. However, only little is known about the antigens that are essentially presented on cancer cells, capable of exposing them to immune cells. Large-scale HLA ligandome analysis has enabled us to exhaustively characterize the immunopeptidomic landscape of epithelial ovarian cancers (EOCs). Additional comparative profiling with the immunopeptidome of a variety of benign sources has unveiled a multitude of ovarian cancer antigens (MUC16, MSLN, LGALS1, IDO1, KLK10) to be presented by HLA class I and class II molecules exclusively on ovarian cancer cells. Most strikingly, ligands derived from mucin 16 and mesothelin, a molecular axis of prognostic importance in EOC, are prominent in a majority of patients. Differential gene-expression analysis has allowed us to confirm the relevance of these targets for EOC and further provided important insights into the relationship between gene transcript levels and HLA ligand presentation.


Assuntos
Apresentação do Antígeno/imunologia , Glicoproteínas de Membrana/imunologia , Glicoproteínas de Membrana/metabolismo , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/metabolismo , Antígeno Ca-125/imunologia , Carcinoma Epitelial do Ovário , Feminino , Proteínas Ligadas por GPI/imunologia , Galectina 1/imunologia , Regulação Neoplásica da Expressão Gênica , Antígenos HLA-DR/imunologia , Antígenos HLA-DR/metabolismo , Antígenos de Histocompatibilidade Classe I/imunologia , Antígenos de Histocompatibilidade Classe I/metabolismo , Antígenos de Histocompatibilidade Classe II/imunologia , Antígenos de Histocompatibilidade Classe II/metabolismo , Humanos , Imunoterapia , Indolamina-Pirrol 2,3,-Dioxigenase/imunologia , Calicreínas/imunologia , Ligantes , Glicoproteínas de Membrana/análise , Glicoproteínas de Membrana/genética , Proteínas de Membrana/imunologia , Neoplasias Epiteliais e Glandulares/imunologia , Neoplasias Epiteliais e Glandulares/metabolismo , Neoplasias Epiteliais e Glandulares/patologia , Neoplasias Ovarianas/patologia , Vacinação
9.
Blood ; 129(14): 1898-1899, 2017 04 06.
Artigo em Inglês | MEDLINE | ID: mdl-28385773
10.
Ann Hematol ; 96(5): 817-827, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28247058

RESUMO

Disease relapse after one or more allogeneic hematopoietic cell transplantations (HCT) represents a therapeutic challenge with all options bearing a significant morbidity and mortality. Haploidentical HCT may induce more pronounced anti-leukemic effects and was evaluated at our center in 25 consecutive patients with disease relapse after preceding HCT receiving haploidentical grafts after in vitro T cell depletion. Overall survival at 1 and 2 years was 32 and 14%, respectively. Of note, patients with complete remission (CR) before haploidentical HCT had a very favorable overall survival of 41.7% at 2 years. Cumulative incidence of non-relapse mortality was 36 and 40% at 1 and 2 years, respectively. With a cumulative incidence for relapse of 36 and 45.6% at 1 and 2 years, disease-free survival (DFS) was 28 and 14.4%, respectively. Here also, patients with CR before haploidentical HCT had a favorable DFS of 42% at 2 years. Only very limited acute (11 patients (44%) with a median grade 1) and chronic graft versus host disease (GvHD) (5 patients (11%), limited grade only) was observed. The main complications and causes of death comprised-besides relapse-infections and bleeding complications. Hence, haploidentical HCT can achieve long-term survival comparable to second transplantation with matched or mismatched donors for patients with otherwise deleterious prognosis and should be considered as a treatment option for patients experiencing disease relapse after previous allogeneic HCT.


Assuntos
Haplótipos , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas , Depleção Linfocítica , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Terapia Combinada , Feminino , Sobrevivência de Enxerto , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Células-Tronco Hematopoéticas/imunologia , Humanos , Estimativa de Kaplan-Meier , Leucemia/complicações , Leucemia/diagnóstico , Leucemia/mortalidade , Leucemia/terapia , Masculino , Pessoa de Meia-Idade , Mortalidade , Recidiva , Retratamento , Terapia de Salvação , Linfócitos T , Doadores de Tecidos , Quimeras de Transplante , Condicionamento Pré-Transplante , Transplante Homólogo , Resultado do Tratamento , Adulto Jovem
11.
Ann Surg Oncol ; 24(6): 1650-1657, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28160138

RESUMO

BACKGROUND: Hyperthermic intraperitoneal chemotherapy (HIPEC) is used to treat peritoneal surface malignancies with application of cytostatic drugs such as oxaliplatin (OX) after cytoreductive surgery. Despite its increased use, evidence for optimal drug dosage, and notably duration of HIPEC, is scarce. METHODS: In this study, OX distribution was comprehensively assessed in nine patients during HIPEC (300 mg OX/m2 body surface area in Physioneal solution for 30 min). Oxaliplatin and its derivatives were measured in peritoneal perfusates over time by liquid chromatography coupled with mass spectrometry (LC-MS), and the resulting total platinum concentration in tissue was analyzed by atomic absorption spectrometry. Additionally, a novel impedance-based real-time cytotoxicity assay was used to evaluate the bioactivity of perfusates ex vivo. RESULTS: Compared with amounts of OX expected in peritoneal perfusates by calculation, only 10-15% of the parent drug could be detected by LC-MS during HIPEC. Notably, the study additionally detected platinum compounds consistent with OX transformation, accounting for a further fraction of the applied drug. The cytotoxic properties of perfusates remained unchanged during HIPEC, with only a slight but significant attenuation evidenced after 30 min. CONCLUSIONS: The bioactivity of peritoneal perfusates ex vivo is a useful parameter for evaluating the actual cytotoxic potential of OX and its derivatives used in HIPEC over time, overcoming important limitations and disadvantages associated with respective drug monitoring only. Ex vivo cytotoxicity assays may be a promising tool to aid guiding future standardization and harmonization of HIPEC protocols based on drug-mediated effects.


Assuntos
Antineoplásicos/farmacologia , Quimioterapia do Câncer por Perfusão Regional , Protocolos Clínicos , Hipertermia Induzida , Compostos Organoplatínicos/farmacologia , Neoplasias Peritoneais/tratamento farmacológico , Projetos de Pesquisa , Adulto , Idoso , Terapia Combinada , Procedimentos Cirúrgicos de Citorredução , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Oxaliplatina , Neoplasias Peritoneais/patologia , Neoplasias Peritoneais/cirurgia , Prognóstico
12.
J Cancer Res Clin Oncol ; 143(5): 759-771, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28210842

RESUMO

PURPOSE: Prolonged aplasia and graft failure (GF) represent life-threatening complications after hematopoietic cell transplantation (HCT) requiring suitable biomarkers for early detection and differentiation between GF and poor graft function (PGF). Uric acid (UA) is a strong immunological danger signal. METHODS: Laboratory results were analyzed from patients undergoing either allogeneic or autologous HCT or induction chemotherapy for acute leukemia (n = 50 per group, n = 150 total). RESULTS: During therapy, UA levels declined from normal values to hypouricemic values (all p < 0.001). Alongside hematopoietic recovery, UA serum levels returned to baseline values. During aplasia, UA levels remained low and started steadily increasing (defined as >two consecutive days, median one 2-day increase) at a median of 1 day before rising leukocytes in allogeneic HCT (p = 0.01) and together with leukocytes in autologous HCT (median one 2-day increase). During induction chemotherapy, a UA increase was also observed alongside rising leukocytes/neutrophils but also several times during aplasia (median 3 increases). Most HCT patients had no detectable leukocytes during aplasia, while some leukocytes remained detectable after induction therapy. No increase in UA levels was observed without concomitant or subsequent rise of leukocytes. CONCLUSIONS: Changes in UA serum levels can indicate incipient or remaining immunological activity after HCT or induction therapy. They may, therefore, help to differentiate between PGF and GF.


Assuntos
Anemia/sangue , Biomarcadores Tumorais/sangue , Medula Óssea/fisiopatologia , Transplante de Células-Tronco Hematopoéticas/métodos , Leucemia Mieloide Aguda/sangue , Leucemia Mieloide Aguda/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangue , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Ácido Úrico/sangue , Adulto , Idoso , Anemia/etiologia , Anemia/imunologia , Anemia/patologia , Contagem de Células Sanguíneas , Medula Óssea/imunologia , Medula Óssea/patologia , Feminino , Sobrevivência de Enxerto/imunologia , Sobrevivência de Enxerto/fisiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Adulto Jovem
13.
Proc Natl Acad Sci U S A ; 113(48): 13827-13832, 2016 11 29.
Artigo em Inglês | MEDLINE | ID: mdl-27834728

RESUMO

Graft-versus-host disease (GVHD) represents the major nonrelapse complication of allogeneic hematopoietic cell transplantation. Although rare, the CNS and the eye can be affected. In this study, manifestation in the retina as part of the CNS and T-cell epitopes recognized by the allogeneic T cells were evaluated. In 2 of 6 patients with posttransplantation retina diseases and 6 of 22 patients without ocular symptoms, antigen-specific T-cell responses against retina-specific epitopes were observed. No genetic differences between donor and recipient could be identified indicating T-cell activation against self-antigens (graft versus self). Transplantation of a preexisting immunity and cross-reactivity with ubiquitous epitopes was excluded in family donors and healthy individuals. In summary, an immunological reaction against retina cells represents a mechanism of graft-versus-host interaction following hematopoietic cell transplantation.


Assuntos
Autoantígenos/imunologia , Epitopos de Linfócito T/imunologia , Doença Enxerto-Hospedeiro/imunologia , Doenças Retinianas/imunologia , Adulto , Idoso , Feminino , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/patologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Ativação Linfocitária/imunologia , Masculino , Pessoa de Meia-Idade , Doenças Retinianas/etiologia , Doenças Retinianas/patologia , Linfócitos T/imunologia , Transplante Homólogo/efeitos adversos
14.
Transpl Immunol ; 36: 25-31, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-27020764

RESUMO

BACKGROUND: Heat shock proteins (HSP) are highly conserved immunogenic proteins serving as potent danger signals. They are upregulated under stress conditions like fever and hypoxia. Extracellular HSP are involved in antigen presentation, cytokine release and maturation of antigen presenting cells. METHODS: The release of the inducible members of the HSP70 family, Hsp72 and Hsp70B', into the serum of 20 patients undergoing allogeneic hematopoietic cell transplantation and 20 healthy donors was evaluated using enzyme linked immunosorbent assay (ELISA) kits. RESULTS: Eight patients (40%) did not receive anti-thymocyte globulin (ATG) for prophylaxis of graft versus host disease (GvHD). These patients had no detectable or low serum levels of Hsp72 (n=3, 0.03 to 1.92ng/ml) which were in line with levels detected in 20 healthy individuals (p=0.07). Measurable HSP was not associated with any medication or transplantation-related procedures. In twelve patients (60%) receiving ATG, detected high levels of HSP reflected cross-reactivity of the rabbit-derived ATG with the anti-rabbit antibody used in the ELISA. CONCLUSIONS: Assumed HSP70 expression detected such ELISA has to be regarded carefully after ATG application. Neither radiochemotherapy, nor inflammation or sepsis during aplasia induced HSP70 release into the serum. Thus, soluble HSP70 may not be involved in the pathogenesis of acute GvHD.


Assuntos
Biomarcadores/sangue , Doença Enxerto-Hospedeiro/diagnóstico , Proteínas de Choque Térmico HSP70/sangue , Proteínas de Choque Térmico HSP72/sangue , Transplante de Células-Tronco Hematopoéticas , Adulto , Idoso , Animais , Reações Cruzadas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Coelhos , Transplante Homólogo
15.
Oncotarget ; 7(11): 13013-30, 2016 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-26887048

RESUMO

The epidermal growth factor receptor HER2/neu is expressed on various cancers and represents a negative prognostic marker, but is also a target for the therapeutic monoclonal antibody Trastuzumab. In about 30% of cases, HER2/neu is expressed on acute lymphoblastic leukemia (ALL) cells and was proposed to be associated with a deleterious prognosis. Here we evaluated clinical data from 65 ALL patients (HER2/neu+, n = 17; HER2/neu-, n = 48) with a median follow-up of 19.4 months (range 0.6-176.5 months) and observed no association of HER2/neu expression with response to chemotherapy, disease free or overall survival. In vitro, treatment of primary ALL cells (CD20+HER2/neu+, CD20+HER2/neu- and CD20-HER2/neu-) with Rituximab and Trastuzumab led to activation of NK cells in strict dependence of the expression of the respective antigen. NK reactivity was more pronounced with Rituximab as compared to Trastuzumab, and combined application could lead to additive effects in cases where both antigens were expressed. Besides providing evidence that HER2/neu expression is no risk factor in ALL patients, our data demonstrates that HER2/neu can be a promising target for Trastuzumab therapy in the subset of ALL patients with the potential to improve disease outcome.


Assuntos
Antineoplásicos/uso terapêutico , Células Matadoras Naturais/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Receptor ErbB-2/biossíntese , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Citotoxicidade Celular Dependente de Anticorpos/efeitos dos fármacos , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Prognóstico , Estudos Retrospectivos , Rituximab/uso terapêutico , Trastuzumab/uso terapêutico , Resultado do Tratamento , Adulto Jovem
16.
BMC Cancer ; 15: 972, 2015 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-26675671

RESUMO

BACKGROUND: Rare sites of metastases, atypical symptoms and paraneoplastic syndromes are often neglected or misinterpreted, especially when they represent early symptoms of an underlying malignant disease. Hence, an interdisciplinary approach to these patients is essential to avoid tumor progression and metastatic spread in order to provide curative treatment options to the patients. We here report the case of a young woman presenting with visual loss which led to diagnosis of a thymic carcinoma. CASE PRESENTATION: A 28-year old white woman presented with subacute loss of vision in the last trimester of her first pregnancy which was first interpreted as an exacerbation of a pre-existing dermatomyositis and treated with steroids. After failure of steroid therapy choroidal metastases from an undifferentiated thymic carcinoma were diagnosed. This also shed a new light on the dermatomyositis the patient had been suffering from for seven years possibly representing a paraneoplastic syndrome from the tumor. Despite aggressive chemotherapy, the patient died from progressive disease eight years after first onset of dermatomyositis and 14 months after initial diagnosis of the thymic carcinoma. CONCLUSIONS: Choroidal metastases from a thymic carcinoma have never been reported before but should be included into the differential diagnosis of choroidal masses.


Assuntos
Neoplasias da Coroide/secundário , Síndromes Paraneoplásicas/etiologia , Complicações Neoplásicas na Gravidez/patologia , Timoma/secundário , Neoplasias do Timo/patologia , Adulto , Dermatomiosite/etiologia , Feminino , Humanos , Síndromes Paraneoplásicas/patologia , Gravidez , Transtornos da Visão/etiologia
17.
J Cancer Res Clin Oncol ; 141(12): 2241-51, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26272482

RESUMO

PURPOSE: Insufficient production of leukocytes, thrombocytes and erythrocytes after allogeneic peripheral blood stem cell transplantation (PBSCT) represents a life-threatening complication. METHODS: In 20 adult patients with poor graft function (PGF defined as transfusion-dependent platelet counts <20,000/µl, or leukocytes <1500/µl, or transfusion-dependent anemia) and variable causes of PGF after allogeneic PBSCT, immunomagnetically selected CD34(+) stem cell boosts (SCB) from matched unrelated (n = 8), mismatched unrelated (n = 11) or haploidentical (n = 1) donors were applied without prior conditioning. RESULTS: Patients received a median of 4.6 × 10(6) CD34(+) cells per kilogram bodyweight (1.9-9.1 × 10(6)) and low T cell numbers (median 0.2 × 10(4), range 0.04-0.6 × 10(4)). All patients showed responses in at least one hematopoietic lineage. Engraftment for platelets, leukocytes and hemoglobin was 88, 88 and 100 % after a median of 14, 13 and 18 days, respectively. With regard to the complete cohort, 90 % (n = 18) showed an increase in platelets (median 76,500/µl, range -7000 to 223,000/µl), 95 % (n = 19) had an increase in leukocytes (median 3110/µl, range 150-13,740/µl) and 90 % (n = 18) improved with regard to hemoglobin (median 1.9 g/dl, range -0.9 to 5.1 g/dl). Due to effective T cell depletion, only one patient developed graft versus host disease (GvHD, grade III) after SCB. Patients were followed for a median of 7.5 months (1-74 months) with 11 patients being alive and disease free with normalized peripheral blood counts at the end of follow-up. CONCLUSIONS: CD34(+)-selected SCB are safe and effective and can durably improve PGF even in patients receiving grafts from unrelated matched or mismatched donors with low incidence of GvHD.


Assuntos
Antígenos CD34/imunologia , Sobrevivência de Enxerto , Doença Enxerto-Hospedeiro/prevenção & controle , Neoplasias Hematológicas/complicações , Transplante de Células-Tronco de Sangue Periférico/efeitos adversos , Células-Tronco/imunologia , Adulto , Estudos de Coortes , Feminino , Seguimentos , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/mortalidade , Neoplasias Hematológicas/terapia , Histocompatibilidade , Humanos , Leucaférese , Masculino , Pessoa de Meia-Idade , Prognóstico , Células-Tronco/citologia , Taxa de Sobrevida , Doadores de Tecidos , Condicionamento Pré-Transplante , Transplante Homólogo , Doadores não Relacionados , Adulto Jovem
18.
Curr Opin Immunol ; 25(2): 277-83, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23619309

RESUMO

In cancer patients, active immunotherapy has gained significant importance in recent years by implementation of novel substances into standard clinical care. These new drugs represent strategies which either use defined cancer associated antigens as vaccines or induce tumor-directed immune responses through generation of a general inflammatory state which has extensive autoinflammatory side effects by induction of autoreactive immune cells. Hence, the definition of suitable target antigens for immunotherapy remains a major challenge. These antigens should ideally be specific markers for individual tumors or should be at least structures overexpressed on the tumor as compared to normal cells. Recent approaches have defined algorithms and refined analytical methods for antigen identification and immunological validation that have already been evaluated in clinical studies. This article summarizes recent developments in tissue analysis on genome, transcriptome and HLA-ligandome levels and of antigen application in recent clinical vaccination trials.


Assuntos
Antígenos de Neoplasias/imunologia , Epitopos/imunologia , Neoplasias/imunologia , Neoplasias/terapia , Ensaios Clínicos como Assunto , Humanos , Imunoterapia , Linfócitos T/imunologia
19.
Cell Stress Chaperones ; 16(5): 495-504, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21442384

RESUMO

Due to their adjuvant effect and their ability to chaperone tumor-associated peptides, heat shock proteins constitute a potent alarm signal for the immune system and can lead to activation of anti-tumor T-cell immunity. Radiofrequency ablation has been reported to induce heat shock protein expression especially that of heat shock protein 70 in sublethally damaged tumor cells. In this study, we evaluated the release of heat shock protein 70 into the serum of cancer-bearing patients directly after radiofrequency ablation. Sera of 22 patients undergoing radiofrequency ablation for the treatment of primary and secondary malignancies of the liver, kidney, and lung, as well as control sera of 20 patients undergoing diagnostic liver biopsy were analyzed using a manufactured heat shock protein 70 ELISA. A significant increase in serum levels of heat shock protein 70 was detectable in the patient cohort 1 day after radiofrequency ablation. More than a twofold increase was observed in nine out of 22 patients, which tended to correlate with favorable clinical outcome. No patient of the control group revealed a comparable increase. Radiofrequency ablation can lead to a release of heat shock protein 70 into the serum, which is transiently detectable 1 day after treatment. Elevated heat shock protein 70 serum levels may constitute a biomarker for favorable clinical outcome.


Assuntos
Ablação por Cateter , Proteínas de Choque Térmico HSP70/sangue , Neoplasias/radioterapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/metabolismo , Biópsia , Feminino , Humanos , Fígado/metabolismo , Fígado/patologia , Masculino , Pessoa de Meia-Idade , Neoplasias/metabolismo , Resultado do Tratamento , Adulto Jovem
20.
Int J Cancer ; 128(11): 2653-62, 2011 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-20715115

RESUMO

Radiofrequency (RF) ablation is a minimally invasive technique routinely applied for the treatment of primary and secondary liver tumors. It induces cell death by thermal coagulative necrosis of tumor tissues, whereas cellular metabolism can still take place in a transition zone surrounding the necrotic area. An increase in heat shock protein expression occurs shortly after treatment, suggesting that the induction of activating signals may stimulate the host immune system. In addition, various effects on immune effectors have also been observed, including stimulation of tumor-directed T lymphocytes. Here, we prospectively assessed the activation of tumor antigen-specific antibodies, as well as antigen-specific CD4(+) and CD8(+) T cells in patients suffering from primary or secondary malignancies and treated by RF ablation with or without concomitant chemotherapy. An increase of antibodies (in 4 patients of 49), CD4(+) T cells or CD8(+) T cells (in 2 patients of 49) could be detected several weeks to months following intervention. These findings suggest that in addition to the local control of tumor growth, RF ablation can provide the appropriate conditions for activating tumor-antigen specific immune responses.


Assuntos
Anticorpos Antineoplásicos/imunologia , Antígenos de Neoplasias/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Ablação por Cateter , Neoplasias/imunologia , Neoplasias/cirurgia , Idoso , Feminino , Humanos , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos
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