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1.
Immunity ; 31(4): 527-8, 2009 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-19833080

RESUMO

Immunotherapy, especially therapeutic vaccination, has a great deal of potential in the treatment of cancer and certain infectious diseases such as HIV (Allison et al., 2006; Fauci et al., 2008; Feldmann and Steinman, 2005). Numerous vaccine candidates have been tested in patients with a variety of tumor types and chronic viral diseases. Often, the best way to assess the clinical potential of these vaccines is to monitor the induced T cell response, and yet there are currently no standards for reporting these results. This letter is an effort to address this problem.


Assuntos
Vacinas Anticâncer/uso terapêutico , Imunoensaio/normas , Monitorização Imunológica/normas , Neoplasias/terapia , Guias de Prática Clínica como Assunto/normas , Linfócitos T/imunologia , Vacinas Virais/uso terapêutico , Viroses/terapia , Vacinas Anticâncer/imunologia , Humanos , Imunoterapia , Vacinas Virais/imunologia
2.
Nature ; 482(7385): 400-4, 2012 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-22318521

RESUMO

Cancer immunoediting, the process by which the immune system controls tumour outgrowth and shapes tumour immunogenicity, is comprised of three phases: elimination, equilibrium and escape. Although many immune components that participate in this process are known, its underlying mechanisms remain poorly defined. A central tenet of cancer immunoediting is that T-cell recognition of tumour antigens drives the immunological destruction or sculpting of a developing cancer. However, our current understanding of tumour antigens comes largely from analyses of cancers that develop in immunocompetent hosts and thus may have already been edited. Little is known about the antigens expressed in nascent tumour cells, whether they are sufficient to induce protective antitumour immune responses or whether their expression is modulated by the immune system. Here, using massively parallel sequencing, we characterize expressed mutations in highly immunogenic methylcholanthrene-induced sarcomas derived from immunodeficient Rag2(-/-) mice that phenotypically resemble nascent primary tumour cells. Using class I prediction algorithms, we identify mutant spectrin-ß2 as a potential rejection antigen of the d42m1 sarcoma and validate this prediction by conventional antigen expression cloning and detection. We also demonstrate that cancer immunoediting of d42m1 occurs via a T-cell-dependent immunoselection process that promotes outgrowth of pre-existing tumour cell clones lacking highly antigenic mutant spectrin-ß2 and other potential strong antigens. These results demonstrate that the strong immunogenicity of an unedited tumour can be ascribed to expression of highly antigenic mutant proteins and show that outgrowth of tumour cells that lack these strong antigens via a T-cell-dependent immunoselection process represents one mechanism of cancer immunoediting.


Assuntos
Exoma/genética , Exoma/imunologia , Vigilância Imunológica/imunologia , Neoplasias/genética , Neoplasias/imunologia , Linfócitos T/imunologia , Algoritmos , Animais , Proteínas de Transporte/genética , Proteínas de Transporte/imunologia , Proteínas de Ligação a DNA/deficiência , Proteínas de Ligação a DNA/genética , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos , Masculino , Metilcolantreno , Camundongos , Proteínas dos Microfilamentos/genética , Proteínas dos Microfilamentos/imunologia , Modelos Imunológicos , Neoplasias/induzido quimicamente , Neoplasias/patologia , Reprodutibilidade dos Testes , Sarcoma/induzido quimicamente , Sarcoma/genética , Sarcoma/imunologia , Sarcoma/patologia
3.
Eur J Nucl Med Mol Imaging ; 42(11): 1700-1706, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26194713

RESUMO

PURPOSE: The molecular specificity of monoclonal antibodies (mAbs) directed against tumor antigens has proven effective for targeted therapy of human cancers, as shown by a growing list of successful antibody-based drug products. We describe a novel, nonlinear compartmental model using PET-derived data to determine the "best-fit" parameters and model-derived quantities for optimizing biodistribution of intravenously injected (124)I-labeled antitumor antibodies. METHODS: As an example of this paradigm, quantitative image and kinetic analyses of anti-A33 humanized mAb (also known as "A33") were performed in 11 colorectal cancer patients. Serial whole-body PET scans of (124)I-labeled A33 and blood samples were acquired and the resulting tissue time-activity data for each patient were fit to a nonlinear compartmental model using the SAAM II computer code. RESULTS: Excellent agreement was observed between fitted and measured parameters of tumor uptake, "off-target" uptake in bowel mucosa, blood clearance, tumor antigen levels, and percent antigen occupancy. CONCLUSION: This approach should be generally applicable to antibody-antigen systems in human tumors for which the masses of antigen-expressing tumor and of normal tissues can be estimated and for which antibody kinetics can be measured with PET. Ultimately, based on each patient's resulting "best-fit" nonlinear model, a patient-specific optimum mAb dose (in micromoles, for example) may be derived.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Neoplasias Colorretais/diagnóstico por imagem , Neoplasias Colorretais/tratamento farmacológico , Modelos Biológicos , Terapia de Alvo Molecular , Tomografia por Emissão de Pósitrons , Medicina de Precisão , Animais , Anticorpos Monoclonais/metabolismo , Neoplasias Colorretais/patologia , Humanos , Radioisótopos do Iodo , Cinética , Camundongos
5.
Proc Natl Acad Sci U S A ; 109(15): 5797-802, 2012 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-22454499

RESUMO

Recombinant poxviruses (vaccinia and fowlpox) expressing tumor-associated antigens are currently being evaluated in clinical trials as cancer vaccines to induce tumor-specific immune responses that will improve clinical outcome. To test whether a diversified prime and boost regimen targeting NY-ESO-1 will result in clinical benefit, we conducted two parallel phase II clinical trials of recombinant vaccinia-NY-ESO-1 (rV-NY-ESO-1), followed by booster vaccinations with recombinant fowlpox-NY-ESO-1 (rF-NY-ESO-1) in 25 melanoma and 22 epithelial ovarian cancer (EOC) patients with advanced disease who were at high risk for recurrence/progression. Integrated NY-ESO-1-specific antibody and CD4(+) and CD8(+) T cells were induced in a high proportion of melanoma and EOC patients. In melanoma patients, objective response rate [complete and partial response (CR+PR)] was 14%, mixed response was 5%, and disease stabilization was 52%, amounting to a clinical benefit rate (CBR) of 72% in melanoma patients. The median PFS in the melanoma patients was 9 mo (range, 0-84 mo) and the median OS was 48 mo (range, 3-106 mo). In EOC patients, the median PFS was 21 mo (95% CI, 16-29 mo), and median OS was 48 mo (CI, not estimable). CD8(+) T cells derived from vaccinated patients were shown to lyse NY-ESO-1-expressing tumor targets. These data provide preliminary evidence of clinically meaningful benefit for diversified prime and boost recombinant pox-viral-based vaccines in melanoma and ovarian cancer and support further evaluation of this approach in these patient populations.


Assuntos
Antígenos de Neoplasias/imunologia , Vetores Genéticos/genética , Melanoma/imunologia , Proteínas de Membrana/imunologia , Neoplasias Ovarianas/imunologia , Vacinação , Vacinas Sintéticas/imunologia , Vaccinia virus/genética , Formação de Anticorpos/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Epitopos de Linfócito T/imunologia , Feminino , Vírus da Varíola das Aves Domésticas/genética , Humanos , Melanoma/patologia , Neoplasias Ovarianas/patologia , Resultado do Tratamento
6.
Eur J Immunol ; 43(4): 989-1000, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23436617

RESUMO

Cancer vaccines have yet to yield clinical benefit, despite the measurable induction of humoral and cellular immune responses. As immunosuppression by CD4(+) CD25(+) regulatory T (Treg) cells has been linked to the failure of cancer immunotherapy, blocking suppression is therefore critical for successful clinical strategies. Here, we addressed whether a lyophilized preparation of Streptococcus pyogenes (OK-432), which stimulates Toll-like receptors, could overcome Treg-cell suppression of CD4(+) T-cell responses in vitro and in vivo. OK-432 significantly enhanced in vitro proliferation of CD4(+) effector T cells by blocking Treg-cell suppression and this blocking effect depended on IL-12 derived from antigen-presenting cells. Direct administration of OK-432 into tumor-associated exudate fluids resulted in a reduction of the frequency and suppressive function of CD4(+) CD25(+) Foxp3(+) Treg cells. Furthermore, when OK-432 was used as an adjuvant of vaccination with HER2 and NY-ESO-1 for esophageal cancer patients, NY-ESO-1-specific CD4(+) T-cell precursors were activated, and NY-ESO-1-specific CD4(+) T cells were detected within the effector/memory T-cell population. CD4(+) T-cell clones from these patients had high-affinity TCRs and recognized naturally processed NY-ESO-1 protein presented by dendritic cells. OK-432 therefore inhibits Treg-cell function and contributes to the activation of high-avidity tumor antigen-specific naive T-cell precursors.


Assuntos
Terapia de Imunossupressão , Streptococcus pyogenes/imunologia , Linfócitos T Reguladores/imunologia , Células Apresentadoras de Antígenos/imunologia , Células Apresentadoras de Antígenos/metabolismo , Antígenos de Neoplasias/administração & dosagem , Antígenos de Neoplasias/imunologia , Antígenos CD4/metabolismo , Vacinas Anticâncer/administração & dosagem , Vacinas Anticâncer/imunologia , Exsudatos e Transudatos/imunologia , Humanos , Interleucina-12/farmacologia , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Proteínas de Membrana/administração & dosagem , Proteínas de Membrana/imunologia , Neoplasias/imunologia , Picibanil/administração & dosagem , Picibanil/imunologia , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/metabolismo
7.
Blood ; 119(13): 3097-104, 2012 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-22323448

RESUMO

Adult T-cell leukemia/lymphoma (ATLL) is an intractable hematologic malignancy caused by human T-lymphotropic virus type 1 (HTLV-1), which infects approximately 20 million people worldwide. Here, we have explored the possible expression of cancer/testis (CT) antigens by ATLL cells, as CT antigens are widely recognized as ideal targets of cancer immunotherapy against solid tumors. A high percentage (87.7%) of ATLL cases (n = 57) expressed CT antigens at the mRNA level: NY-ESO-1 (61.4%), MAGE-A3 (31.6%), and MAGE-A4 (61.4%). CT antigen expression was confirmed by immunohistochemistry. This contrasts with other types of lymphoma or leukemia, which scarcely express these CT antigens. Humoral immune responses, particularly against NY-ESO-1, were detected in 11.6% (5 of 43) and NY-ESO-1-specific CD8(+) T-cell responses were observed in 55.6% (5 of 9) of ATLL patients. NY-ESO-1-specific CD8(+) T cells recognized autologous ATLL cells and produced effector cytokines. Thus, ATLL cells characteristically express CT antigens and therefore vaccination with CT antigens can be an effective immunotherapy of ATLL.


Assuntos
Antígenos de Neoplasias/fisiologia , Antígenos/fisiologia , Imunoterapia/métodos , Leucemia-Linfoma de Células T do Adulto/terapia , Terapia de Alvo Molecular/métodos , Testículo/imunologia , Adulto , Antígenos/imunologia , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/metabolismo , Linhagem Celular , Feminino , Regulação Leucêmica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Imunidade Humoral/genética , Imunoterapia/tendências , Leucemia-Linfoma de Células T do Adulto/genética , Leucemia-Linfoma de Células T do Adulto/imunologia , Leucemia-Linfoma de Células T do Adulto/metabolismo , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Pessoa de Meia-Idade , Terapia de Alvo Molecular/tendências , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo
8.
J Immunol ; 188(8): 3851-8, 2012 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-22427632

RESUMO

Tumor Ag-specific CD4(+) T cells play important functions in tumor immunosurveillance, and in certain cases they can directly recognize HLA class II-expressing tumor cells. However, the underlying mechanism of intracellular Ag presentation to CD4(+) T cells by tumor cells has not yet been well characterized. We analyzed two naturally occurring human CD4(+) T cell lines specific for different peptides from cytosolic tumor Ag NY-ESO-1. Whereas both lines had the same HLA restriction and a similar ability to recognize exogenous NY-ESO-1 protein, only one CD4(+) T cell line recognized NY-ESO-1(+) HLA class II-expressing melanoma cells. Modulation of Ag processing in melanoma cells using specific molecular inhibitors and small interfering RNA revealed a previously undescribed peptide-selective Ag-presentation pathway by HLA class II(+) melanoma cells. The presentation required both proteasome and endosomal protease-dependent processing mechanisms, as well as cytosolic heat shock protein 90-mediated chaperoning. Such tumor-specific pathway of endogenous HLA class II Ag presentation is expected to play an important role in immunosurveillance or immunosuppression mediated by various subsets of CD4(+) T cells at the tumor local site. Furthermore, targeted activation of tumor-recognizing CD4(+) T cells by vaccination or adoptive transfer could be a suitable strategy for enhancing the efficacy of tumor immunotherapy.


Assuntos
Antígenos de Neoplasias/imunologia , Linfócitos T CD4-Positivos/imunologia , Epitopos de Linfócito T/imunologia , Proteínas de Choque Térmico HSP90/imunologia , Peptídeos/imunologia , Apresentação de Antígeno , Antígenos de Neoplasias/genética , Linfócitos T CD4-Positivos/citologia , Linhagem Celular Tumoral , Clonagem Molecular , Citocinas/biossíntese , Citocinas/imunologia , Citosol/imunologia , Citosol/metabolismo , Endossomos/genética , Endossomos/imunologia , Epitopos de Linfócito T/genética , Feminino , Proteínas de Choque Térmico HSP90/genética , Antígenos de Histocompatibilidade Classe II/genética , Antígenos de Histocompatibilidade Classe II/imunologia , Humanos , Ativação Linfocitária/imunologia , Melanoma/imunologia , Melanoma/patologia , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/patologia , Peptídeos/genética , Complexo de Endopeptidases do Proteassoma/genética , Complexo de Endopeptidases do Proteassoma/imunologia , RNA Interferente Pequeno/genética
9.
Nat Rev Cancer ; 5(8): 615-25, 2005 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16034368

RESUMO

Cancer/testis (CT) antigens, of which more than 40 have now been identified, are encoded by genes that are normally expressed only in the human germ line, but are also expressed in various tumour types, including melanoma, and carcinomas of the bladder, lung and liver. These immunogenic proteins are being vigorously pursued as targets for therapeutic cancer vaccines. CT antigens are also being evaluated for their role in oncogenesis--recapitulation of portions of the germline gene-expression programme might contribute characteristic features to the neoplastic phenotype, including immortality, invasiveness, immune evasion, hypomethylation and metastatic capacity.


Assuntos
Antígenos de Neoplasias/imunologia , Neoplasias/imunologia , Antígenos de Neoplasias/genética , Gametogênese/imunologia , Expressão Gênica , Mutação em Linhagem Germinativa , Humanos , Masculino , Neoplasias/genética , Testículo
10.
Proc Natl Acad Sci U S A ; 108(49): 19695-700, 2011 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-22114198

RESUMO

One of the main challenges in cancer research is the development of vaccines that induce effective and long-lived protective immunity against tumors. Significant progress has been made in identifying members of the cancer testis antigen family as potential vaccine candidates. However, an ideal form for antigen delivery that induces robust and sustainable antigen-specific T-cell responses, and in particular of CD8(+) T lymphocytes, remains to be developed. Here we report the use of a recombinant nonpathogenic clone of Trypanosoma cruzi as a vaccine vector to induce vigorous and long-term T cell-mediated immunity. The rationale for using the highly attenuated T. cruzi clone was (i) the ability of the parasite to persist in host tissues and therefore to induce a long-term antigen-specific immune response; (ii) the existence of intrinsic parasite agonists for Toll-like receptors and consequent induction of highly polarized T helper cell type 1 responses; and (iii) the parasite replication in the host cell cytoplasm, leading to direct antigen presentation through the endogenous pathway and consequent induction of antigen-specific CD8(+) T cells. Importantly, we found that parasites expressing a cancer testis antigen (NY-ESO-1) were able to elicit human antigen-specific T-cell responses in vitro and solid protection against melanoma in a mouse model. Furthermore, in a therapeutic protocol, the parasites expressing NY-ESO-1 delayed the rate of tumor development in mice. We conclude that the T. cruzi vector is highly efficient in inducing T cell-mediated immunity and protection against cancer cells. More broadly, this strategy could be used to elicit a long-term T cell-mediated immunity and used for prophylaxis or therapy of chronic infectious diseases.


Assuntos
Antígenos de Neoplasias/imunologia , Vacinas Anticâncer/imunologia , Proteínas de Membrana/imunologia , Trypanosoma cruzi/imunologia , Animais , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/metabolismo , Western Blotting , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/parasitologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/parasitologia , Vacinas Anticâncer/administração & dosagem , Linhagem Celular Tumoral , Células Cultivadas , Doença de Chagas/imunologia , Doença de Chagas/parasitologia , Doença de Chagas/prevenção & controle , Ensaio de Imunoadsorção Enzimática , Vetores Genéticos/administração & dosagem , Vetores Genéticos/imunologia , Humanos , Imunização/métodos , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neoplasias Experimentais/imunologia , Neoplasias Experimentais/patologia , Neoplasias Experimentais/prevenção & controle , Transfecção/métodos , Trypanosoma cruzi/genética , Trypanosoma cruzi/metabolismo
11.
Proc Natl Acad Sci U S A ; 108(40): 16723-8, 2011 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-21933959

RESUMO

Ipilimumab, a monoclonal antibody against cytotoxic T lymphocyte antigen 4 (CTLA-4), has been shown to improve survival in patients with advanced metastatic melanoma. It also enhances immunity to NY-ESO-1, a cancer/testis antigen expressed in a subset of patients with melanoma. To characterize the association between immune response and clinical outcome, we first analyzed NY-ESO-1 serum antibody by ELISA in 144 ipilimumab-treated patients with melanoma and found 22 of 140 (16%) seropositive at baseline and 31 of 144 (22%) seropositive following treatment. These NY-ESO-1-seropositive patients had a greater likelihood of experiencing clinical benefit 24 wk after ipilimumab treatment than NY-ESO-1-seronegative patients (P = 0.02, relative risk = 1.8, two-tailed Fisher test). To understand why some patients with NY-ESO-1 antibody failed to experience clinical benefit, we analyzed NY-ESO-1-specific CD4(+) and CD8(+) T-cell responses by intracellular multicytokine staining in 20 NY-ESO-1-seropositive patients and found a surprising dissociation between NY-ESO-1 antibody and CD8 responses in some patients. NY-ESO-1-seropositive patients with associated CD8(+) T cells experienced more frequent clinical benefit (10 of 13; 77%) than those with undetectable CD8(+) T-cell response (one of seven; 14%; P = 0.02; relative risk = 5.4, two-tailed Fisher test), as well as a significant survival advantage (P = 0.01; hazard ratio = 0.2, time-dependent Cox model). Together, our data suggest that integrated NY-ESO-1 immune responses may have predictive value for ipilimumab treatment and argue for prospective studies in patients with established NY-ESO-1 immunity. The current findings provide a strong rationale for the clinical use of modulators of immunosuppression with concurrent approaches to favor tumor antigen-specific immune responses, such as vaccines or adoptive transfer, in patients with cancer.


Assuntos
Anticorpos Monoclonais/farmacologia , Antígenos de Neoplasias/imunologia , Linfócitos T CD8-Positivos/imunologia , Antígeno CTLA-4/imunologia , Melanoma/imunologia , Proteínas de Membrana/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/imunologia , Ensaio de Imunoadsorção Enzimática , Humanos , Imuno-Histoquímica , Ipilimumab , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Análise de Sobrevida
12.
Invest New Drugs ; 31(2): 425-34, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22864522

RESUMO

Background Arginine deiminase (ADI) is an enzyme that degrades arginine, an amino acid that is important for growth and development of normal and neoplastic cells. Melanoma cells are auxotrophic for arginine, because they lack argininosuccinatesynthetase (ASS), a key enzyme required for the synthesis of arginine. Patients and methods Patients with advanced melanoma were treated with 40, 80 or 160 IU/m(2) ADI-PEG 20 i.m. weekly. Primary endpoints were toxicity and tumor response, secondary endpoints included metabolic response by (18)FDG-PET, pharmacodynamic (PD) effects upon circulating arginine levels, and argininosuccinate synthetase tumor expression by immunohistochemistry. Results 31 previously treated patients were enrolled. The main toxicities were grade 1 and 2 adverse events including injection site pain, rash, and fatigue. No objective responses were seen. Nine patients achieved stable disease (SD), with 2 of these durable for >6 months. Four of the 9 patients with SD had uveal melanoma. PD analysis showed complete plasma arginine depletion in 30/31 patients by day 8. Mean plasma levels of ADI-PEG 20 correlated inversely with ADI-PEG 20 antibody levels. Immunohistochemical ASS expression analysis in tumor tissue was negative in 24 patients, whereas 5 patients had <5 % cells positive. Conclusions ADI-PEG 20 is well tolerated in advanced melanoma patients and leads to consistent, but transient, arginine depletion. Although no RECIST responses were observed, the encouraging rate of SD in uveal melanoma patients indicates that it may be worthwhile to evaluate ADI-PEG 20 in this melanoma subgroup.


Assuntos
Hidrolases/uso terapêutico , Melanoma/tratamento farmacológico , Polietilenoglicóis/uso terapêutico , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Uveais/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Relação Dose-Resposta a Droga , Feminino , Seguimentos , Humanos , Hidrolases/farmacocinética , Técnicas Imunoenzimáticas , Masculino , Dose Máxima Tolerável , Melanoma/metabolismo , Melanoma/patologia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Polietilenoglicóis/farmacocinética , Prognóstico , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/secundário , Taxa de Sobrevida , Distribuição Tecidual , Neoplasias Uveais/metabolismo , Neoplasias Uveais/secundário
13.
J Immunol ; 186(2): 1218-27, 2011 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-21149605

RESUMO

Immunization of cancer patients with vaccines containing full-length tumor Ags aims to elicit specific Abs and both CD4(+) and CD8(+) T cells. Vaccination with protein Ags, however, often elicits only CD4(+) T cell responses without inducing Ag-specific CD8(+) T cells, as exogenous protein is primarily presented to CD4(+) T cells. Recent data revealed that Ab-mediated targeting of protein Ags to cell surface receptors on dendritic cells could enhance the induction of both CD4(+) and CD8(+) T cells. We investigated in this study if these observations were applicable to NY-ESO-1, a cancer-testis Ag widely used in clinical cancer vaccine trials. We generated two novel targeting proteins consisting of the full-length NY-ESO-1 fused to the C terminus of two human mAbs against the human mannose receptor and DEC-205, both internalizing molecules expressed on APC. These targeting proteins were evaluated for their ability to activate NY-ESO-1-specific human CD4(+) and CD8(+) T cells in vitro. Both targeted NY-ESO-1 proteins rapidly bound to their respective targets on APC. Whereas nontargeted and Ab-targeted NY-ESO-1 proteins similarly activated CD4(+) T cells, cross-presentation to CD8(+) T cells was only efficiently induced by targeted NY-ESO-1. In addition, both mannose receptor and DEC-205 targeting elicited specific CD4(+) and CD8(+) T cells from PBLs of cancer patients. Receptor-specific delivery of NY-ESO-1 to APC appears to be a promising vaccination strategy to efficiently generate integrated and broad Ag-specific immune responses against NY-ESO-1 in cancer patients.


Assuntos
Antígenos CD/metabolismo , Antígenos de Neoplasias/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Lectinas Tipo C/metabolismo , Lectinas de Ligação a Manose/metabolismo , Proteínas de Membrana/imunologia , Receptores de Superfície Celular/metabolismo , Sequência de Aminoácidos , Células Apresentadoras de Antígenos/imunologia , Células Apresentadoras de Antígenos/metabolismo , Antígenos CD/genética , Antígenos CD/imunologia , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/metabolismo , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Linhagem Celular , Células Clonais , Apresentação Cruzada/genética , Apresentação Cruzada/imunologia , Testes Imunológicos de Citotoxicidade , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Humanos , Lectinas Tipo C/genética , Lectinas Tipo C/imunologia , Receptor de Manose , Lectinas de Ligação a Manose/genética , Lectinas de Ligação a Manose/imunologia , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Antígenos de Histocompatibilidade Menor , Dados de Sequência Molecular , Ligação Proteica/imunologia , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/imunologia , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/imunologia , Proteínas Recombinantes de Fusão/metabolismo
14.
Nature ; 450(7171): 903-7, 2007 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-18026089

RESUMO

The capacity of immunity to control and shape cancer, that is, cancer immunoediting, is the result of three processes that function either independently or in sequence: elimination (cancer immunosurveillance, in which immunity functions as an extrinsic tumour suppressor in naive hosts); equilibrium (expansion of transformed cells is held in check by immunity); and escape (tumour cell variants with dampened immunogenicity or the capacity to attenuate immune responses grow into clinically apparent cancers). Extensive experimental support now exists for the elimination and escape processes because immunodeficient mice develop more carcinogen-induced and spontaneous cancers than wild-type mice, and tumour cells from immunodeficient mice are more immunogenic than those from immunocompetent mice. In contrast, the equilibrium process was inferred largely from clinical observations, including reports of transplantation of undetected (occult) cancer from organ donor into immunosuppressed recipients. Herein we use a mouse model of primary chemical carcinogenesis and demonstrate that equilibrium occurs, is mechanistically distinguishable from elimination and escape, and that neoplastic cells in equilibrium are transformed but proliferate poorly in vivo. We also show that tumour cells in equilibrium are unedited but become edited when they spontaneously escape immune control and grow into clinically apparent tumours. These results reveal that, in addition to destroying tumour cells and sculpting tumour immunogenicity, the immune system of a naive mouse can also restrain cancer growth for extended time periods.


Assuntos
Neoplasia Residual/imunologia , Sarcoma/imunologia , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/farmacologia , Proliferação de Células/efeitos dos fármacos , Proteínas de Ligação a DNA/deficiência , Proteínas de Ligação a DNA/genética , Progressão da Doença , Feminino , Genes RAG-1/genética , Imunidade Ativa/efeitos dos fármacos , Imunidade Ativa/imunologia , Imunocompetência/imunologia , Interferon gama/imunologia , Masculino , Metilcolantreno , Camundongos , Modelos Imunológicos , Neoplasia Residual/induzido quimicamente , Neoplasia Residual/patologia , Sarcoma/induzido quimicamente , Sarcoma/patologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia
15.
Proc Natl Acad Sci U S A ; 107(7): 3093-8, 2010 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-20133697

RESUMO

We have shown previously that cancer/testis (CT) antigen, CT45, is expressed in various epithelial cancers at a frequency of <5% to approximately 35%. In this study, the protein expression of CT45 was examined in non-Hodgkin B-cell lymphomas and classical Hodgkin lymphoma by immunohistochemical analysis. Serological response to CT45 was also evaluated by ELISA using CT45 recombinant protein and sera from patients with Hodgkin lymphoma. None of the 80 low-grade B-cell lymphomas, including chronic lymphocytic leukemia/small lymphocytic lymphoma, follicular lymphoma, and mantle cell lymphoma, expressed CT45. In comparison, CT45 was expressed in 28 of 126 (22%) diffuse large B-cell lymphomas (DLBCL). A remarkably high percentage (42/72, 58%) of classical Hodgkin lymphoma contained CT45-positive Reed-Sternberg cells. Nodular sclerosis and mixed-cellularity subtypes had similar frequency of CT45 expression, but most EBV-positive cases were CT45 negative. Gray-zone lymphoma (cases with features of both DLBCL and classical Hodgkin lymphoma) also showed frequent (64%) CT45 expression. Evaluation of reactive lymphoid tissues showed scattered CT45-positive lymphocytes in a single case of florid follicular hyperplasia, raising the possibility that this case was an evolving malignancy. Despite frequent CT45 expression, only 1 of 67 Hodgkin lymphoma patients had detectable anti-CT45 antibodies in the serum, suggesting that the immune response to CT45 may be suppressed. In conclusion, classical Hodgkin lymphoma has the highest frequency of CT45 expression among all malignancies tested to date, the frequency of CT45 expression in DLBCL is similar to that seen in epithelial cancers, and low-grade non-Hodgkin B-cell lymphomas do not express CT45.


Assuntos
Antígenos de Neoplasias/metabolismo , Doença de Hodgkin/metabolismo , Linfoma de Células B/metabolismo , Antígenos de Neoplasias/imunologia , Ensaio de Imunoadsorção Enzimática , Humanos , Imuno-Histoquímica , Imunofenotipagem , Hibridização In Situ , Células de Reed-Sternberg/metabolismo
16.
Proc Natl Acad Sci U S A ; 107(17): 7875-80, 2010 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-20385810

RESUMO

NY-ESO-1 is a "cancer-testis" antigen frequently expressed in epithelial ovarian cancer (EOC) and is among the most immunogenic tumor antigens defined to date. In an effort to understand in vivo tolerance mechanisms, we assessed the phenotype and function of NY-ESO-1-specific CD8(+) T cells derived from peripheral blood lymphocytes (PBLs), tumor-infiltrating lymphocytes (TILs), and tumor-associated lymphocytes (TALs) of EOC patients with NY-ESO-1-expressing tumors, with or without humoral immunity to NY-ESO-1. Whereas NY-ESO-1-specific CD8(+) T cells were readily detectable ex vivo with tetramers in TILs and TALs of seropositive patients, they were only detectable in PBLs following in vitro stimulation. Compared with PBLs, tumor-derived NY-ESO-1-specific CD8(+) T cells demonstrated impaired effector function, preferential usage of dominant T-cell receptor, and enriched coexpression of inhibitory molecules LAG-3 and PD-1. Expression of LAG-3 and PD-1 on CD8(+) T cells was up-regulated by IL-10, IL-6 (cytokines found in tumor ascites), and tumor-derived antigen-presenting cells. Functionally, CD8(+)LAG-3(+)PD-1(+) T cells were more impaired in IFN-gamma/TNF-alpha production compared with LAG-3(+)PD-1(-) or LAG-3(-)PD-1(-) subsets. Dual blockade of LAG-3 and PD-1 during T-cell priming efficiently augmented proliferation and cytokine production by NY-ESO-1-specific CD8(+) T cells, indicating that antitumor function of NY-ESO-1-specific CD8(+) T cells could potentially be improved by therapeutic targeting of these inhibitory receptors.


Assuntos
Antígenos CD/metabolismo , Antígenos de Neoplasias/metabolismo , Proteínas Reguladoras de Apoptose/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Regulação Neoplásica da Expressão Gênica/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Proteínas de Membrana/metabolismo , Neoplasias Ovarianas/imunologia , Anticorpos Monoclonais/farmacologia , Antígenos de Neoplasias/imunologia , Linfócitos T CD8-Positivos/imunologia , Citocinas/metabolismo , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Linfócitos do Interstício Tumoral/imunologia , Proteínas de Membrana/imunologia , Receptor de Morte Celular Programada 1 , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Proteína do Gene 3 de Ativação de Linfócitos
17.
Proc Natl Acad Sci U S A ; 107(11): 5088-93, 2010 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-20194765

RESUMO

Autoantibodies, a hallmark of both autoimmunity and cancer, represent an easily accessible surrogate for measuring adaptive immune responses to cancer. Sera can now be assayed for reactivity against thousands of proteins using microarrays, but there is no agreed-upon standard to analyze results. We developed a set of tailored quality control and normalization procedures based on ELISA validation to allow patient comparisons and determination of individual cutoffs for specificity and sensitivity. Sera from 60 patients with pancreatic cancer, 51 patients with ovarian cancer, and 53 age-matched healthy donors were used to assess the binding of IgG antibodies against a panel of >8000 human antigens using protein microarrays and fluorescence detection. The resulting data interpretation led to the definition and ranking of proteins with preferred recognition by the sera from cancer patients in comparison with healthy donors, both by frequency and strength of signal. We found that 202 proteins were preferentially immunogenic in ovarian cancer sera compared to 29 in pancreatic cancer, with few overlaps. Correlates of autoantibody signatures with known tumor expression of corresponding antigens, functional pathways, clinical stage, and outcome were examined. Serological analysis of arrays displaying the complete human proteome (seromics) represents a new era in cancer immunology, opening the way to defining the repertoire of the humoral immune response to cancer.


Assuntos
Neoplasias Ovarianas/sangue , Neoplasias Pancreáticas/sangue , Análise Serial de Proteínas/métodos , Proteoma/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Especificidade de Anticorpos , Autoanticorpos/imunologia , Biomarcadores Tumorais/imunologia , Doadores de Sangue , Estudos de Casos e Controles , Ensaio de Imunoadsorção Enzimática , Feminino , Genes Neoplásicos , Humanos , Pessoa de Meia-Idade , Proteínas de Neoplasias/sangue , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/imunologia , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/imunologia , Reprodutibilidade dos Testes
18.
Int J Cancer ; 131(5): E649-58, 2012 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-22109656

RESUMO

The spontaneous immune responses against XAGE-1b (GAGED2a) were analyzed in non-small cell lung cancer (NSCLC) patients. An antibody response against XAGE-1b (GAGED2a) was observed in 10% (20/200) of NSCLC patients and in 19% (13/69) of stage IIIB/IV lung adenocarcinoma patients. A CD4 T-cell response was detected in 88% (14/16) and a CD8 T-cell response in 67% (6/9) in the XAGE-1b (GAGED2a) antibody-positive patients examined. Frequent antibody responses and CD4 and CD8 T-cell responses in XAGE-1b (GAGED2a) antibody-positive patients indicate the strong immunogenicity of the XAGE-1b (GAGED2a) antigen in NSCLC patients. We established T-cell clones from PBMCs of antibody-positive patients and determined the DRB1*04:05-restricted XAGE-1b (GAGED2a) 18-31 peptide (14-mer) as a CD4 T cell epitope and the A*02:06-restricted XAGE-1b (GAGED2a) 21-29 peptide (9-mer) as a CD8 T cell epitope. As for peptide recognition, CD4 and CD8 T-cell clones responded to naturally processed antigen. The CD4 T-cell clone recognized DCs pulsed with the synthetic protein or a lysate from XAGE-1b-transfected 293T cells. The CD8 T-cell clone showed cytotoxicity against a tumor expressing XAGE-1b (GAGED2a) and the appropriate HLA class I allele. These findings establish XAGE-1b (GAGED2a) as a promising target for a lung cancer vaccine.


Assuntos
Anticorpos Antineoplásicos/sangue , Antígenos de Neoplasias/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Carcinoma Pulmonar de Células não Pequenas/imunologia , Neoplasias Pulmonares/imunologia , Adenocarcinoma/genética , Adenocarcinoma/imunologia , Adenocarcinoma/metabolismo , Anticorpos Antineoplásicos/imunologia , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/metabolismo , Apoptose , Western Blotting , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/patologia , Carcinoma de Células Grandes/genética , Carcinoma de Células Grandes/imunologia , Carcinoma de Células Grandes/metabolismo , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/imunologia , Carcinoma de Células Escamosas/metabolismo , Estudos de Casos e Controles , Proliferação de Células , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Células Dendríticas/patologia , Ensaio de Imunoadsorção Enzimática , Epitopos de Linfócito T/imunologia , Epitopos de Linfócito T/metabolismo , Humanos , Interferon gama/metabolismo , Pulmão/imunologia , Pulmão/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Estadiamento de Neoplasias , Fragmentos de Peptídeos/imunologia , Prognóstico , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Tumorais Cultivadas
19.
Int J Cancer ; 130(3): 584-92, 2012 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-21413013

RESUMO

NY-ESO-1 is a prototypic cancer/testis antigen. In a recent phase I clinical trial, we vaccinated 13 patients bearing NY-ESO-1-expressing tumors with a complex of cholesterol-bearing hydrophobized pullulan (CHP) and NY-ESO-1 protein (CHP-NY-ESO-1) and showed efficient induction of NY-ESO-1 antibody, and CD4 and CD8 T cell responses using peripheral blood from the patients. In our study, we analyzed heteroclitic serological responses in those patients after vaccination. Serological response against 11 tumor antigens including MAGE-A1, MAGE-A3, MAGE-A4, CT7/MAGEC1, CT10/MAGEC2, CT45, CT46/HORMAD1, SOX2, SSX2, XAGE1B and p53 was examined by enzyme-linked immunosorbent assay (ELISA) using sera from ten vaccinated patients. Expression of tumor antigens was determined by reverse transcription-polymerase chain reaction or immunohistochemistry. Eight of nine patients who showed antibody responses against NY-ESO-1 also showed an antibody response against at least 1 of these 11 tumor antigens after vaccination. In one patient, seven tumor antigens were recognized. Specificity analysis of the antibody response by ELISA using control recombinant proteins and synthetic peptides and by Western blot showed that the response was not against His6-tag and/or bacterial products included in a preparation of CHP-NY-ESO-1 used for vaccination. Thus, heteroclitic serological responses appear to be indicative of the overall immune response against the tumor, and their analysis could be useful for immune monitoring in cancer vaccine.


Assuntos
Anticorpos Antineoplásicos/sangue , Antígenos de Neoplasias/imunologia , Vacinas Anticâncer/imunologia , Neoplasias Esofágicas/imunologia , Proteínas de Membrana/imunologia , Neoplasias da Próstata/imunologia , Animais , Anticorpos Antineoplásicos/imunologia , Antígenos de Neoplasias/metabolismo , Linhagem Celular Tumoral , Neoplasias Esofágicas/sangue , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias da Próstata/sangue
20.
Cancer Immun ; 12: 15, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23390370

RESUMO

Cell surface proteins (CSPs) are excellent targets for the development of diagnostic and therapeutic reagents, and it is estimated that 10-20% of all genes in the human genome encode CSPs. In an effort to integrate all data publicly available for genes encoding cell surface proteins, a database (SurfaceomeDB) was developed. SurfaceomeDB is a gene-centered portal containing different types of information, including annotation for gene expression, protein domains, somatic mutations in cancer, and protein-protein interactions for all human genes encoding CSPs. SurfaceomeDB was implemented as an integrative and relational database in a user-friendly web interface, where users can search for gene name, gene annotation, or keywords. There is also a streamlined graphical representation of all data provided and links to the most important data repositories and databases, such as NCBI, UCSC Genome Browser, and EBI.


Assuntos
Bases de Dados Genéticas , Genoma Humano , Proteínas de Membrana/genética , Neoplasias/genética , Genômica/métodos , Humanos
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