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1.
Cell ; 183(2): 347-362.e24, 2020 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-33064988

RESUMO

Neoantigens arise from mutations in cancer cells and are important targets of T cell-mediated anti-tumor immunity. Here, we report the first open-label, phase Ib clinical trial of a personalized neoantigen-based vaccine, NEO-PV-01, in combination with PD-1 blockade in patients with advanced melanoma, non-small cell lung cancer, or bladder cancer. This analysis of 82 patients demonstrated that the regimen was safe, with no treatment-related serious adverse events observed. De novo neoantigen-specific CD4+ and CD8+ T cell responses were observed post-vaccination in all of the patients. The vaccine-induced T cells had a cytotoxic phenotype and were capable of trafficking to the tumor and mediating cell killing. In addition, epitope spread to neoantigens not included in the vaccine was detected post-vaccination. These data support the safety and immunogenicity of this regimen in patients with advanced solid tumors (Clinicaltrials.gov: NCT02897765).


Assuntos
Vacinas Anticâncer/imunologia , Imunoterapia/métodos , Medicina de Precisão/métodos , Idoso , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/imunologia , Linfócitos T CD8-Positivos/imunologia , Vacinas Anticâncer/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/imunologia , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Melanoma/tratamento farmacológico , Melanoma/imunologia , Pessoa de Meia-Idade , Mutação , Nivolumabe/uso terapêutico , Receptor de Morte Celular Programada 1/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/imunologia
2.
Cell Rep Med ; 1(8): 100141, 2020 11 17.
Artigo em Inglês | MEDLINE | ID: mdl-33294862

RESUMO

T cells use highly diverse receptors (TCRs) to identify tumor cells presenting neoantigens arising from genetic mutations and establish anti-tumor activity. Immunotherapy harnessing neoantigen-specific T cells to target tumors has emerged as a promising clinical approach. To assess whether a comprehensive peripheral mononuclear blood cell analysis predicts responses to a personalized neoantigen cancer vaccine combined with anti-PD-1 therapy, we characterize the TCR repertoires and T and B cell frequencies in 21 patients with metastatic melanoma who received this regimen. TCR-α/ß-chain sequencing reveals that prolonged progression-free survival (PFS) is strongly associated with increased clonal baseline TCR repertoires and longitudinal repertoire stability. Furthermore, the frequencies of antigen-experienced T and B cells in the peripheral blood correlate with repertoire characteristics. Analysis of these baseline immune features enables prediction of PFS following treatment. This method offers a pragmatic clinical approach to assess patients' immune state and to direct therapeutic decision making.


Assuntos
Antígenos de Neoplasias/imunologia , Células Sanguíneas/patologia , Melanoma/tratamento farmacológico , Melanoma/imunologia , Receptor de Morte Celular Programada 1/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Vacinas Anticâncer/imunologia , Linhagem Celular , Linhagem Celular Tumoral , Feminino , Células HEK293 , Humanos , Imunoterapia/métodos , Células Jurkat , Estudos Longitudinais , Masculino , Melanoma/patologia , Fenótipo , Intervalo Livre de Progressão , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia
3.
Dev Cell ; 48(5): 617-630.e3, 2019 03 11.
Artigo em Inglês | MEDLINE | ID: mdl-30799229

RESUMO

During mammalian embryogenesis, de novo hematopoiesis occurs transiently in multiple anatomical sites including the yolk sac, dorsal aorta, and heart tube. A long-unanswered question is whether these local transient hematopoietic mechanisms are essential for embryonic growth. Here, we show that endocardial hematopoiesis is critical for cardiac valve remodeling as a source of tissue macrophages. Colony formation assay from explanted heart tubes and genetic lineage tracing with the endocardial specific Nfatc1-Cre mouse revealed that hemogenic endocardium is a de novo source of tissue macrophages in the endocardial cushion, the primordium of the cardiac valves. Surface marker characterization, gene expression profiling, and ex vivo phagocytosis assay revealed that the endocardially derived cardiac tissue macrophages play a phagocytic and antigen presenting role. Indeed, genetic ablation of endocardially derived macrophages caused severe valve malformation. Together, these data suggest that transient hemogenic activity in the endocardium is indispensable for the valvular tissue remodeling in the heart.


Assuntos
Endocárdio/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Valvas Cardíacas/citologia , Macrófagos/metabolismo , Animais , Embrião de Mamíferos/metabolismo , Hematopoese/fisiologia , Mesoderma/metabolismo , Camundongos Transgênicos , Fatores de Transcrição NFATC/metabolismo , Saco Vitelino
4.
Blood Adv ; 2(11): 1229-1242, 2018 06 12.
Artigo em Inglês | MEDLINE | ID: mdl-29853524

RESUMO

Despite the addition of tyrosine kinase inhibitors (TKIs) to the treatment of patients with BCR-ABL1+ B-cell precursor acute lymphoblastic leukemia (BCR-ABL1+ BCP-ALL), relapse both with and without BCR-ABL1 mutations is a persistent clinical problem. To identify BCR-ABL1-independent genetic mediators of response to the TKI dasatinib, we performed in vivo and in vitro RNA interference (RNAi) screens in a transplantable syngeneic mouse model of BCR-ABL1+ BCP-ALL. By using a novel combination of a longitudinal screen design and independent component analysis of screening data, we identified hairpins that have distinct behavior in different therapeutic contexts as well as in the in vivo vs in vitro settings. In the set of genes whose loss sensitized BCR-ABL1+ BCP-ALL cells to dasatinib, we identified Pafah1b3, which regulates intracellular levels of platelet-activating factor (PAF), as an in vivo-specific mediator of therapeutic response. Pafah1b3 loss significantly sensitized leukemia cells to the multiple TKIs, indicating that inhibition of PAFAH1B3 in combination with TKI treatment may be an effective therapeutic strategy for BCR-ABL1+ BCP-ALL patients. PAF-induced cell death as well as surface levels of PAF receptor (PAFR) in our model are altered upon dasatinib treatment and depend on the local leukemia microenvironment; the response of Pafah1b3 KO vs overexpressing cells to dasatinib is also dependent on microenvironmental context. Antagonism of the PAFR partially reverses the observed sensitization to TKI treatment upon Pafah1b3 loss in vivo, suggesting that signaling via the PAF/PAFR pathway is at least partially responsible for this effect.


Assuntos
1-Alquil-2-acetilglicerofosfocolina Esterase/metabolismo , Dasatinibe/farmacologia , Proteínas de Fusão bcr-abl/metabolismo , Neoplasias Experimentais , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Inibidores de Proteínas Quinases/farmacologia , 1-Alquil-2-acetilglicerofosfocolina Esterase/genética , Animais , Proteínas de Fusão bcr-abl/genética , Camundongos , Camundongos Knockout , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/enzimologia , Neoplasias Experimentais/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/enzimologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética
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