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1.
Rinsho Ketsueki ; 60(9): 1221-1228, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31597847

RESUMO

Gene and protein expression profiling has clarified that tumor cells in angioimmunoblastic T-cell lymphoma (AITL) have T follicular helper (TFH) cell characteristics. In AITL, typical genomic abnormalities have been reported that combine G17V RHOA mutations, gene mutations involved in epigenetic pathways, and those involved in T-cell receptor signal pathways. Besides AITL, some lymphomas display a TFH phenotype, prompting the proposal of a new disease classification encompassing those. Interestingly, lymphomas with TFH phenotype characteristics also share most genomic abnormalities with AITL. Furthermore, because AITL genomic abnormalities are highly disease specific, they can be used for diagnosis. Although AITL is a refractory disease, several new drugs have been approved for relapsed and refractory cases. Precision medicine targeting genomic aberrations characteristic of AITL is being investigated.


Assuntos
Linfadenopatia Imunoblástica/diagnóstico , Linfadenopatia Imunoblástica/terapia , Linfoma de Células T/diagnóstico , Linfoma de Células T/terapia , Humanos , Mutação , Fenótipo , Receptores de Antígenos de Linfócitos T/genética , Transdução de Sinais , Linfócitos T Auxiliares-Indutores , Proteína rhoA de Ligação ao GTP/genética
2.
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
3.
Mol Biol (Mosk) ; 53(3): 456-466, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31184611

RESUMO

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative therapy for hematopoietic malignancies. The graft-derived donor lymphocytes are capable of eliminating the residual recipient malignant cells in the course of allogeneic immune response, thus decreasing the chances of a relapse of the disease. Foreign peptides of the recipient presented by the MHC molecules are able to elicit the immune response immunologically. These polymorphic peptides are known as minor histocompatibility antigens (MiHAs). MiHAs occur due to the nonsynonymous single nucleotide polymorphisms in human genome. Transfusion of T cells specific to MiHAs presented predominantly in the cells of hematopoietic origin will allow the targeted elimination of residual malignant clones avoiding undesirable damage to healthy tissues. To induce the immune response, the donor must be homozygous by the MiHA allele and the recipient must either be homozygous or heterozygous by the alternative MiHA allele. The therapeutic mismatch occurs in 25% of cases under the optimal frequency of allelic variants. Minor antigen ACC-1Y originates from polymorphism in the BCL-2A1 gene; its immunogenic mismatch occurrence approaches the theoretical maximum. In addition, BCL2A1 is overexpressed in cells of various lymphomas. ACC-1Y is presented on allele HLA-A*24:02, which is relatively frequent in the Russian population. Combination of these factors makes the minor antigen ACC-1Y a promising target for immunotherapy. Transfusion of donor CD8^(+) lymphocytes modified with transgenic MiHA-specific TCR is one of the promising methods of posttransplant leukemia therapy and relapse prophylaxis. We obtained a sequence of high-affinity ACC-1Y-specific TCR after the antigen-specific expansion of T cells derived from a healthy ACC-IY^(-/-) donor. We cloned this sequence into the lentiviral vector and obtained the assembled viral particles. Further, we transduced the CD8^(+) lymphocyte culture and demonstrated its antigen-specific cytotoxic activity. It is suggested that CD8^(+) lymphocytes modified by the described method could be potentially transferred to recipients as a therapy against relapse after allo-HSCT.


Assuntos
Engenharia Celular , Transplante de Células-Tronco Hematopoéticas , Antígenos de Histocompatibilidade Menor/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/metabolismo , Aloenxertos , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/imunologia , Neoplasias Hematológicas/terapia , Humanos , Antígenos de Histocompatibilidade Menor/genética , Receptores de Antígenos de Linfócitos T/genética , Federação Russa , Prevenção Secundária/métodos
4.
Hematol Oncol ; 37 Suppl 1: 95-100, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31187533

RESUMO

Chimeric antigen receptor (CAR) T-cell therapy has dramatically shifted the landscape of treatment for lymphoid malignancies, especially diffuse large B-cell lymphoma (DLBCL) and acute lymphoblastic leukemia (ALL). However, there continue to be significant limitations of this therapy, such as incomplete or nonsustained responses and severe toxicities in a subset of patients. Furthermore, expanding the role of CAR T-cell therapy to new disease types is an important next step. In this review, we will highlight landmark trials for anti-CD19 CAR T cells and first-in-human trials of novel CARs, as well as discuss promising innovative CAR designs that are still undergoing preclinical development. Lastly, we will discuss toxicity and mechanisms of CAR T-cell resistance and failure, as well as potential future treatment approaches to these common issues.


Assuntos
Imunoterapia Adotiva , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores de Antígenos Quiméricos/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Animais , Antígenos CD19 , Antígenos de Neoplasias/imunologia , Ensaios Clínicos como Assunto , Engenharia Genética , Humanos , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/métodos , Neoplasias/diagnóstico , Neoplasias/imunologia , Neoplasias/terapia , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos Quiméricos/genética , Pesquisa , Resultado do Tratamento
5.
Hematol Oncol ; 37 Suppl 1: 48-52, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31187535

RESUMO

Chimeric antigen receptor (CAR) T-cell therapy has the potential to revolutionize the management of B-cell lymphomas and possibly other cancers. Two anti-CD19 CAR T-cell products, axicabtagene ciloleucel and tisagenlecleucel, have been approved for the management of relapsed/refractory large B-cell lymphoma after two lines of systemic therapy. Additional trials are ongoing to evaluate these and other CAR T products at earlier stages of the disease course as well as in other lymphomas. While the potential to induce durable remissions with a single CAR T-cell infusion even in patients who are chemorefractory has generated much enthusiasm in the field, practitioners need to familiarize themselves with the unique toxicities associated with these therapies. This review will discuss the grading and management of the two most common toxicities, cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), observed acutely after this therapy. In addition, late toxicities including prolonged cytopenias and on-target off-tumor effects will be reviewed.


Assuntos
Imunoterapia Adotiva/efeitos adversos , Neoplasias/imunologia , Neoplasias/terapia , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores de Antígenos Quiméricos/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Animais , Antígenos CD19/imunologia , Antígenos de Neoplasias/imunologia , Biomarcadores , Ensaios Clínicos como Assunto , Citocinas/metabolismo , Gerenciamento Clínico , Humanos , Imunoterapia Adotiva/métodos , Linfoma/imunologia , Linfoma/patologia , Linfoma/terapia , Neoplasias/mortalidade , Neoplasias/patologia , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos Quiméricos/genética , Resultado do Tratamento
6.
Immunogenetics ; 71(7): 465-478, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31123763

RESUMO

Invariant NKT (iNKT) cells in both humans and non-human primates are activated by the glycolipid antigen, α-galactosylceramide (α-GalCer). However, the extent to which the molecular mechanisms of antigen recognition and in vivo phenotypes of iNKT cells are conserved among primate species has not been determined. Using an evolutionary genetic approach, we found a lack of diversifying selection in CD1 genes over 45 million years of evolution, which stands in stark contrast to the history of the MHC system for presenting peptide antigens to T cells. The invariant T cell receptor (TCR)-α chain was strictly conserved across all seven primate clades. Invariant NKT cells from rhesus macaques (Macaca mulatta) bind human CD1D-α-GalCer tetramer and are activated by α-GalCer-loaded human CD1D transfectants. The dominant TCR-ß chain cloned from a rhesus-derived iNKT cell line is nearly identical to that found in the human iNKT TCR, and transduction of the rhesus iNKT TCR into human Jurkat cells show that it is sufficient for binding human CD1D-α-GalCer tetramer. Finally, we used a 20-color flow cytometry panel to probe tissue phenotypes of iNKT cells in a cohort of rhesus macaques. We discovered several tissue-resident iNKT populations that have not been previously described in non-human primates but are known in humans, such as TCR-γδ iNKTs. These data reveal a diversity of iNKT cell phenotypes despite convergent evolution of the genes required for lipid antigen presentation and recognition in humans and non-human primates.


Assuntos
Antígenos CD1/genética , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Primatas/genética , Sequência de Aminoácidos , Animais , Antígenos CD1/metabolismo , Sequência Conservada , Evolução Molecular , Feminino , Humanos , Células Jurkat , Macaca mulatta/imunologia , Masculino , Fenótipo , Primatas/imunologia , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/metabolismo
7.
Nat Commun ; 10(1): 2087, 2019 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-31064990

RESUMO

T cells expressing CD19-targeting chimeric antigen receptors (CARs) reveal high efficacy in the treatment of B cell malignancies. Here, we report that T cell receptor fusion constructs (TRuCs) comprising an antibody-based binding domain fused to T cell receptor (TCR) subunits can effectively reprogram an intact TCR complex to recognize tumor surface antigens. Unlike CARs, TRuCs become a functional component of the TCR complex. TRuC-T cells kill tumor cells as potently as second-generation CAR-T cells, but at significant lower cytokine release and despite the absence of an extra co-stimulatory domain. TRuC-T cells demonstrate potent anti-tumor activity in both liquid and solid tumor xenograft models. In several models, TRuC-T cells are more efficacious than respective CAR-T cells. TRuC-T cells are shown to engage the signaling capacity of the entire TCR complex in an HLA-independent manner.


Assuntos
Imunoterapia Adotiva/métodos , Neoplasias/terapia , Receptores de Antígenos de Linfócitos T/imunologia , Receptores Artificiais/imunologia , Anticorpos de Cadeia Única/imunologia , Linfócitos T/imunologia , Animais , Antígenos CD19/imunologia , Antígenos de Neoplasias/imunologia , Linhagem Celular Tumoral , Feminino , Humanos , Camundongos , Camundongos Endogâmicos NOD , Neoplasias/imunologia , Cultura Primária de Células , Domínios Proteicos , Receptores de Antígenos de Linfócitos T/genética , Receptores Artificiais/genética , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/imunologia , Anticorpos de Cadeia Única/genética , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Iran J Allergy Asthma Immunol ; 18(2): 143-152, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-31066250

RESUMO

Assessment of the number of T-cell receptor excision circles (TREC) and kappa-deleting recombination excision circles (KREC) copies has been recently described as biomarkers of newly formed T and B cells respectively. In this study, we aimed to explore the effects of demographic variables including age, gender, weight, height and ethnicity on these two episomal DNA molecules. Second, for the first time in our country, we determined the reference values of TREC and KREC copy numbers in different age groups of Iranian healthy individuals as a threshold for identifying T cell and B cell lymphopenia. The TREC and KREC copy numbers were evaluated in 251 dried blood spot (DBS) samples from healthy volunteers (age range: 0-60 years). Six primary immunodeficiency (PID) patients were included as disease controls. TREC and KREC copies were markedly reduced with increasing age. Although the levels of TREC and KREC were higher in females than males, this difference did not reach statistical significance. These findings suggest that demographic variables including age should be considered for interpretation results of the TREC/KREC assay.


Assuntos
Fatores Etários , Linfócitos B/fisiologia , Linfopenia/diagnóstico , Receptores de Antígenos de Linfócitos B/genética , Receptores de Antígenos de Linfócitos T/genética , Linfócitos T/fisiologia , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Dosagem de Genes , Humanos , Lactente , Recém-Nascido , Irã (Geográfico) , Linfopenia/imunologia , Masculino , Pessoa de Meia-Idade , Padrões de Referência , Adulto Jovem
9.
Ann Lab Med ; 39(5): 438-446, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31037862

RESUMO

BACKGROUND: Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired pluripotent hematopoietic stem cell disorder associated with an increase in the number of glycosyl-phosphatidyl inositol (GPI)-deficient blood cells. We investigated PNH clonal proliferation in the three cell lineages-granulocytes, T lymphocytes, and red blood cells (RBCs)-by analyzing PIGA gene mutations and T-cell receptor (TCR) clonality. METHODS: Flow cytometry was used on peripheral blood samples from 24 PNH patients to measure the GPI-anchored protein (GPI-AP) deficient fraction in each blood cell lineage. PIGA gene mutations were analyzed in granulocytes and T lymphocytes by Sanger sequencing. A TCR clonality assay was performed in isolated GPI-AP deficient T lymphocytes. RESULTS: The GPI-AP deficient fraction among the three lineages was the highest in granulocytes, followed by RBCs and T lymphocytes. PIGA mutations were detected in both granulocytes and T lymphocytes of 19 patients (79.2%), with a higher mutation burden in granulocytes. The GPI-AP deficient fractions of granulocytes and T lymphocytes correlated moderately (rs=0.519, P=0.049) and strongly (rs=0.696, P=0.006) with PIGA mutation burden, respectively. PIGA mutations were more frequently observed in patients with clonal rearrangements in TCR genes (P=0.015). The PIGA mutation burden of T lymphocytes was higher in patients with clonal TCRB rearrangement. CONCLUSIONS: PIGA mutations were present in approximately 80% of PNH patients. PNH clone size varies according to blood cell lineage, and clonal cells may obtain proliferation potential or gain a survival advantage over normal cells.


Assuntos
Proliferação de Células , Granulócitos/citologia , Hemoglobinúria Paroxística/diagnóstico , Proteínas de Membrana/genética , Linfócitos T/citologia , Adolescente , Adulto , Idoso , Linhagem da Célula , Criança , Feminino , Proteínas Ligadas por GPI/deficiência , Proteínas Ligadas por GPI/genética , Rearranjo Gênico , Granulócitos/metabolismo , Hemoglobinúria Paroxística/genética , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/metabolismo , Linfócitos T/metabolismo , Adulto Jovem
10.
J Biol Chem ; 294(15): 5805-5806, 2019 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-30979848

RESUMO

T-cell receptors (TCRs) recognize pathogens to ignite immune responses, making them attractive scaffolds for development as immunotherapeutics. However, manipulation of TCRs has been impeded by difficulties in their engineering and expression. Wagner and colleagues now establish new platforms to generate high-affinity TCR variants that potently activate T cells, and they also create soluble TCR fusion proteins that specifically recognize cognate peptides. This work provides specific tools to combat cytomegalovirus (CMV) infection and helps illuminate a general path to actuation of engineered TCR-based therapeutics.


Assuntos
Expressão Gênica , Engenharia de Proteínas , Animais , Humanos , Receptores de Antígenos de Linfócitos T/genética , Solubilidade
12.
Nat Commun ; 10(1): 1670, 2019 04 11.
Artigo em Inglês | MEDLINE | ID: mdl-30975989

RESUMO

Esophageal squamous cell carcinoma (ESCC) ranks fourth among cancer-related deaths in China due to the lack of actionable molecules. We performed whole-exome and T-cell receptor (TCR) repertoire sequencing on multi-regional tumors, normal tissues and blood samples from 39 ESCC patients. The data revealed 12.8% of ERBB4 mutations at patient level and functional study supported its oncogenic role. 18% of patients with early BRCA1/2 variants were associated with high-level contribution of signature 3, which was validated in an independent large cohort (n = 508). Furthermore, knockdown of BRCA1/2 dramatically increased sensitivity to cisplatin in ESCC cells. 5% of patients harbored focal high-level amplification of CD274 that led to massive expression of PD-L1, and might be more sensitive to immune checkpoint blockade. Finally, we found a tight correlation between genomic and TCR repertoire intra-tumor heterogeneity (ITH). Collectively, we reveal high-level ITH in ESCC, identify several potential actionable targets and may provide novel insight into ESCC treatment.


Assuntos
Antineoplásicos/farmacologia , Carcinogênese/genética , Neoplasias Esofágicas/genética , Carcinoma de Células Escamosas do Esôfago/genética , Regulação Neoplásica da Expressão Gênica , Adulto , Idoso , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/antagonistas & inibidores , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , China , Estudos de Coortes , Variações do Número de Cópias de DNA , Resistencia a Medicamentos Antineoplásicos/genética , Neoplasias Esofágicas/sangue , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/terapia , Carcinoma de Células Escamosas do Esôfago/sangue , Carcinoma de Células Escamosas do Esôfago/patologia , Carcinoma de Células Escamosas do Esôfago/terapia , Esôfago/patologia , Esôfago/cirurgia , Feminino , Amplificação de Genes , Perfilação da Expressão Gênica , Genômica/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular/métodos , Medicina de Precisão/métodos , Receptores de Antígenos de Linfócitos T/antagonistas & inibidores , Receptores de Antígenos de Linfócitos T/genética , Transcriptoma/genética , Sequenciamento Completo do Exoma/métodos
13.
Allergol. immunopatol ; 47(2): 141-151, mar.-abr. 2019. tab
Artigo em Inglês | IBECS | ID: ibc-180802

RESUMO

Background: The del22q11 syndrome patients present immunological abnormalities associated to thymus alterations. Up to 75% of them present cardiopathies and thymus is frequently removed during surgery. The thymectomy per se has a deleterious effect concerning lymphocyte subpopulations, and T cell function. When compared to healthy controls, these patients have higher infections propensity of variable severity. The factors behind these variations are unknown. We compared immunological profiles of del22q11.2 Syndrome patients with and without thymectomy to establish its effect in the immune profile. Methods: Forty-six del22q11.2 syndrome patients from 1 to 16 years old, 19 of them with partial or total thymectomy were included. Heart disease type, heart surgery, infections events and thymus resection were identified. Immunoglobulin levels, flow cytometry for lymphocytes subpopulations and TREC levels were determined, and statistical analyses were performed. Results: The thymectomy group had a lower lymphocyte index, both regarding total cell count and when comparing age-adjusted Z scores. Also, CD3+, CD4+ and CD8+ lower levels were observed in this group, the lowest count in those patients who had undergone thymus resection during the first year of life. Their TREC level median was 23.6/μL vs 16.1 miL in the non-thymus group (p = 0.22). No differences were identified regarding immunoglobulin levels or infection events frequencies over the previous year. Conclusion: Patients with del22q11.2 syndrome subjected to thymus resection present lower lymphocyte and TREC indexes when compared to patients without thymectomy. This situation may be influenced by the age at the surgery and the time elapsed since the procedure


No disponible


Assuntos
Humanos , Masculino , Feminino , Lactente , Pré-Escolar , Criança , Adolescente , Linfócitos T/fisiologia , Subpopulações de Linfócitos T/fisiologia , Timectomia/métodos , Timo/cirurgia , Cromossomos Humanos Par 22/imunologia , Deleção Cromossômica , Citometria de Fluxo , Receptores de Antígenos de Linfócitos T/genética
14.
J Exp Clin Cancer Res ; 38(1): 168, 2019 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-30995926

RESUMO

BACKGROUND: Chimeric antigen receptor (CAR)-engineered T cells have displayed outstanding performance in the treatment of patients with hematological malignancies. However, their efficacy against solid tumors has been largely limited. METHODS: In this study, human osteosarcoma cell lines were prepared, flow cytometry using antibodies against CD166 was performed on different cell samples. CD166-specific T cells were obtained by viral gene transfer of corresponding DNA plasmids and selectively expanded using IL-2 and IL-15. The ability of CD166.BBζ CAR-T cells to kill CD166+ osteosarcoma cells was evaluated in vitro and in vivo. RESULTS: CD166 was selectively expressed on four different human osteosarcoma cell lines, indicating its role as the novel target for CAR-T cell therapy. CD166.BBζ CAR-T cells killed osteosarcoma cell lines in vitro; the cytotoxicity correlated with the level of CD166 expression on the tumor cells. Intravenous injection of CD166.BBζ CAR-T cells into mice resulted in the regression of the tumor with no obvious toxicity. CONCLUSIONS: Together, the data suggest that CD166.BBζ CAR-T cells may serve as a new therapeutic strategy in the future clinical practice for the treatment of osteosarcoma.


Assuntos
Antígenos CD/administração & dosagem , Moléculas de Adesão Celular Neuronais/administração & dosagem , Proteínas Fetais/administração & dosagem , Imunoterapia Adotiva/métodos , Osteossarcoma/terapia , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos Quiméricos/imunologia , Ligante 4-1BB/administração & dosagem , Ligante 4-1BB/genética , Ligante 4-1BB/imunologia , Animais , Antígenos CD/genética , Antígenos CD/imunologia , Moléculas de Adesão Celular Neuronais/genética , Moléculas de Adesão Celular Neuronais/imunologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proteínas Fetais/genética , Proteínas Fetais/imunologia , Citometria de Fluxo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Interleucina-15/imunologia , Interleucina-2/genética , Interleucina-2/imunologia , Camundongos , Osteossarcoma/genética , Osteossarcoma/imunologia , Osteossarcoma/patologia , Receptores de Antígenos de Linfócitos T/administração & dosagem , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos Quiméricos/administração & dosagem , Receptores de Antígenos Quiméricos/genética , Transdução de Sinais/imunologia , Linfócitos T/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Cancer Res ; 79(7): 1299-1301, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30936076

RESUMO

Deep sequencing of T-cell receptors enables the comprehensive profiling of lymphocyte populations and the characterization of the repertoire of T-cell responses against tumors, which could be applied to diagnose cancers. Ostmeyer and colleagues introduce a novel approach to characterize TCR patterns correlating with antigen recognition. By projecting the large TCR sequence space into a handful of biophysicochemical descriptors for key residues and seeking TCRs with similar antigen-binding capabilities even in the absence of identical amino acids, this approach presents several advantages over current methods.See related article by Ostmeyer et al., p. 1671.


Assuntos
Receptores de Antígenos de Linfócitos T/genética , Linfócitos T/imunologia , Sequenciamento de Nucleotídeos em Larga Escala , Ligação Proteica/imunologia
17.
Oncol Rep ; 41(6): 3455-3463, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30942469

RESUMO

CD19 chimeric antigen receptor (CAR) T cell therapy has changed the outcomes of relapsed/refractory B­cell leukemia and lymphoma. However, its efficacy in patients with relapsed/refractory non­Hodgkin lymphoma (NHL) has been less impressive compared with that in patients with acute lymphoid leukemia. Furthermore, immune checkpoints have a critical role in the immune system. Several clinical trials have confirmed the dramatic effects of programmed death­1/programmed death­ligand 1 (PD­1/PD­L1) inhibitors in numerous malignancies, but the immune­associated adverse events of PD­1/PD­L1 inhibitors may occur in a number of systems. The aim of the present study was to investigate the combination of CD19 CAR­T cells with a reduced dose of PD­1 inhibitor. This method is expected to overcome the side-effects of PD­1 inhibitors, while maintaining therapeutic efficacy. The findings demonstrated that a reduced dose of PD­1 inhibitor did not affect the transfection rate, proliferation rate or cytokine secretion of CD19 CAR­T cells. An interesting finding of the present study was that the number of PD­1­positive cells CAR­T cells, measured by flow cytometry, declined when they were cultured in vitro, but returned to high levels with gradual prolongation of the co­culture time of CD19 CAR­T cells with lymphoma cells; however, there was no change in the mRNA expression of T cells and CAR­T cells during this process. This phenomenon may be one of the reasons why the curative effect of CAR­T cells on B­cell lymphoma is unsatisfactory compared with B­cell leukemia. The synergistic effect of a reduced­dose PD­1 inhibitor combined with CD19 CAR­T cells from T cells highly expressing PD­1 was confirmed in a mouse trial. Mice in the combined treatment group achieved the longest survival time. In this group, the proportion of CAR­T cells and the level of interleukin­6 were higher compared with those in the CAR­T cell group. In conclusion, a reduced dose of a PD­1 inhibitor combined with CD19 CAR­T cells appears to be a promising treatment option for relapsed/refractory B­NHL exhibiting high PD­1 expression by T cells. This method may achieve good clinical efficacy while reducing the side-effects of PD­1 inhibitors.


Assuntos
Linfoma/terapia , Nivolumabe/administração & dosagem , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Adulto , Antígenos CD19/genética , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/genética , Antígeno B7-H1/imunologia , Proliferação de Células/efeitos dos fármacos , Feminino , Citometria de Fluxo , Regulação Neoplásica da Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/imunologia , Humanos , Imunoterapia Adotiva/métodos , Linfoma/genética , Linfoma/imunologia , Linfoma/patologia , Masculino , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Receptor de Morte Celular Programada 1/genética , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/imunologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Int J Mol Sci ; 20(8)2019 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-31013813

RESUMO

The generation of immune cells from human pluripotent stem cells (embryonic stem cells and induced pluripotent stem cells) has been of keen interest to regenerative medicine. Pluripotent stem cell-derived immune cells such as natural killer cells, macrophages, and lymphoid cells, especially T cells, can be used in immune cell therapy to treat incurable cancers. Moreover, since the advent of chimeric antigen receptor (CAR) technology, the success of CAR-T cells in the clinic has galvanized new efforts to harness the power of CAR technology to generate CAR-engineered immune cells from pluripotent stem cells. This review provides a summary of pluripotent stem cell-derived immune cells and CAR technology, together with perspectives on combining pluripotent stem-cell derived immune cells and CAR engineering to pave a new way for developing next generation immune cell therapy.


Assuntos
Receptores de Antígenos de Linfócitos T/metabolismo , Receptores de Antígenos Quiméricos/metabolismo , Células-Tronco/citologia , Células-Tronco/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Animais , Diferenciação Celular/imunologia , Humanos , Imunoterapia , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Células-Tronco Pluripotentes/citologia , Células-Tronco Pluripotentes/metabolismo , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos Quiméricos/genética , Transplante de Células-Tronco
19.
Nat Commun ; 10(1): 1019, 2019 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-30833553

RESUMO

The αß T cell receptor (TCR) repertoire on mature T cells is selected in the thymus, but the basis for thymic selection of MHC-restricted TCRs from a randomly generated pre-selection repertoire is not known. Here we perform comparative repertoire sequence analyses of pre-selection and post-selection TCR from multiple MHC-sufficient and MHC-deficient mouse strains, and find that MHC-restricted and MHC-independent TCRs are primarily distinguished by features in their non-germline CDR3 regions, with many pre-selection CDR3 sequences not compatible with MHC-binding. Thymic selection of MHC-independent TCR is largely unconstrained, but the selection of MHC-specific TCR is restricted by both CDR3 length and specific amino acid usage. MHC-restriction disfavors TCR with CDR3 longer than 13 amino acids, limits positively charged and hydrophobic amino acids in CDR3ß, and clonally deletes TCRs with cysteines in their CDR3 peptide-binding regions. Together, these MHC-imposed structural constraints form the basis to shape VDJ recombination sequences into MHC-restricted repertoires.


Assuntos
Regiões Determinantes de Complementaridade/química , Regiões Determinantes de Complementaridade/imunologia , Complexo Principal de Histocompatibilidade/imunologia , Receptores de Antígenos de Linfócitos T/química , Receptores de Antígenos de Linfócitos T/imunologia , Timo/imunologia , Sequência de Aminoácidos , Animais , Regiões Determinantes de Complementaridade/genética , Ativação Linfocitária , Complexo Principal de Histocompatibilidade/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Antígenos de Linfócitos T/genética , Análise de Sequência de Proteína , Linfócitos T/imunologia , Linfócitos T/metabolismo , Recombinação V(D)J
20.
Crit Rev Oncol Hematol ; 136: 1-12, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30878123

RESUMO

Adoptive cellular therapy (ACT) is an immunotherapy which involves the passive transfer of lymphocytes into a lymphodepleted host after ex vivo stimulation and expansion. Tumor-infiltrating lymphocytes (TILs) have shown objective tumor responses mainly restricted to melanoma and rely on a laborious manufacturing process. These limitations led to emergence of engineered cells, where normal peripheral blood lymphocytes are modified to express T cell receptors (TCRs) or chimeric antigen receptors (CARs) specific for tumor-associated antigens (TAAs). To date, CD19-targeted chimeric antigen receptor T (CAR T) cells have been the most extensively studied, showing complete and durable responses in B-cell malignancies. Antitumor responses with engineered T cells have often been accompanied by undesired toxicities in clinical trials including cytokine release syndrome (CRS) and neurotoxicity. In this review, we provide an overview of adoptive cellular strategies, early and ongoing clinical trials, adverse events and strategies to mitigate side effects and overcome limitations.


Assuntos
Imunoterapia Adotiva/métodos , Linfócitos T/transplante , Antígenos de Neoplasias/imunologia , Ensaios Clínicos como Assunto/métodos , Humanos , Imunoterapia Adotiva/efeitos adversos , Linfócitos do Interstício Tumoral/metabolismo , Linfócitos do Interstício Tumoral/transplante , Melanoma/terapia , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/metabolismo , Linfócitos T/fisiologia
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