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1.
Lancet ; 398(10297): 314-324, 2021 07 24.
Artigo em Inglês | MEDLINE | ID: mdl-34175021

RESUMO

BACKGROUND: CARTITUDE-1 aimed to assess the safety and clinical activity of ciltacabtagene autoleucel (cilta-cel), a chimeric antigen receptor T-cell therapy with two B-cell maturation antigen-targeting single-domain antibodies, in patients with relapsed or refractory multiple myeloma with poor prognosis. METHODS: This single-arm, open-label, phase 1b/2 study done at 16 centres in the USA enrolled patients aged 18 years or older with a diagnosis of multiple myeloma and an Eastern Cooperative Oncology Group performance status score of 0 or 1, who received 3 or more previous lines of therapy or were double-refractory to a proteasome inhibitor and an immunomodulatory drug, and had received a proteasome inhibitor, immunomodulatory drug, and anti-CD38 antibody. A single cilta-cel infusion (target dose 0·75 × 106 CAR-positive viable T cells per kg) was administered 5-7 days after start of lymphodepletion. The primary endpoints were safety and confirmation of the recommended phase 2 dose (phase 1b), and overall response rate (phase 2) in all patients who received treatment. Key secondary endpoints were duration of response and progression-free survival. This trial is registered with ClinicalTrials.gov, NCT03548207. FINDINGS: Between July 16, 2018, and Oct 7, 2019, 113 patients were enrolled. 97 patients (29 in phase 1b and 68 in phase 2) received a cilta-cel infusion at the recommended phase 2 dose of 0·75 × 106 CAR-positive viable T cells per kg. As of the Sept 1, 2020 clinical cutoff, median follow-up was 12·4 months (IQR 10·6-15·2). 97 patients with a median of six previous therapies received cilta-cel. Overall response rate was 97% (95% CI 91·2-99·4; 94 of 97 patients); 65 (67%) achieved stringent complete response; time to first response was 1 month (IQR 0·9-1·0). Responses deepened over time. Median duration of response was not reached (95% CI 15·9-not estimable), neither was progression-free survival (16·8-not estimable). The 12-month progression-free rate was 77% (95% CI 66·0-84·3) and overall survival rate was 89% (80·2-93·5). Haematological adverse events were common; grade 3-4 haematological adverse events were neutropenia (92 [95%] of 97 patients), anaemia (66 [68%]), leukopenia (59 [61%]), thrombocytopenia (58 [60%]), and lymphopenia (48 [50%]). Cytokine release syndrome occurred in 92 (95%) of 97 patients (4% were grade 3 or 4); with median time to onset of 7·0 days (IQR 5-8) and median duration of 4·0 days (IQR 3-6). Cytokine release syndrome resolved in all except one with grade 5 cytokine release syndrome and haemophagocytic lymphohistiocytosis. CAR T-cell neurotoxicity occurred in 20 (21%) patients (9% were grade 3 or 4). 14 deaths occurred in the study; six due to treatment-related adverse events, five due to progressive disease, and three due to treatment-unrelated adverse events. INTERPRETATION: A single cilta-cel infusion at the target dose of 0·75 × 106 CAR-positive viable T cells per kg led to early, deep, and durable responses in heavily pretreated patients with multiple myeloma with a manageable safety profile. The data from this study formed the basis for recent regulatory submissions. FUNDING: Janssen Research & Development and Legend Biotech.


Assuntos
Antígeno de Maturação de Linfócitos B/administração & dosagem , Imunoterapia Adotiva/métodos , Mieloma Múltiplo/tratamento farmacológico , Receptores de Antígenos Quiméricos/administração & dosagem , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Estados Unidos
2.
Nature ; 518(7539): 337-43, 2015 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-25363779

RESUMO

Genome-wide association studies have identified loci underlying human diseases, but the causal nucleotide changes and mechanisms remain largely unknown. Here we developed a fine-mapping algorithm to identify candidate causal variants for 21 autoimmune diseases from genotyping data. We integrated these predictions with transcription and cis-regulatory element annotations, derived by mapping RNA and chromatin in primary immune cells, including resting and stimulated CD4(+) T-cell subsets, regulatory T cells, CD8(+) T cells, B cells, and monocytes. We find that ∼90% of causal variants are non-coding, with ∼60% mapping to immune-cell enhancers, many of which gain histone acetylation and transcribe enhancer-associated RNA upon immune stimulation. Causal variants tend to occur near binding sites for master regulators of immune differentiation and stimulus-dependent gene activation, but only 10-20% directly alter recognizable transcription factor binding motifs. Rather, most non-coding risk variants, including those that alter gene expression, affect non-canonical sequence determinants not well-explained by current gene regulatory models.


Assuntos
Doenças Autoimunes/genética , Epigênese Genética/genética , Polimorfismo de Nucleotídeo Único/genética , Doenças Autoimunes/imunologia , Doenças Autoimunes/patologia , Sequência de Bases , Cromatina/genética , Sequência Consenso/genética , Elementos Facilitadores Genéticos/genética , Epigenômica , Estudo de Associação Genômica Ampla , Humanos , Motivos de Nucleotídeos , Especificidade de Órgãos , Linfócitos T/imunologia , Linfócitos T/metabolismo , Fatores de Transcrição/metabolismo
3.
Blood ; 119(21): 4878-88, 2012 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-22474248

RESUMO

The transcription factor C/EBPα is a critical mediator of myeloid differentiation and is often functionally impaired in acute myeloid leukemia. Recent studies have suggested that oncogenic FLT3 activity disrupts wild-type C/EBPα function via phosphorylation on serine 21 (S21). Despite the apparent role of pS21 as a negative regulator of C/EBPα transcription activity, the mechanism by which phosphorylation tips the balance between transcriptionally competent and inhibited forms remains unresolved. In the present study, we used immuno-affinity purification combined with quantitative mass spectrometry to delineate the proteins associated with C/EBPα on chromatin. We identified DEK, a protein with genetic links to leukemia, as a member of the C/EBPα complexes, and demonstrate that this association is disrupted by S21 phosphorylation. We confirmed that DEK is recruited specifically to chromatin with C/EBPα to enhance GCSFR3 promoter activation. In addition, we demonstrated that genetic depletion of DEK reduces the ability of C/EBPα to drive the expression of granulocytic target genes in vitro and disrupts G-CSF-mediated granulocytic differentiation of fresh human BM-derived CD34(+) cells. Our data suggest that C/EBPα and DEK coordinately activate myeloid gene expression and that S21 phosphorylation on wild-type C/EBPα mediates protein interactions that regulate the differentiation capacity of hematopoietic progenitors.


Assuntos
Proteínas Estimuladoras de Ligação a CCAAT/fisiologia , Diferenciação Celular/genética , Proteínas Cromossômicas não Histona/fisiologia , Células Mieloides/fisiologia , Proteínas Oncogênicas/fisiologia , Anticorpos/farmacologia , Proteínas Estimuladoras de Ligação a CCAAT/antagonistas & inibidores , Proteínas Estimuladoras de Ligação a CCAAT/genética , Proteínas Estimuladoras de Ligação a CCAAT/metabolismo , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/fisiologia , Células Cultivadas , Proteínas Cromossômicas não Histona/antagonistas & inibidores , Proteínas Cromossômicas não Histona/genética , Proteínas Cromossômicas não Histona/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Células HEK293 , Hematopoese/efeitos dos fármacos , Hematopoese/genética , Humanos , Células K562 , MAP Quinase Quinase Quinases/antagonistas & inibidores , MAP Quinase Quinase Quinases/metabolismo , Células Mieloides/efeitos dos fármacos , Células Mieloides/metabolismo , Proteínas Oncogênicas/antagonistas & inibidores , Proteínas Oncogênicas/genética , Proteínas Oncogênicas/metabolismo , Fosforilação/efeitos dos fármacos , Fosforilação/fisiologia , Proteínas de Ligação a Poli-ADP-Ribose , Ligação Proteica/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia
4.
Mol Cell Proteomics ; 10(11): O111.011064, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21788404

RESUMO

Despite intense, continued interest in global analyses of signaling cascades through mass spectrometry-based studies, the large-scale, systematic production of phosphoproteomics data has been hampered in-part by inefficient fractionation strategies subsequent to phosphopeptide enrichment. Here we explore two novel multidimensional fractionation strategies for analysis of phosphopeptides. In the first technique we utilize aliphatic ion pairing agents to improve retention of phosphopeptides at high pH in the first dimension of a two-dimensional RP-RP. The second approach is based on the addition of strong anion exchange as the second dimension in a three-dimensional reversed phase (RP)-strong anion exchange (SAX)-RP configuration. Both techniques provide for automated, online data acquisition, with the 3-D platform providing the highest performance both in terms of separation peak capacity and the number of unique phosphopeptide sequences identified per µg of cell lysate consumed. Our integrated RP-SAX-RP platform provides several analytical figures of merit, including: (1) orthogonal separation mechanisms in each dimension; (2) high separation peak capacity (3) efficient retention of singly- and multiply-phosphorylated peptides; (4) compatibility with automated, online LC-MS analysis. We demonstrate the reproducibility of RP-SAX-RP and apply it to the analysis of phosphopeptides derived from multiple biological contexts, including an in vitro model of acute myeloid leukemia in addition to primary polyclonal CD8(+) T-cells activated in vivo through bacterial infection and then purified from a single mouse.


Assuntos
Fracionamento Celular/métodos , Fosfoproteínas/metabolismo , Imunidade Adaptativa , Animais , Automação Laboratorial , Linfócitos T CD8-Positivos/metabolismo , Extratos Celulares/química , Fracionamento Celular/instrumentação , Linhagem Celular Tumoral , Cromatografia por Troca Iônica , Humanos , Leucemia Mieloide Aguda , Listeriose/imunologia , Listeriose/metabolismo , Listeriose/patologia , Camundongos , Camundongos Endogâmicos C57BL , Fragmentos de Peptídeos/isolamento & purificação , Fosfoproteínas/química , Fosfoproteínas/isolamento & purificação , Proteólise , Reprodutibilidade dos Testes , Espectrometria de Massas por Ionização por Electrospray , Tirosina Quinase 3 Semelhante a fms/química , Tirosina Quinase 3 Semelhante a fms/isolamento & purificação , Tirosina Quinase 3 Semelhante a fms/metabolismo
5.
J Hematol Oncol ; 11(1): 69, 2018 05 22.
Artigo em Inglês | MEDLINE | ID: mdl-29788981

RESUMO

BACKGROUND: The international, phase 3 COMPARZ study demonstrated that pazopanib and sunitinib have comparable efficacy as first-line therapy in patients with advanced renal cell carcinoma, but that safety and quality-of-life profiles favor pazopanib. Our report analyzed pazopanib and sunitinib safety in Asian and non-Asian subpopulations. METHODS: Patients were randomized 1:1 to receive pazopanib 800 mg once daily (continuous dosing) or sunitinib 50 mg once daily in 6-week cycles (4 weeks on, 2 weeks off). RESULTS: Safety population was composed of 363 Asian patients and 703 non-Asian patients. Asian patients had similar duration of exposure to either drug compared with non-Asian patients, although Asian patients had a higher frequency of dose modifications. Overall, hematologic toxicities, cytopenias, increased AST/ALT, and palmar-plantar erythrodysesthesia (PPE) were more prevalent in Asian patients, whereas gastrointestinal toxicities were more prevalent in non-Asian patients. Among Asian patients, hematologic adverse events and most non-hematologic AEs were more common in sunitinib-treated versus pazopanib-treated patients. Among Asian patients, the most common grade 3/4 AEs with pazopanib were hypertension (grade 3, 22%) and alanine aminotransferase increased (grade 3, 12%; grade 4, 1%); the most common grade 3/4 AEs with sunitinib were thrombocytopenia/platelet count decreased (grade 3, 36%; grade 4, 10%), neutropenia/neutrophil count decreased (grade 3, 24%; grade 4, 3%) hypertension (grade 3, 20%), and PPE (grade 3, 15%). CONCLUSIONS: A distinct pattern and severity of adverse events was observed in Asians when compared with non-Asians with both pazopanib and sunitinib. However, the two drugs were well tolerated in both subpopulations. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00720941 , Registered July 22, 2008 ClinicalTrials.gov, NCT01147822 , Registered June 22, 2010.


Assuntos
Carcinoma de Células Renais/tratamento farmacológico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etnologia , Neoplasias Renais/tratamento farmacológico , Pirimidinas/uso terapêutico , Sulfonamidas/uso terapêutico , Sunitinibe/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Povo Asiático , Carcinoma de Células Renais/etnologia , Carcinoma de Células Renais/patologia , Feminino , Humanos , Indazóis , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Pirimidinas/efeitos adversos , Sulfonamidas/efeitos adversos , Sunitinibe/efeitos adversos , População Branca , Adulto Jovem
6.
J Clin Oncol ; 35(35): 3916-3923, 2017 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-28902533

RESUMO

Purpose This phase III trial evaluated the efficacy and safety of pazopanib versus placebo in patients with locally advanced renal cell carcinoma (RCC) at high risk for relapse after nephrectomy. Patients and Methods A total of 1,538 patients with resected pT2 (high grade) or ≥ pT3, including N1, clear cell RCC were randomly assigned to pazopanib or placebo for 1 year; 403 patients received a starting dose of 800 mg or placebo. To address toxicity attrition, the 800-mg starting dose was lowered to 600 mg, and the primary end point analysis was changed to disease-free survival (DFS) for pazopanib 600 mg versus placebo (n = 1,135). Primary analysis was performed after 350 DFS events in the intent-to-treat (ITT) pazopanib 600 mg group (ITT600mg), and DFS follow-up analysis was performed 12 months later. Secondary end point analyses included DFS with ITT pazopanib 800 mg (ITT800mg) and safety. Results The primary analysis results of DFS ITT600mg favored pazopanib but did not show a significant improvement over placebo (hazard ratio [HR], 0.86; 95% CI, 0.70 to 1.06; P = .165). The secondary analysis of DFS in ITT800mg (n = 403) yielded an HR of 0.69 (95% CI, 0.51 to 0.94). Follow-up analysis in ITT600mg yielded an HR of 0.94 (95% CI, 0.77 to 1.14). Increased ALT and AST were common adverse events leading to treatment discontinuation in the pazopanib 600 mg (ALT, 16%; AST, 5%) and 800 mg (ALT, 18%; AST, 7%) groups. Conclusion The results of the primary DFS analysis of pazopanib 600 mg showed no benefit over placebo in the adjuvant setting.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Pirimidinas/uso terapêutico , Sulfonamidas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Inibidores da Angiogênese/efeitos adversos , Carcinoma de Células Renais/irrigação sanguínea , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/cirurgia , Quimioterapia Adjuvante , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Feminino , Humanos , Indazóis , Neoplasias Renais/irrigação sanguínea , Neoplasias Renais/patologia , Neoplasias Renais/cirurgia , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Nefrectomia , Placebos , Pirimidinas/efeitos adversos , Sulfonamidas/efeitos adversos , Adulto Jovem
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