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1.
Radiat Oncol ; 16(1): 237, 2021 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-34911546

RESUMO

BACKGROUND: Magnetic Resonance Image guided Stereotactic body radiotherapy (MRgRT) is an emerging technology that is increasingly used in treatment of visceral cancers, such as pancreatic adenocarcinoma (PDAC). Given the variable response rates and short progression times of PDAC, there is an unmet clinical need for a method to assess early RT response that may allow better prescription personalization. We hypothesize that quantitative image feature analysis (radiomics) of the longitudinal MR scans acquired before and during MRgRT may be used to extract information related to early treatment response. METHODS: Histogram and texture radiomic features (n = 73) were extracted from the Gross Tumor Volume (GTV) in 0.35T MRgRT scans of 26 locally advanced and borderline resectable PDAC patients treated with 50 Gy RT in 5 fractions. Feature ratios between first (F1) and last (F5) fraction scan were correlated with progression free survival (PFS). Feature stability was assessed through region of interest (ROI) perturbation. RESULTS: Linear normalization of image intensity to median kidney value showed improved reproducibility of feature quantification. Histogram skewness change during treatment showed significant association with PFS (p = 0.005, HR = 2.75), offering a potential predictive biomarker of RT response. Stability analyses revealed a wide distribution of feature sensitivities to ROI delineation and was able to identify features that were robust to variability in contouring. CONCLUSIONS: This study presents a proof-of-concept for the use of quantitative image analysis in MRgRT for treatment response prediction and providing an analysis pipeline that can be utilized in future MRgRT radiomic studies.


Assuntos
Adenocarcinoma/radioterapia , Imageamento por Ressonância Magnética/métodos , Neoplasias Pancreáticas/radioterapia , Radioterapia Guiada por Imagem/métodos , Adenocarcinoma/diagnóstico por imagem , Adenocarcinoma/mortalidade , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/mortalidade , Carga Tumoral
2.
J Autism Dev Disord ; 48(7): 2558-2566, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29429009

RESUMO

We compared the prevalence of self-injurious behaviors (SIB) in preschoolers aged 30-68 months with autism spectrum disorder (ASD) (n = 691) versus other developmental delays and disorders (DD) (n = 977) accounting for sociodemographic, cognitive, and medical factors. SIB prevalence was higher in ASD versus all DD [adjusted odds-ratio (aOR) 2.13 (95% confidence interval (95% CI) 1.53, 2.97)]. In subgroup analyses, SIB prevalence was higher in ASD versus DD without ASD symptoms [aOR 4.42 (95% CI 2.66, 7.33)], but was similar between ASD and DD with ASD symptoms [aOR 1.09 (95% CI 0.68, 1.77)]. We confirmed higher prevalence of SIB in ASD versus DD, independent of confounders. In children with DD, SIB prevalence increased with more ASD symptoms. These findings are informative to clinicians, researchers, and policymakers.


Assuntos
Transtorno do Espectro Autista/complicações , Deficiências do Desenvolvimento/complicações , Comportamento Autodestrutivo/epidemiologia , Pré-Escolar , Feminino , Humanos , Masculino , Prevalência
3.
J Autism Dev Disord ; 47(2): 285-296, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27830427

RESUMO

In this study, we explored potential associations among self-injurious behaviors (SIB) and a diverse group of protective and risk factors in children with autism spectrum disorder from two databases: Autism and Developmental Disabilities Monitoring (ADDM) Network and the Autism Speaks-Autism Treatment Network (AS-ATN). The presence of SIB was determined from children's records in ADDM and a parent questionnaire in AS-ATN. We used multiple imputation to account for missing data and a non-linear mixed model with site as a random effect to test for associations. Despite differences between the two databases, similar associations were found; SIB were associated with developmental, behavioral, and somatic factors. Implications of these findings are discussed in relation to possible etiology, future longitudinal studies, and clinical practice.


Assuntos
Transtorno do Espectro Autista/epidemiologia , Comportamento Autodestrutivo/epidemiologia , Criança , Comorbidade , Estudos Transversais , Bases de Dados Factuais , Feminino , Humanos , Masculino , Fatores de Proteção , Fatores de Risco , Estados Unidos/epidemiologia
4.
Ann Oncol ; 25(4): 848-851, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24608191

RESUMO

BACKGROUND: The purpose of the study was to determine whether breast cancers (BCs) that develop in women previously irradiated for Hodgkin lymphoma (HL) are biologically similar to sporadic BC. MATERIALS AND METHODS: We retrospectively reviewed the charts of patients who developed BC after radiotherapy (RT) for HL. Tumors were classified as ductal carcinoma in situ (DCIS) or invasive carcinoma. Invasive carcinomas were further characterized according to the subtype: hormone receptor (HR)+/human epidermal growth factor receptor 2 (HER2)-, HR+/HER2+, HR-/HER2+, and HR-/HER2-. BCs after HL were compared with four age-matched sporadic, non-breast cancer (BRCA) I or II mutated BCs. RESULTS: One hundred forty-seven HL patients who were treated with RT between 1966 and 1999 and subsequently developed BCs were identified. Of these, 65 patients with 71 BCs had complete pathologic information. The median age at HL diagnosis was 23 (range, 10-48). The median age at BC diagnosis was 44 (range, 28-66). The median time to developing BC was 20 years. Twenty cancers (28%) were DCIS and 51 (72%) were invasive. Of the 51 invasive cancers, 24 (47%) were HR+/HER2-, 2 (4%) were HR+/HER2+, 5 (10%) were HR-/HER2+, and 20 (39%) were HR-/HER2-. There were no differences in BC histologic subtype according to the age at which patients were exposed to RT, the use of chemotherapy for HL treatment, or the time from RT exposure to the development of BC. In a 4 : 1 age-matched comparison to sporadic BCs, BCs after HL were more likely to be HR-/HER2- (39% versus 14%) and less likely to be HR+/HER2- (47% versus 61%) or HR+/HER2+ (4% versus 14%) (P = 0.0003). CONCLUSION(S): BCs arising in previously irradiated breast tissue were more likely to be triple negative compared with age-matched sporadic invasive cancers and less likely to be HR positive. Further studies will be important to determine the molecular pathways of carcinogenesis in breast tissue that is exposed to RT.


Assuntos
Neoplasias da Mama/etiologia , Neoplasias da Mama/patologia , Doença de Hodgkin/radioterapia , Radioterapia/efeitos adversos , Adolescente , Adulto , Idoso , Neoplasias da Mama/classificação , Neoplasias da Mama/genética , Criança , Feminino , Doença de Hodgkin/complicações , Humanos , Pessoa de Meia-Idade , Receptor ErbB-2/genética
5.
Br J Cancer ; 109(9): 2412-23, 2013 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-24129241

RESUMO

BACKGROUND: Adoptive therapy with tumour-infiltrating lymphocytes (TILs) induces durable complete responses (CR) in ∼20% of patients with metastatic melanoma. The recruitment of T cells through CXCR3/CCR5 chemokine ligands is critical for immune-mediated rejection. We postulated that polymorphisms and/or expression of CXCR3/CCR5 in TILs and the expression of their ligands in tumour influence the migration of TILs to tumours and tumour regression. METHODS: Tumour-infiltrating lymphocytes from 142 metastatic melanoma patients enrolled in adoptive therapy trials were genotyped for CXCR3 rs2280964 and CCR5-Δ32 deletion, which encodes a protein not expressed on the cell surface. Expression of CXCR3/CCR5 in TILs and CXCR3/CCR5 and ligand genes in 113 available parental tumours was also assessed. Tumour-infiltrating lymphocyte data were validated by flow cytometry (N=50). RESULTS: The full gene expression/polymorphism model, which includes CXCR3 and CCR5 expression data, CCR5-Δ32 polymorphism data and their interaction, was significantly associated with both CR and overall response (OR; P=0.0009, and P=0.007, respectively). More in detail, the predicted underexpression of both CXCR3 and CCR5 according to gene expression and polymorphism data (protein prediction model, PPM) was associated with response to therapy (odds ratio=6.16 and 2.32, for CR and OR, respectively). Flow cytometric analysis confirmed the PPM. Coordinate upregulation of CXCL9, CXCL10, CXCL11, and CCL5 in pretreatment tumour biopsies was associated with OR. CONCLUSION: Coordinate overexpression of CXCL9, CXCL10, CXCL11, and CCL5 in pretreatment tumours was associated with responsiveness to treatment. Conversely, CCR5-Δ32 polymorphism and CXCR3/CCR5 underexpression influence downregulation of the corresponding receptors in TILs and were associated with likelihood and degree of response.


Assuntos
Interleucina-2/uso terapêutico , Melanoma/tratamento farmacológico , Melanoma/metabolismo , Receptores CCR5/metabolismo , Receptores CXCR3/metabolismo , Adolescente , Adulto , Idoso , Biópsia , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Feminino , Expressão Gênica , Genótipo , Humanos , Ligantes , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/patologia , Masculino , Melanoma/genética , Melanoma/patologia , Pessoa de Meia-Idade , Polimorfismo Genético , Receptores CCR5/genética , Receptores CXCR3/genética , Transdução de Sinais , Regulação para Cima , Adulto Jovem
6.
Ann Oncol ; 24(4): 1044-8, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23136225

RESUMO

INTRODUCTION: To assess the efficacy of an abbreviated Stanford V regimen in patients with early-stage Hodgkin lymphoma (HL). PATIENTS AND METHODS PATIENTS: with untreated nonbulky stage I-IIA supradiaphragmatic HL were eligible for the G4 study. Stanford V chemotherapy was administered for 8 weeks followed by radiation therapy (RT) 30 Gy to involved fields (IF). Freedom from progression (FFP), disease-specific survival (DSS) and overall survival (OS) were estimated. RESULTS: All 87 enrolled patients completed the abbreviated regimen. At a median follow-up of 10 years, FFP, DSS and OS are 94%, 99% and 94%, respectively. Therapy was well tolerated with no treatment-related deaths. CONCLUSIONS: Mature results of the abbreviated Stanford V regimen in nonbulky early-stage HL are excellent and comparable to the results from other contemporary therapies.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Doença de Hodgkin/tratamento farmacológico , Doença de Hodgkin/radioterapia , Adolescente , Adulto , Bleomicina/administração & dosagem , Terapia Combinada , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Etoposídeo/administração & dosagem , Feminino , Seguimentos , Doença de Hodgkin/patologia , Humanos , Masculino , Mecloretamina/administração & dosagem , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prednisona/administração & dosagem , Resultado do Tratamento , Vimblastina/administração & dosagem , Vincristina/administração & dosagem
7.
Gene Ther ; 20(5): 575-80, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-22972494

RESUMO

Transforming growth factor ß (TGF-ß) is a cytokine with complex biological functions that may involve tumor promotion or tumor suppression. It has been reported that multiple types of tumors secrete TGF-ß, which can inhibit tumor-specific cellular immunity and may represent a major obstacle to the success of tumor immunotherapy. In this study, we sought to enhance tumor immunotherapy using genetically modified antigen-specific T cells by interfering with TGF-ß signaling. We constructed three γ-retroviral vectors, one that expressed TGF-ß-dominant-negative receptor II (DNRII) or two that secreted soluble TGF-ß receptors: soluble TGF-ß receptor II (sRII) and the sRII fused with mouse IgG Fc domain (sRIIFc). We demonstrated that T cells genetically modified with these viral vectors were resistant to exogenous TGF-ß-induced smad-2 phosphorylation in vitro. The functionality of antigen-specific T cells engineered to resist TGF-ß signaling was further evaluated in vivo using the B16 melanoma tumor model. Antigen-specific CD8+ T cells (pmel-1) or CD4+ T cells (tyrosinase-related protein-1) expressing DNRII dramatically improved tumor treatment efficacy. There was no enhancement in the B16 tumor treatment using cells secreting soluble receptors. Our data support the potential application of the blockade of TGF-ß signaling in tumor-specific T cells for cancer immunotherapy.


Assuntos
Imunoterapia , Melanoma Experimental/terapia , Proteínas Serina-Treonina Quinases/genética , Receptores de Fatores de Crescimento Transformadores beta/genética , Linfócitos T/imunologia , Fator de Crescimento Transformador beta/genética , Animais , Células Apresentadoras de Antígenos/imunologia , Apoptose/imunologia , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular Tumoral , Engenharia Genética , Vetores Genéticos , Humanos , Fragmentos Fc das Imunoglobulinas/genética , Fragmentos Fc das Imunoglobulinas/imunologia , Imunoglobulina G/genética , Imunoglobulina G/imunologia , Melanoma Experimental/genética , Melanoma Experimental/imunologia , Camundongos , Proteínas Serina-Treonina Quinases/imunologia , Receptor do Fator de Crescimento Transformador beta Tipo II , Receptores de Fatores de Crescimento Transformadores beta/imunologia , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/imunologia , Retroviridae/genética , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Linfócitos T/citologia , Fator de Crescimento Transformador beta/antagonistas & inibidores , Fator de Crescimento Transformador beta/imunologia , Resultado do Tratamento
8.
Gene Ther ; 16(8): 1042-9, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19494842

RESUMO

Genetically engineered lymphocytes hold promise for the treatment of genetic disease, viral infections and cancer. However, current methods for genetic transduction of peripheral blood lymphocytes rely on viral vectors, which are hindered by production and safety-related problems. In this study, we demonstrated an efficient novel nonviral platform for gene transfer to lymphocytes. The Sleeping Beauty transposon-mediated approach allowed for long-term stable expression of transgenes at approximately 50% efficiency. Utilizing transposon constructs expressing tumor antigen-specific T-cell receptor genes targeting p53 and MART-1, we demonstrated sustained expression and functional reactivity of transposon-engineered lymphocytes on encountering target antigen presented on tumor cells. We found that transposon- and retroviral-modified lymphocytes had comparable transgene expression and phenotypic function. These results demonstrate the promise of nonviral ex vivo genetic modification of autologous lymphocytes for the treatment of cancer and immunologic disease.


Assuntos
Elementos de DNA Transponíveis , Técnicas de Transferência de Genes , Genes Codificadores dos Receptores de Linfócitos T , Linfócitos T/imunologia , Transposases/genética , Antígenos de Neoplasias , Humanos , Imunoterapia Adotiva/métodos , Transdução Genética
9.
Gene Ther ; 15(21): 1411-23, 2008 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-18496571

RESUMO

In human gene therapy applications, lentiviral vectors may have advantages over gamma-retroviral vectors in several areas, including the ability to transduce nondividing cells, resistance to gene silencing and a potentially safer integration site profile. However, unlike gamma-retroviral vectors it has been problematic to drive the expression of multiple genes efficiently and coordinately with approaches such as internal ribosome entry sites or dual promoters. Using different 2A peptides, lentiviral vectors expressing two-gene T-cell receptors directed against the melanoma differentiation antigens gp100 and MART-1 were constructed. We demonstrated that addition of amino-acid spacer sequences (GSG or SGSG) before the 2A sequence is a prerequisite for efficient synthesis of biologically active T-cell receptors and that addition of a furin cleavage site followed by a V5 peptide tag yielded optimal T-cell receptor gene expression. Furthermore, we determined that the furin cleavage site was recognized in lymphocytes and accounted for removal of residual 2A peptides at the post-translational level with an efficiency of 20-30%, which could not be increased by addition of multiple furin cleavage sites. The novel bicistronic lentiviral vector developed herein afforded robust anti-melanoma activities to engineered peripheral blood lymphocytes, including cytokine secretion, cell proliferation and lytic activity. Such optimal vectors may have immediate applications in cancer gene therapy.


Assuntos
Genes Codificadores dos Receptores de Linfócitos T , Terapia Genética/métodos , Vetores Genéticos/genética , Imunoterapia Adotiva/métodos , Lentivirus/genética , Antígenos de Neoplasias/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Linhagem Celular Tumoral , Furina/genética , Engenharia Genética , Humanos , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Antígeno MART-1 , Melanoma/imunologia , Melanoma/terapia , Glicoproteínas de Membrana/imunologia , Proteínas de Neoplasias/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/terapia , Transdução Genética/métodos , Antígeno gp100 de Melanoma
10.
Gene Ther ; 10(20): 1754-65, 2003 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-12939642

RESUMO

Recombinant expression vectors represent a powerful way to deliver whole antigens (Ags) for immunization. Sustained Ag expression in vector-infected dendritic cells (DC) combines Ag-specific stimulation with powerful costimulation and, simultaneously, through 'self-selection' of ad hoc epitopes broadens the scope of immunization beyond restrictions posed by individual patients' human leukocyte antigen (HLA) phenotype. In this study, therefore, we evaluated the efficiency of a recombinant vaccinia virus encoding the gp100/PMel17 melanoma Ag (rVV-gp100) to infect immature (iDC) or mature dendritic cells (mDC) derived from circulating mononuclear cells and the effect of infection on their status of maturation. In addition, we tested the ability of rVV-gp100-infected iDC and mDC to present the HLA-A*0201-associated gp100:209-217 epitope (g209). Irrespective of status of maturation, rVV-gp100 infection induced gp100 expression while only partially reversing the expression of some maturation markers. However, endogenous presentation of the wild-type g209 epitope was inefficient. The low efficiency was epitope-specific since infection of DC with rVV encoding a gp100 construct containing the modified gp100:209-217 (210M) (g209-2M) epitope characterized by high binding affinity for HLA-A*0201 restored efficient Ag presentation. Presentation of an HLA-class II-associated epitope and cytokine release by DC was not altered by rVV infection. Thus, Ag expression driven by rVV may be an efficient strategy for whole Ag delivery. However, since the effectiveness of Ag processing and presentation is subject to stringent HLA/epitope pairing, and for other yet undefined rules, the assumption that whole Ag delivery may circumvent HLA restriction is incorrect and recombinant expression vectors encoding well-characterized polyepitopic constructs may prove more effective.


Assuntos
Células Dendríticas/imunologia , Epitopos/imunologia , Terapia Genética/métodos , Vetores Genéticos/administração & dosagem , Antígenos HLA-A/imunologia , Vaccinia virus/genética , Apresentação de Antígeno , Linfócitos T CD4-Positivos/imunologia , Vacinas Anticâncer , Linhagem Celular , Células Clonais , Citometria de Fluxo , Antígeno HLA-A2 , Humanos , Interferon gama/imunologia , Melanoma/imunologia , Melanoma/terapia , Glicoproteínas de Membrana/genética , Proteínas de Neoplasias/genética , Peptídeos , Receptores de Antígenos de Linfócitos T/imunologia , Antígeno gp100 de Melanoma
11.
Cancer Res ; 61(22): 8100-4, 2001 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-11719435

RESUMO

To identify novel, tumor-specific target antigens for vaccine development, we studied immune responses to P.polypeptide, an M(r) 110,000 integral melanosomal membrane protein associated with the Prader-Willi syndrome. Together with expressed sequence tag (EST) and serial analyses of gene expression (SAGE) library analyses, reverse transcription-PCR and Northern blotting verified that P.polypeptide expression was limited to melanoma and melanocytes. A single dominant epitope corresponding to positions 427-435 (IMLCLIAAV) was identified using allele-specific epitope forecasting combined with work in HLA-A*0201/K(b) transgenic mice. This epitope was then used to generate de novo human P.polypeptide-specific CD8+ T cells capable of recognizing P.polypeptide expressing human tumor cell lines in an HLA-A*0201-restricted fashion. Thus, P.polypeptide may be valuable in the creation of novel therapeutic anticancer vaccines.


Assuntos
Antígenos de Neoplasias/imunologia , Vacinas Anticâncer/imunologia , Melanoma/imunologia , Melanossomas/imunologia , Peptídeos/imunologia , Animais , Apresentação de Antígeno , Antígenos de Neoplasias/biossíntese , Antígenos de Neoplasias/genética , Linfócitos T CD8-Positivos/imunologia , Epitopos/imunologia , Epitopos de Linfócito T/imunologia , Antígenos H-2/imunologia , Antígenos HLA-A/imunologia , Antígeno HLA-A2 , Humanos , Melanoma/genética , Melanoma/metabolismo , Melanossomas/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Peptídeos/genética , RNA Mensageiro/biossíntese , RNA Mensageiro/genética
12.
J Immunol ; 167(11): 6356-65, 2001 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-11714800

RESUMO

IL-2-dependent activated cells undergo apoptotic death when IL-2 is withdrawn either in vitro or after in vivo cell transfer. To attempt to sustain their survival after IL-2 withdrawal, melanoma-reactive human T lymphocytes were retrovirally transduced with an exogenous human IL-2 gene. Transduced PBMC and cloned CD8+ T cells produced IL-2 and maintained viability after IL-2 withdrawal. Upon restimulation, IL-2 transductants proliferated in the absence of exogenous IL-2 and could be actively grown, and their survival could be maintained without added IL-2 for over 8 wk. PBMCs similarly transduced with a control vector did not produce IL-2 and failed to proliferate in the absence of IL-2. A CD8+ T cell clone, when transduced with an IL-2 gene, manifested the same phenotypes as PBMCs in the absence of exogenous IL-2. Furthermore, an Ab reactive with the alpha-chain of IL-2R complex reduced the viability mediated by IL-2 secretion of the IL-2 transductants. Moreover, transduction of an IL-2 gene did not affect the high degree of recognition and specificity of transductants against melanoma targets. These tumor-reactive IL-2 transductants may be valuable for in vitro studies and for improved adoptive transfer therapies for patients with metastatic melanoma.


Assuntos
Imunoterapia Adotiva , Interleucina-2/genética , Interleucina-2/farmacologia , Melanoma/genética , Melanoma/imunologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/patologia , Transdução Genética , Comunicação Autócrina/genética , Comunicação Autócrina/imunologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/patologia , Vacinas Anticâncer/imunologia , Vacinas Anticâncer/farmacologia , Divisão Celular/genética , Divisão Celular/imunologia , Sobrevivência Celular/genética , Sobrevivência Celular/imunologia , Células Clonais/imunologia , Células Clonais/metabolismo , Células Clonais/patologia , Técnicas de Cocultura , Meios de Cultivo Condicionados/metabolismo , Meios de Cultivo Condicionados/farmacologia , Humanos , Imunoterapia Adotiva/métodos , Interleucina-2/metabolismo , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Ativação Linfocitária/genética , Melanoma/patologia , Melanoma/terapia , Glicoproteínas de Membrana/imunologia , Glicoproteínas de Membrana/farmacologia , Fragmentos de Peptídeos/imunologia , Fragmentos de Peptídeos/farmacologia , Transdução Genética/métodos , Células Tumorais Cultivadas , Antígeno gp100 de Melanoma
13.
J Immunother ; 24(4): 323-33, 2001.
Artigo em Inglês | MEDLINE | ID: mdl-11565834

RESUMO

An autologous melanoma cell line selected for loss of expression of the immunodominant MART-1 and gp100 antigens was initially used to carry out a mixed lymphocyte tumor culture (MLTC) in a patient who expressed the human leukocyte antigen (HLA)-AI and HLA-A2 class I major histocompatibility complex alleles. Ten clones identified from this MLTC seemed to recognize melanoma in an HLA-A1-restricted manner but failed to recognize a panel of previously described melanoma antigens. The screening of an autologous melanoma cDNA library with one HLA-Al-restricted melanoma-reactive T-cell clone resulted in the isolation of a cDNA clone called AIM-2 (antigen isolated from immunoselected melanoma-2). The AIM-2 transcript seemed to have retained an intronic sequence based on its alignment with genomic sequences as well as expressed sequence tags. This transcript was not readily detected after Northern blot analysis of melanoma mRNA, indicating that only low levels of this product may be expressed in tumor cells. Quantitative reverse transcriptase-polymerase chain reaction analysis, however, demonstrated a correlation between T-cell recognition and expression in HLA-A1-expressing tumor cell lines. A peptide that was encoded within a short open reading frame of 23 amino acids and conformed to the HLA-A1 binding motif RSDSGQQARY was found to represent the T-cell epitope. The AIM-2-reactive T-cell clone recognized a number of neuroectodermal tumors as well as breast, ovarian, and colon carcinomas that expressed HLA-A1, indicating that this represents a widely expressed tumor antigen. Thus, AIM-2 may represent a potential target for the development of vaccines in patients bearing tumors of a variety of histologies.


Assuntos
Antígenos de Neoplasias/imunologia , Linfócitos T CD8-Positivos/imunologia , Antígeno HLA-A1/imunologia , Interferon gama/isolamento & purificação , Melanoma/imunologia , Proteínas Nucleares/genética , Proteínas Nucleares/isolamento & purificação , Sequência de Aminoácidos , Sequência de Bases , Células Cultivadas , Proteínas de Ligação a DNA , Epitopos/imunologia , Expressão Gênica , Humanos , Teste de Cultura Mista de Linfócitos , Dados de Sequência Molecular , Células Tumorais Cultivadas
14.
J Immunother ; 24(4): 363-73, 2001.
Artigo em Inglês | MEDLINE | ID: mdl-11565838

RESUMO

This report describes a phase I study of the adoptive transfer of cloned melanoma antigen-specific T lymphocytes for therapy of patients with advanced melanoma. Clones were derived from peripheral blood lymphocytes or tumor-infiltrating lymphocytes of patients who had received prior immunization with the melanoma-associated antigen, gpl00. In response to its cognate antigen, each clone used for treatment secreted large amounts of interferon-gamma and granulocyte-macrophage colony-stimulating factor, lesser amounts of interleukin (IL)-2 and tumor necrosis factor-alpha, and little or no IL-4 and IL-10. Clones also demonstrated recognition of human leukocyte antigen-matched melanomas using cytokine secretion and lysis assays. Twelve patients received 2 cycles of cells alone; 11 patients received additional cycles of cells and were randomized between two schedules of IL-2 (125,000 IU/kg subcutaneously daily for 12 days versus 720,000 IU/kg intravenously every 8 h for 4 days). A total of 51 cycles of cells were administered, with an average of 1 x 10(10) cells per cycle. Peripheral blood samples were analyzed for persistence of transferred cells by T-cell receptor-specific polymerase chain reaction. Transferred cells reached a maximum level at 1 h after transfer but rapidly declined to undetectable levels by 2 weeks. One minor response and one mixed response were observed (both in the high-dose IL-2 arm). This report demonstrates the safety and feasibility of cloned T-cell transfer as a therapy for patients with cancer. The lack of clinical effectiveness of this protocol suggests that transfer of different or additional cell types or that modulation of the recipient host environment is required for successful therapy.


Assuntos
Imunoterapia Adotiva , Interleucina-2/farmacologia , Melanoma/terapia , Glicoproteínas de Membrana/imunologia , Fragmentos de Peptídeos/imunologia , Linfócitos T/imunologia , Adulto , Idoso , Células Clonais , Feminino , Humanos , Interferon gama/metabolismo , Masculino , Melanoma/imunologia , Melanoma/secundário , Pessoa de Meia-Idade , Antígeno gp100 de Melanoma
15.
J Clin Oncol ; 19(15): 3477-82, 2001 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-11481353

RESUMO

PURPOSE: The present study attempted to identify characteristics that correlated with clinical response to interleukin (IL)-2 therapy in patients with metastatic melanoma. PATIENTS AND METHODS: We retrospectively evaluated laboratory and clinical characteristics of 374 consecutive patients with metastatic melanoma treated with high-dose intravenous bolus IL-2 (720,000 IU/kg) from July 1, 1988, to December 31, 1999, at the Surgery Branch of the National Cancer Institute. RESULTS: The overall objective response rate was 15.5%. Pretreatment parameters such as patient demographics, laboratory values, and prior therapy did not correlate with response; however, 53.6% of patients with only subcutaneous and/or cutaneous metastases responded, compared with 12.4% of patients with disease at other sites (P2 =.000001). During therapy, patients who were responders tended to have received more doses during course 1 (16.2 +/- 0.3 doses v 14.5 +/- 0.2 doses; P2 =.0095); however, when limited to patients who were able to complete both cycles of course 1, there was no statistically significant difference (P2 =.27). Responders had a higher maximum lymphocyte count immediately after therapy compared with nonresponders (P2 =.0026). The development of abnormal thyroid function tests and vitiligo after therapy was associated with response (thyroid-stimulating hormone, P2 =.01; free T4, P2 =.0049; vitiligo, P2 < 10(-6)), although thyroid dysfunction may have been related more to the length of IL-2 therapy than to response. CONCLUSION: The presence of metastases only to subcutaneous and/or cutaneous sites, lymphocytosis immediately after treatment, and long-term immunologic side effects, especially vitiligo, were associated with antitumor response to IL-2 therapy.


Assuntos
Interleucina-2/uso terapêutico , Melanoma/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Relação Dose-Resposta a Droga , Feminino , Humanos , Injeções Intravenosas , Interleucina-2/efeitos adversos , Linfocitose/induzido quimicamente , Masculino , Melanoma/sangue , Melanoma/secundário , Pessoa de Meia-Idade , Proteínas Recombinantes/uso terapêutico , Estudos Retrospectivos , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/secundário , Tireotropina/sangue , Tiroxina/sangue , Resultado do Tratamento
16.
J Urol ; 166(1): 68-72, 2001 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-11435825

RESUMO

PURPOSE: Patients with metastatic renal cell carcinoma have a reported 5-year survival of 0% to 20%. The ability to predict which patients would benefit from nephrectomy and interleukin-2 (IL-2) therapy before any treatment is initiated would be useful for maximizing the advantage of therapy and improving the quality of life. MATERIALS AND METHODS: A retrospective analysis of the x-rays and charts of patients treated at the National Institutes of Health Surgery Branch between 1985 and 1996, who presented with metastatic renal cancer beyond the locoregional area and the primary tumor in place, was performed. Preoperative computerized tomography or magnetic resonance imaging, or radiological reports if no scans were available, were used to obtain an estimate of the volume of retroperitoneal lymphadenopathy. Operative notes were used to evaluate whether all lymphadenopathy was resected or disease left in situ, or if any extrarenal resection, including venacavotomy, was performed. Mean survival rate was calculated from the time of nephrectomy to the time of death or last clinical followup. If patients received IL-2 therapy, the response to treatment was recorded. Mean survival and response rate for IL-2 were compared among patients in 3 separate analyses. Patients without preoperatively detected lymphadenopathy were compared with those with at least 1 cm.3 retroperitoneal lymphadenopathy. Also, the patients who had detectable lymphadenopathy were divided into subgroups consisting of all resected, incompletely resected, unresectable and unknown if all disease was resected. Each subgroup was compared with patients without detectable preoperative lymphadenopathy. Patients with less than were compared to those with greater than 50 cm.3 retroperitoneal lymphadenopathy. Patients undergoing extrarenal resection at nephrectomy (complex surgery) due to direct invasion of the tumor into another intra-abdominal organ were compared with those undergoing radical nephrectomy alone, regardless of lymph node status. Statistical analysis was done with the Mantel-Cox test for comparison of survival on Kaplan-Meier curves and with Fisher's exact test for response rates for IL-2. RESULTS: A total of 154 patients with metastatic renal cell carcinoma underwent cytoreductive nephrectomy as preparation for IL-2 based regimens. There were 82 patients with metastatic renal cell carcinoma and no preoperative retroperitoneal lymphadenopathy who survived longer (median 14.7 months) than the 72 with lymphadenopathy (median 8.5, p = 0.0004). Patients with incompletely resected, unresectable or an unknown volume resected had decreased survival compared to those with no retroperitoneal lymphadenopathy. A multivariate analysis of survival was performed evaluating the known prognostic indicators, performance status and tumor burden, as represented by the number of organs involved with metastases, and the new prognostic factor, lymphadenopathy. Lymphadenopathy was more closely associated with survival than performance status, and appeared to be a new prognostic variable. Patients with and without retroperitoneal lymphadenopathy at initial presentation had similar rates for treatment with IL-2 (54% for both groups). Of the 82 patients with no lymphadenopathy 11 (13%) had long-term survival greater than 5 years. Of the 6 complete responses to IL-2, 5 occurred in this group. Only 1 other patient with incompletely resected retroperitoneal lymphadenopathy survived longer than 5 years. No significant difference in survival was seen between patients who did or did not undergo complex surgery. CONCLUSIONS: Patients who presented with metastatic renal cancer and retroperitoneal lymphadenopathy had a shorter survival than those with no detectable retroperitoneal lymphadenopathy. It is warranted to continue to perform complex extrarenal resection during nephrectomy since no significant difference in the response rate for IL-2 or mean survival compared with those of patients undergoing nephrectomy alone is currently detectable.


Assuntos
Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/secundário , Neoplasias Renais/mortalidade , Neoplasias Renais/terapia , Linfonodos/patologia , Adulto , Idoso , Carcinoma de Células Renais/terapia , Terapia Combinada , Feminino , Humanos , Interleucina-2/administração & dosagem , Neoplasias Renais/patologia , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estadiamento de Neoplasias , Nefrectomia/métodos , Valor Preditivo dos Testes , Prognóstico , Modelos de Riscos Proporcionais , Espaço Retroperitoneal , Estudos Retrospectivos , Taxa de Sobrevida
17.
J Immunol ; 167(3): 1809-20, 2001 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-11466407

RESUMO

The melanoma patient's immune response to tumor has been extensively studied. Yet, the frequently observed coexistence of tumor-associated Ag (TAA)-specific T cells with their target cells in vivo remains unexplained. Loss of TAA expression might contribute to this paradox. We studied TAA expression in metastases by obtaining fine-needle aspirations from 52 tumor lesions in 30 patients with melanoma before and soon after immunotherapy. Limitations due to low amounts of starting material were overcome with a high fidelity antisense RNA amplification method. TAA expression was measured by quantitative real-time PCR of anti-sense RNA. Decrease in gp100/Pmel-17 TAA preceded tumor disappearance in several instances and could be best explained by immune selection because most patients had received gp100/Pmel-17-specific vaccination. Conversely, immune selection was absent in nonregressing lesions. These observations suggest that vaccination, when successful, triggers a broad inflammatory reaction that can lead to tumor destruction despite immune selection. Additionally, lack of clinical response might be attributed to lack of this initiating event rather than immune escape. This study provides an insight into the natural history of tumors and defines a strategy for the characterization of gene expression in tumors during therapy.


Assuntos
Antígenos de Neoplasias/biossíntese , Vacinas Anticâncer/imunologia , Proteínas de Neoplasias/biossíntese , Adulto , Idoso , Antígenos de Neoplasias/genética , Vacinas Anticâncer/administração & dosagem , Feminino , Amplificação de Genes , Regulação Neoplásica da Expressão Gênica/imunologia , Humanos , Cinética , Antígeno MART-1 , Masculino , Melanoma/genética , Melanoma/imunologia , Melanoma/secundário , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Regressão Neoplásica Espontânea , RNA Antissenso/genética , Testículo/imunologia , Fatores de Tempo , Células Tumorais Cultivadas
18.
J Immunother ; 24(3): 212-20, 2001.
Artigo em Inglês | MEDLINE | ID: mdl-11394498

RESUMO

Tyrosinase has many advantages as a target antigen for the immunotherapy of patients with melanoma because it is expressed in nearly all melanoma specimens with a high degree of cellular homogeneity, and its distribution in normal tissues is limited to melanocytes. To broaden our ability to direct cellular immune responses against this protein, we pursued an investigation to identify new shared human leukocyte antigen (HLA)-A2.1 restricted epitopes from tyrosinase. Peptides were synthesized that fit a permissive HLA-A2.1 binding motif and did not span common sites of polymorphism. The binding affinity of each peptide to HLA-A2.1 relative to a standard peptide with intermediate binding affinity was evaluated in a competitive inhibition assay. Twelve peptides were selected that had binding affinities within 80% of that of the standard peptide, and these were used to stimulate peripheral blood mononuclear cells (PBMC) in vitro from three HLA-A2.1+ patients with metastatic melanoma. Cytotoxic T lymphocytes that specifically recognized peptide-pulsed target cells as well as HLA-A2.1+ tyrosinase+ melanoma cells were raised from one patient with tyrosinase:8-17 (CLLWSFQTSA). To evaluate further the immunogenicity of this peptide, PBMC from 23 HLA-A2.1+ patients were stimulated in vitro with tyrosinase:8-17. Eleven bulk T-cell cultures demonstrated specific peptide recognition, and six of these also recognized HLA-A2.1+ tyrosinase+ melanoma cells. These data suggest that tyrosinase:8-17 may be clinically useful for the treatment of patients with melanoma.


Assuntos
Antígenos de Neoplasias/imunologia , Antígeno HLA-A2/imunologia , Melanoma/enzimologia , Melanoma/imunologia , Monofenol Mono-Oxigenase/imunologia , Sequência de Aminoácidos , Animais , Antígenos de Neoplasias/genética , Células COS , Vacinas Anticâncer/genética , Vacinas Anticâncer/imunologia , Vacinas Anticâncer/uso terapêutico , Citocinas/biossíntese , Epitopos/genética , Epitopos/imunologia , Epitopos/uso terapêutico , Antígeno HLA-A2/genética , Humanos , Melanoma/genética , Melanoma/terapia , Monofenol Mono-Oxigenase/genética , Monofenol Mono-Oxigenase/uso terapêutico , Fragmentos de Peptídeos/genética , Fragmentos de Peptídeos/imunologia , Fragmentos de Peptídeos/uso terapêutico , Linfócitos T Citotóxicos/imunologia , Células Tumorais Cultivadas
19.
Nature ; 411(6835): 380-4, 2001 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-11357146

RESUMO

Studies of the administration of interleukin-2 to patients with metastatic melanoma or kidney cancer have shown that immunological manipulations can mediate the durable regression of metastatic cancer. The molecular identification of cancer antigens has opened new possibilities for the development of effective immunotherapies for patients with cancer. Clinical studies using immunization with peptides derived from cancer antigens have shown that high levels of lymphocytes with anti-tumour activity can be raised in cancer-bearing patients. Highly avid anti-tumour lymphocytes can be isolated from immunized patients and grown in vitro for use in cell-transfer therapies. Current studies are aimed at understanding the mechanisms that enable the cancer to escape from immune attack.


Assuntos
Imunoterapia , Neoplasias/imunologia , Neoplasias/terapia , Antígenos de Neoplasias/imunologia , Vacinas Anticâncer/imunologia , Humanos , Imunização , Interleucina-2/imunologia , Interleucina-2/uso terapêutico , Neoplasias/prevenção & controle , Neoplasias/virologia , Linfócitos T/imunologia
20.
J Immunol ; 166(9): 5817-25, 2001 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-11313426

RESUMO

Selection of T cell-directed immunization strategies is based extensively on discordant information derived from preclinical models. We characterized the kinetics of T cell selection in response to repeated antigenic challenge. By enumerating with epitope/HLA tetrameric complexes (tHLA) vaccine-elicited T cell precursor frequencies (Tc-pf) in melanoma patients exposed to the modified gp100 epitope gp100:209-217 (g209-2M) we observed in most patients that the Tc-pf increased with number of immunizations. One patient's kinetics were further characterized. Dissociation kinetics of g209-2M/tHLA suggested enrichment of T cell effector populations expressing TCR with progressively higher affinity. Furthermore, vaccine-elicited T cells maintained the ability to express IFN-gamma ex vivo and proliferate in vitro. Thus, repeated exposure to immunogenic peptides benefited immune competence. These results provide a rationale for immunization strategies.


Assuntos
Vacinas Anticâncer/administração & dosagem , Vacinas Anticâncer/imunologia , Epitopos de Linfócito T/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Linfócitos T/metabolismo , Células Clonais , Relação Dose-Resposta Imunológica , Regulação para Baixo/imunologia , Epitopos de Linfócito T/metabolismo , Antígenos HLA/análise , Humanos , Esquemas de Imunização , Cinética , Ligantes , Ativação Linfocitária , Contagem de Linfócitos , Melanoma/imunologia , Glicoproteínas de Membrana/administração & dosagem , Glicoproteínas de Membrana/imunologia , Proteínas de Neoplasias/administração & dosagem , Proteínas de Neoplasias/imunologia , Fragmentos de Peptídeos/administração & dosagem , Fragmentos de Peptídeos/imunologia , Peptídeos , Ligação Proteica/imunologia , Células-Tronco/imunologia , Células-Tronco/metabolismo , Células-Tronco/patologia , Linfócitos T/imunologia , Linfócitos T/patologia , Células Tumorais Cultivadas , Antígeno gp100 de Melanoma
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