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1.
Recent Results Cancer Res ; 214: 93-128, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31473850

RESUMO

As a specifically programmable, living immunotherapeutic drug, chimeric antigen receptor (CAR)-modified T cells are providing an alternative treatment option for a broad variety of diseases including so far refractory cancer. By recognizing a tumor-associated antigen, the CAR triggers an anti-tumor response of engineered patient's T cells achieving lasting remissions in the treatment of leukemia and lymphoma. During the last years, significant progress was made in optimizing the CAR design, in manufacturing CAR-engineered T cells, and in the clinical management of patients showing promise to establish adoptive CAR T cell therapy as an effective treatment option in the forefront.


Assuntos
Imunoterapia Adotiva , Neoplasias/terapia , Receptores de Antígenos Quiméricos , Antígenos de Neoplasias/imunologia , Ensaios Clínicos como Assunto , Humanos , Receptores de Antígenos de Linfócitos T , Linfócitos T/imunologia
2.
Recent Results Cancer Res ; 214: 153-167, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31473852

RESUMO

After more than a century of efforts to establish cancer immunotherapy in clinical practice, the advent of checkpoint inhibition (CPI) therapy was a critical breakthrough toward this direction (Hodi et al. in Cell Rep 13(2):412-424, 2010; Wolchok et al. in N Engl J Med 369(2):122-133, 2013; Herbst et al. in Nature 515(7528):563-567, 2014; Tumeh et al. in Nature 515(7528):568-571, 2014). Further, CPIs shifted the focus from long studied shared tumor-associated antigens to mutated ones. As cancer is caused by mutations in somatic cells, the concept to utilize these correlates of 'foreignness' to enable recognition and lysis of the cancer cell by T cell immunity seems an obvious thing to do.


Assuntos
Vacinas Anticâncer , Epitopos/imunologia , Imunoterapia , Neoplasias/terapia , Antígenos de Neoplasias/imunologia , Humanos
3.
Anticancer Res ; 39(11): 6259-6263, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31704855

RESUMO

BACKGROUND/AIM: Kita-Kyushu lung cancer antigen-1 (KK-LC-1) is a known cancer/testis antigen. Our group has previously shown KK-LC-1 gene expression in gastric cancer. However, could not be detected the KK-LC-1 protein due to the lack of an appropriate antibody. Here, we assessed our original monoclonal antibody (Kmab34B3) and, using it, assessed the expression of KK-LC-1 in gastric cancer. PATIENTS AND METHODS: We evaluated an original monoclonal antibody against KK-LC-1 (Kmab34B3), and used this antibody to compare KK-LC-1 protein expression in tumour and non-tumour stomach cells from gastric cancer patients. RESULTS: Kmab34B3 stained testicular germ cells, and tumour cells in nine out of 11 (82%) specimens. In non-tumorous areas, Kmab34B3 stained 13 out of 29 (45%) pyloric gland specimens. Furthermore, Kmab34B3 also stained intestinal metaplasia positive and negative areas. CONCLUSION: Kmab34B3 was able to detect KK-LC-1 protein within tumour cells and the pyloric gland where the gene has been shown to be expressed. Therefore, it might be an attractive tool for detecting KK-LC-1 expression in precancerous and cancerous stomach cells.


Assuntos
Anticorpos Monoclonais , Antígenos de Neoplasias/análise , Neoplasias Gástricas/imunologia , Estômago/imunologia , Antígenos de Neoplasias/genética , Expressão Gênica , Humanos , Metaplasia/imunologia , Lesões Pré-Cancerosas/imunologia , Piloro/imunologia
4.
Drugs Today (Barc) ; 55(9): 575-585, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31584574

RESUMO

Patients with metastatic triple-negative breast cancer (mTNBC) that has progressed on first-line therapy have a poor prognosis with limited therapeutic options. Sacituzumab govitecan (SG) is a novel antibody-drug conjugate (ADC) that has shown promising efficacy in mTNBC. SG is comprised of SN-38, the active metabolite of irinotecan, conjugated via a hydrolyzable linker to the humanized RS7 antibody targeting trophoblast cell surface antigen 2 (Trop-2), a glycoprotein that is expressed at high levels in many epithelial solid tumors. It has received breakthrough therapy status by the U.S. Food and Drug Administration (FDA) for the treatment of patients with pretreated mTNBC. In this review, we summarize available data regarding the pharmacology, pharmacokinetics, safety and efficacy of SG and describe ongoing and future clinical studies investigating this agent.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Camptotecina/análogos & derivados , Imunoconjugados/uso terapêutico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Antígenos de Neoplasias , Camptotecina/uso terapêutico , Moléculas de Adesão Celular , Feminino , Humanos , Estados Unidos , United States Food and Drug Administration
5.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 27(5): 1463-1468, 2019 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-31607299

RESUMO

OBJECTIVE: To investigate the transcriptional regulation of transcription factor MZF-1 on acute monocytic leukemia-related gene MLAA-34. METHODS: The effect of MZF-1 on the transcriptional activity of MLAA-34 gene promoter was analyzed by luciferase reporter gene detection system and site-directed mutation technique. The EMSA and ChIP assay were used to verify whether MZF-1 directly and specifically binds to the core region of MLAA-34 promoter. The over-expression vector and interference vector of MZF-1 were constructed to transfect U937 cells, and RT-PCR and Western blot were used to detect the transcription and expression changes of MLAA-34 gene. RESULTS: The transcription factor MZF-1 had a regulatory effect on MLAA-34 gene expression, and the relative luciferase activity was decreased after MZF-1 binding point mutation (P<0.01). EMSA and ChIP experiments demonstrated that MZF-1 could directly bind to MLAA-34 promoter and play a regulatory role. In the over-expression test, the increase of MZF-1 could up-regulate the expression of MLAA-34 (P<0.05). In the interference test, the decrease of MZF-1 could down-regulate the expression of MLAA-34 (P<0.05). CONCLUSION: Transcription factor MZF-1 can bind to the transcriptional regulatory region on the promoter of MLAA-34 gene and promote the transcription of MLAA-34 gene in acute monocytic leukemia.


Assuntos
Antígenos de Neoplasias/genética , Proteínas Reguladoras de Apoptose/genética , Fatores de Transcrição Kruppel-Like/metabolismo , Leucemia Monocítica Aguda , Regulação Neoplásica da Expressão Gênica , Genes Reporter , Fator 1-alfa Nuclear de Hepatócito , Humanos , Regiões Promotoras Genéticas , Transcrição Genética
6.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 50(3): 373-378, 2019 May.
Artigo em Chinês | MEDLINE | ID: mdl-31631606

RESUMO

Objective: To establish a radiomic model for predicting lymph node (LN) metastasis in patients with non-small cell lung cancer (NSCLC). Methods: The prediction model was developed using a training cohort comprising 100 patients with clinicopathologically confirmed NSCLC. Data were gathered from January 2014 to December 2015. Radiomic features of NSCLC were obtained from non-contrast and enhancement computed tomography (CT). Lasso-logistic regression models were established for data dimension reduction, feature selection, and radiomics signature building. Consistency coefficient ( ICCs) was used to evaluate the consistency between observer interior and interobserver.The consistency index (C-index)is used to evalutate the prediction of lymph node metastasis by using the radiomics signature, shown with the area under the receiver operating characteristic curve ( AUC).Multivariate logistic regression analyses were performed to develop the prediction model, considering radiomics signature and clinicopathologic risk factors. The radiomics model was validated in a validation cohort comprising 100 consecutive NSCLC patients from January 2016 to December 2017 in terms of its calibration and discrimination. AUC was used to evaluate the predictive effectiveness of the model, and Delong test was used to compare models. Hosmer-Lemeshow good of fit test was used to evaluate the calibration of prediction models.The results were represented by correction curves to compare the consistency between the predicted results of the model and the actual probability of LN metastasis. Results: The consistency between observer interior and interobserver was good, with ICCs higher than 0.75.The radiomics signature, including 22 selected features, was associated with LN metastasis. AUC was 0.781 in training cohort and 0.776 in validation cohort. The individualized prediction model identified radiomics signature, neuron specific enolase (CEA), cytokeratin 19 fragment antigen 21-1 (CYFRA21-1), and carbohydrate antigen 125 (CA125) as independent predictors. The model showed good discrimination, with 0.836 AUC in the training cohort, and 0.821 AUC in the validation cohort. The model in both the training and validation cohorts had good calibration,which demonstrated high consistency with the actual LN metastasis. Conclusion: The radiomics model incorporating radiomics signature and clinical risk factors can be conveniently used to facilitate preoperative individualized prediction of LN metastasis in patients with NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/patologia , Metástase Linfática/diagnóstico , Antígenos de Neoplasias/genética , Antígeno Ca-125/genética , Humanos , Queratina-19/genética , Modelos Logísticos , Linfonodos , Proteínas de Membrana/genética , Fosfopiruvato Hidratase/genética , Valor Preditivo dos Testes , Estudos Retrospectivos
7.
Gan To Kagaku Ryoho ; 46(10): 1467-1472, 2019 Oct.
Artigo em Japonês | MEDLINE | ID: mdl-31631122

RESUMO

Cancer antigens are classified into shared antigens and tumor-specific antigens based on their expression pattern or immunogenicity. Neo-antigens are defined as a subset of tumor-specific antigens generated by non-synonymous mutations, Indel gene mutation or gene fusions, presented by major histocompatibility complex molecules that were recognized by effector CD8+ T cells. Cancer cells with inherent genetic instability form abnormal proteins that have not been previously recognized by the immune system and these proteins become highly immunogenic antigens(neo-antigens)that can spontaneously trigger CD8+ T cell responses. Cancer cells that present extremely immunogenic neo-antigens are eliminated from the host through the process of carcinogenesis. Therefore, recognition of neo-antigens could be an important subject of the clinical utility of both neo-antigen cancer vaccine and adoptive TCR-T cell therapy as cancer immunotherapies. Furthermore, monitoring the quantity and quality of the neo-antigen derived in each patient could deduce the clinical response to immune checkpoint inhibitors such as anti-PD-1 therapy in various cancers. Here we review the evidence for the relevance of tumor neo-antigens and host immune response. We discuss the utility as a biomarker for cancer immunotherapy using the neoantigen expression in tumor tissues and the development of neo-antigen-targeted cancer vaccine and T cell mediated therapies.


Assuntos
Vacinas Anticâncer , Neoplasias , Antígenos de Neoplasias , Humanos , Imunoterapia , Mutação
8.
Anticancer Res ; 39(9): 5071-5076, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31519617

RESUMO

BACKGROUND/AIM: Approximately 20% of pleural effusions are associated with cancer; about 50% require invasive procedures to perform diagnosis. Determination of the concentration of soluble cytokeratin 19-fragments (CYFRA21-1) may help identify patients with malignant effusions. However, pathologies other than cancer can increase its concentration. The identification of these possible false positives with routine tests CRP, ADA, % polymorphonuclear cells (PN) may improve diagnostic accuracy. This study aimed to determine the diagnostic accuracy of CYFRA21-1 in the detection of malignant pleural effusions and the possible false positives. MATERIALS AND METHODS: Analysis of CYFRA21-1, adenosine deaminase (ADA), C-reactive protein (CRP), and the percentage of polymorphonuclear leukocytes (PN%) in the fluid from 643 consecutive undiagnosed pleural effusions was performed. RESULTS: CYFRA21-1 showed 38.7% sensitivity and 97.3% specificity at 175 ng/ml cut-off. Effusions not suspicious of a false-positive showed 39.0% sensitivity and 98.2% specificity, while effusions suspicious of false positive showed lower sensitivity (36.4%) and specificity (95.0%). CONCLUSION: The diagnostic accuracy of CYFRA21-1 in pleural effusions can be improved by classification according to the possibility of false positives.


Assuntos
Antígenos de Neoplasias/metabolismo , Biomarcadores Tumorais , Queratina-19/metabolismo , Derrame Pleural/diagnóstico , Derrame Pleural/metabolismo , Biópsia , Feminino , Humanos , Masculino , Derrame Pleural/etiologia , Curva ROC , Valores de Referência , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
9.
Anticancer Res ; 39(9): 5171-5177, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31519630

RESUMO

BACKGROUND/AIM: The aim of this study was to analyze the pretreatment cytokeratin serum levels in head and neck squamous cell carcinoma (HNSCC) by three assays in relation to selected clinicopathological characteristics in an effort to find diagnostic/prognostic biomarkers for HNSCC and determine the best assay. PATIENTS AND METHODS: In total, 46 patients with HNSCC with different subsite (oropharyngeal-21 cases, hypopharyngeal-4 and laryngeal-21) were included in this prospective study. MonoTotal, Cyfra 21-1, and TPS radioimmunoassay kits were used to analyze cytokeratin fragments serum levels. RESULTS: Statistically significant differences in serum levels of TPS and Cyfra 21-1 were found between low (stage I-II)- and high-stage (stage III-IV) tumors (p=0.0057; p=0.0138 respectively). Cyfra21-1 assay showed significant differences between tumors of different sites with prominent elevation being found in oropharyngeal carcinomas and between patients with p16 positive and p16 negative HNSCC (p=0.0242), being elevated in p16 positive tumors. CONCLUSION: The present study is the first to compare cytokeratin serum levels between various subgroups of HNSCC using three different assays. Cyfra 21-1 seems to be the most useful for clinical practice. The relation between elevated Cyfra 21-1 serum levels and p16 expression requires further investigation.


Assuntos
Antígenos de Neoplasias/sangue , Biomarcadores Tumorais , Queratina-19/sangue , Peptídeos/sangue , Carcinoma de Células Escamosas de Cabeça e Pescoço/sangue , Carcinoma de Células Escamosas de Cabeça e Pescoço/diagnóstico , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Prognóstico , Carcinoma de Células Escamosas de Cabeça e Pescoço/mortalidade , Carcinoma de Células Escamosas de Cabeça e Pescoço/terapia
10.
Nat Med ; 25(9): 1341-1355, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31501612

RESUMO

Chimeric antigen receptor (CAR) T cell therapy for B cell malignancies has surpassed expectations, driving an ever-expanding number of clinical trials and the first US Food and Drug Administration approvals of cell therapies for the treatment of cancer. This experience has illuminated some generalizable requirements for CAR T cell efficacy as well as the interplay between disease biology and clinical outcomes. Major CAR intrinsic variables affecting T cell behavior have been defined, and mechanisms of tumor resistance are increasingly understood. Here, we review the clinical experience with CAR T cells amassed to date, including but not limited to B cell malignancies, emphasizing factors associated with efficacy, resistance and major barriers to success. We also discuss how these insights are driving next-generation clinical trials, including those in solid tumors.


Assuntos
Antígenos de Neoplasias/uso terapêutico , Imunoterapia Adotiva/tendências , Neoplasias/terapia , Antígenos de Neoplasias/imunologia , Humanos , Neoplasias/imunologia , Linfócitos T/imunologia , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia , Estados Unidos , United States Food and Drug Administration
11.
Gan To Kagaku Ryoho ; 46(9): 1367-1371, 2019 Sep.
Artigo em Japonês | MEDLINE | ID: mdl-31530772

RESUMO

Recent advances in cancer immunotherapies, such as immune checkpoint inhibitors(ICIs), have shown some durable clinical responses in patients with various types of advanced cancers. The development of the next-generation sequencing technologies can result in a comprehensive characterization of the human cancer genomes. Personalized immunotherapy and precision cancer medicine might enable the next generation of rational cancer immunotherapy. Conventional cancer vaccines are designed to target tumor-associated antigens(TAAs), which are overexpressed in cancers. However, since TAAs are also expressed in normal tissues, cancer vaccine against TAAs can potentially initiate central and peripheral tolerance responses, which results in low vaccination efficiency. Cancer neoantigens derived from somatic mutations in tumor tissue represent highly immunogenic and can escape from central thymic tolerance. They are suggested to provide tumor specific targets for personalized cancer vaccines. Therefore, neoantigen-based cancer vaccine, which can induce tumor-specific cytotoxic T lymphocytes( CTLs), should be developed. The efficacy of current immunotherapies also remains limited due to the immunosuppressive tumor microenvironment, which leads to CTLs exhaustion or anergy and the escape of tumor cells from immune attack. The combination of neoantigen-based cancer vaccine and ICIs should be a potential therapeutic approach. In this paper, we provide a brief overview of the recent advances in the development of neoantigen-based cancer vaccines.


Assuntos
Vacinas Anticâncer , Neoplasias , Antígenos de Neoplasias , Humanos , Imunoterapia , Medicina de Precisão , Microambiente Tumoral
12.
Gan To Kagaku Ryoho ; 46(9): 1372-1376, 2019 Sep.
Artigo em Japonês | MEDLINE | ID: mdl-31530773

RESUMO

T cells are critical effector immune cells, and mutation-derived neoantigens are critical tumor-specific antigens in natural immune responses to cancer(cancer immunosurveillance). However, the underlying mechanisms are poorly understood, particularly in the human clinical setting, such as how many tumor antigens are related to cancer elimination and whether immunodominance of antigens exist in humans. Furthermore, it is unclear whether specific T cells recognizing neoantigens can control cancer for a long time in an equilibrium state. Cancer immunotherapy including immune checkpoint inhibitors (ICIs)such as PD-1 and CTLA-4 blockades has attracted much attention for cancer treatment, but they remain effective only in a minority of patients. However, the efficacy of ICIs, which is characterized by long term durable responses has suggested that host immunity, if re-activated, can eliminate cancer cells or maintain cancer for a long time(therapeutically induced cancer immune elimination or equilibrium). Recent reports show that the loss of neoantigens has occurred at the DNA and RNA level as results of both naturally and therapeutically induced tumor-specific immune responses, leading to tumor immune escape(re-escape). Here we focus on the role of neoantigens in naturally and therapeutically induced immunoediting revealed by cancer immunogenomics approaches utilizing clinical samples to develop effective neoantigen-based cancer immunotherapies.


Assuntos
Neoplasias , Antígenos de Neoplasias , Humanos , Imunoterapia , Mutação , Linfócitos T
13.
Gan To Kagaku Ryoho ; 46(9): 1377-1381, 2019 Sep.
Artigo em Japonês | MEDLINE | ID: mdl-31530774

RESUMO

Immune checkpoint blockades have brought about great benefits to cancer patient survival; however, the effect is yet limited and the overall objective rates are not satisfactory across cancer types. Understanding T cell discrimination against cancer and development of biomarkers are both indispensable for future application. In this brief review, we introduce proteogenomics HLA ligandome analysis, which combines conventional proteomics using mass spectrometry with genomic analysis data. The approach directly and comprehensively captures immunopeptidome of cancer cells, revealing an unprecedented number of antigens that can be targeted by T cells. Intriguingly, the repertoire comprises unique classes of peptides: neoantigens that arise from gene mutation, spliced peptides generated by the proteasomes, and non-coding region derived peptides. These findings demonstrate the diversity of T cell discrimination against cancer cells, and the accumulation of individual antigen data would contribute to development of precision medicine.


Assuntos
Neoplasias , Proteogenômica , Antígenos de Neoplasias , Humanos , Espectrometria de Massas , Medicina de Precisão
14.
Magy Onkol ; 63(3): 165-171, 2019 Sep 18.
Artigo em Húngaro | MEDLINE | ID: mdl-31533135

RESUMO

In the immune defense against cancer, cell-mediated adaptive immune response is considered of primary importance, in which T lymphocytes play a key role. Activation, expansion and function of antigen-specific T cells is a multistep process and its outcome depends on the balance of positive and negative regulatory mechanisms controlling each step. Many factors can hamper the development of an efficient antitumor immune response, such as insufficient expression of tumor antigens or of molecules necessary for their processing, inhibitory molecular interactions (e.g. immune checkpoints), immune suppressive factors or suppressor cells. Various therapeutic strategies have been developed in order to increase the efficiency of antitumor immune defense, of which the application of immune checkpoint inhibitors, antibodies blocking the brakes of immune response, is the most widespread. These immunomodulatory antibodies had more favorable effect than traditional treatment modalities on a widening spectrum of tumor types, still the majority of patients do not or only transiently respond. Therefore, great efforts are made to develop rational combinations of immune and other therapies, and to identify resistance mechanisms and biomarkers predicting therapy outcome.


Assuntos
Imunoterapia , Neoplasias/imunologia , Neoplasias/terapia , Linfócitos T/imunologia , Antígenos de Neoplasias/imunologia , Humanos , Fatores Imunológicos/imunologia
15.
Yi Chuan ; 41(8): 725-735, 2019 Aug 20.
Artigo em Chinês | MEDLINE | ID: mdl-31447423

RESUMO

Oropharyngeal cancer is one type of head and neck squamous cell carcinoma that is commonly associated with human papillomavirus (HPV) infection. Its incidence is increasing year by year. However, in the clinical treatment, it is found that the overall prognosis of HPV positive oropharyngeal cancer patients is better than that of HPV negative patients. But till now, the underlying mechanism that leads to this phenomenon has not been fully elucidated. This research analyzed the immune cell infiltration and function, as well as neoantigen loads between HPV positive and negative patients by bioinformatic analysis using the TCGA database, and found that the overall survival rate of HPV positive patients was significantly higher than those in the HPV negative group. Analysis of the relative abundance of immune cells in tumor tissues showed that CD8 + T cells in HPV positive patients were significantly increased compared to those in HPV negative patients, and the expression levels of effector molecules, like IFN-γ and Granzyme B, were significantly upregulated. Meanwhile, the analysis of tumor neoantigen load (TNB) showed that the TNB of HPV positive patients was lower than that of the HPV negative group. This study provides some basic theoretical support for the treating HPV-related oropharyngeal cancer.


Assuntos
Antígenos de Neoplasias/análise , Linfócitos T CD8-Positivos/citologia , Neoplasias Orofaríngeas/diagnóstico , Infecções por Papillomavirus/diagnóstico , Humanos , Neoplasias Orofaríngeas/virologia , Infecções por Papillomavirus/complicações , Prognóstico
16.
Drugs Today (Barc) ; 55(8): 513-528, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31461088

RESUMO

Despite incessant advancement in the therapeutic regimens against colorectal cancer (CRC), treatment failure, metastasis and serious side effects associated with the available therapeutic options demand specific targeted therapies that could help in improving the survival rate with significantly less toxicity, fewer untoward effects and improved efficacy. In-depth studies highlighted the potential of CRC to be immune-responsive, thereby opening a new door in the development of strategies to combat CRC. Immunotherapy has attracted a myriad of researchers with a hope that it could potentially increase the efficacy of the treatment regimens in parallel to the reduction of toxicity. Colorectal tumors undergo immune evasion, suppressing patients' immunity and making them susceptible to infections. Therefore, a viable option could be stimulating a patient's own immune system with the help of immune modulators to fight against CRC. This review briefly discusses the immune responsiveness of CRC as well as tumor-associated antigens in CRC, and highlights the current endeavors of the scientific community in the field of immune modulators against CRC that are under development including varied types of vaccines, checkpoint inhibitors and adoptive T-cell therapy.


Assuntos
Neoplasias Colorretais/terapia , Imunoterapia/tendências , Antígenos de Neoplasias , Humanos , Imunoterapia Adotiva
17.
Cancer Immunol Immunother ; 68(9): 1401-1415, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31414180

RESUMO

Although CAR T-cell therapy has demonstrated tremendous clinical efficacy especially in hematological malignancies, severe treatment-associated toxicities still compromise the widespread application of this innovative technology. Therefore, developing novel approaches to abrogate CAR T-cell-mediated side effects is of great relevance. Several promising strategies pursue the selective antibody-based depletion of adoptively transferred T cells via elimination markers. However, given the limited half-life and tissue penetration, dependence on the patients' immune system and on-target/off-side effects of proposed monoclonal antibodies, we sought to exploit αCAR-engineered T cells to efficiently eliminate CAR T cells. For comprehensive and specific recognition, a small peptide epitope (E-tag) was incorporated into the extracellular spacer region of CAR constructs. We provide first proof-of-concept for targeting this epitope by αE-tag CAR T cells, allowing an effective killing of autologous E-tagged CAR T cells both in vitro and in vivo whilst sparing cells lacking the E-tag. In addition to CAR T-cell cytotoxicity, the αE-tag-specific T cells can be empowered with cancer-fighting ability in case of relapse, hence, have versatile utility. Our proposed methodology can most probably be implemented in CAR T-cell therapies regardless of the targeted tumor antigen aiding in improving overall safety and survival control of highly potent gene-modified cells.


Assuntos
Epitopos de Linfócito T/genética , Imunoterapia Adotiva/métodos , Fragmentos de Peptídeos/genética , Neoplasias da Próstata/terapia , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos Quiméricos/genética , Linfócitos T Citotóxicos/imunologia , Animais , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/imunologia , Autoantígenos/imunologia , Citotoxicidade Imunológica , Epitopos de Linfócito T/imunologia , Engenharia Genética , Humanos , Masculino , Camundongos , Recidiva Local de Neoplasia , Células PC-3 , Neoplasias da Próstata/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Medicine (Baltimore) ; 98(32): e16764, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31393394

RESUMO

Numerous studies have shown that the blood of cancer patients are generally in hypercoagulable statement. The aim of the present research is to study the relationships of plasma fibrinogen (Fbg) levels with clinicopathological stages (CS) and tumor markers of non-small cell lung cancer (NSCLC).Baseline information, plasma Fbg levels, CS, and expression level of tumor markers were collected from medical records retrospectively. Unitary linear regression was used to analyze the relationships between continuous variables and Fbg, and multiple linear regression was used to analyze the relationships between categorical variables and Fbg. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (Version 4) for NSCLC were adopted to evaluate CS.A total of 652 NSCLC patients were included. Compared with the females, male patients had higher mean plasma Fbg levels (P < .001). The later the N stages (P = .002), M stages (P = .002), and CS (P = .001) were, the higher the average plasma Fbg levels were. The levels of squamous cell carcinoma antigen (P = .001), carbohydrate antigen 125 (P = .041), and neuron-specific enolase (P < .001) were positively correlated with plasma Fbg concentration. The plasma level of Fbg in lung adenocarcinoma patients (P < .001) was the lowest, while that of lung squamous cell carcinoma patients (P < .001) was the highest in NSCLC patients.The plasma Fbg concentration is related to gender, CS, and tumor markers in patients with NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/patologia , Fibrinogênio/análise , Neoplasias Pulmonares/patologia , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Antígenos de Neoplasias/sangue , Biomarcadores Tumorais , Antígeno Ca-125/análise , Carcinoma Pulmonar de Células não Pequenas/sangue , Feminino , Humanos , Neoplasias Pulmonares/sangue , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Fosfopiruvato Hidratase/sangue , Estudos Retrospectivos , Serpinas/sangue , Fatores Sexuais
20.
Medicine (Baltimore) ; 98(35): e16924, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31464928

RESUMO

Autoimmune hepatitis (AIH) is a disorder of unknown etiology in which immune-mediated liver damage progresses to cirrhosis or hepatocellular carcinoma (HCC). The mainstay therapy for AIH is steroids and other immunosuppressive treatments. Currently, there are no validated markers for monitoring immune-mediated hepatic inflammation. Galectin-9 has recently been identified as a potential biomarker in patients with chronic liver disease. The objective of this study was to determine whether Galectin-9 and other serum proteins are associated with active disease in AIH patients.We enrolled 77 Japanese patients with well-documented AIH who were identified from the National Hospital Organization-AIH-liver-network database, as well as 32 patients with chronic hepatitis C (CHC), 27 patients with SLE, and 17 healthy control subjects. Serum levels of galectin-9, and markers of liver injury were measured and compared between groups.Serum levels of galectin-9 were significantly higher in AIH patients than in CHC patients (13.8 ±â€Š4.9 ng/mL vs 8.9 ±â€Š3.0 ng/mL, P < .001) or healthy controls (13.8 ±â€Š4.9 ng/mL vs 5.0 ±â€Š1.3 ng/mL, P < .001). In AIH group, serum galectin-9 levels weakly correlated with alanine aminotransferase levels or total bilirubin (TB) and strongly correlated with C-X-C motif chemokine 10 (CXCL10) and Mac-2 binding protein glycosylation isomer (M2BPGi) levels, but did not correlate with the histological grade of liver fibrosis. Steroid treatment of AIH patients significantly reduced serum galectin-9 levels (14.1 ±â€Š4.9 ng/mL vs 8.3 ±â€Š3.8 ng/mL, P < .001). SLE patients exhibited higher galectin-9 levels, whereas the galectin-9 levels did not correlate with liver function tests such as alanine aminotransferase levels.Serum galectin-9 correlated with disease status in AIH patients and could thus be useful biomarkers to detect hepatic autoimmunity. Because circulating galectin-9 reflects autoimmune-mediated inflammation, it may have additional utility as a biomarker for other autoimmune disorders.


Assuntos
Antígenos de Neoplasias/sangue , Biomarcadores Tumorais/sangue , Biomarcadores/sangue , Proteínas de Transporte/sangue , Galectinas/sangue , Glicoproteínas/sangue , Hepatite Autoimune/metabolismo , Adulto , Estudos de Casos e Controles , Feminino , Hepatite C Crônica/sangue , Hepatite C Crônica/metabolismo , Hepatite Autoimune/sangue , Humanos , Japão , Masculino , Glicoproteínas de Membrana/sangue , Pessoa de Meia-Idade , Esteroides/administração & dosagem , Esteroides/farmacologia , Regulação para Cima/efeitos dos fármacos , Adulto Jovem
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