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1.
Cancers (Basel) ; 14(3)2022 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-35158772

RESUMO

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer related death worldwide. Most patients present with advanced disease, and current gold-standard management using tyrosine kinase inhibitors or immune checkpoint inhibitors (ICIs) offers modest clinical benefit. Cellular immune therapies targeting HCC are currently being tested in the laboratory and in clinical trials. Here, we review the landscape of cellular immunotherapy for HCC, defining antigenic targets, outlining the range of cell therapy products being applied in HCC (such as CAR-T and TCR-T), and exploring how advanced engineering solutions may further enhance this therapeutic approach.

2.
EJHaem ; 2(4): 848-853, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-35845220

RESUMO

Progressive multifocal leukoencephalopathy (PML) is an opportunistic brain infection with few treatment options and poor survival when reversal of the underlying immune dysfunction is not achievable. JC polyomavirus reactivation resulting in PML can rarely complicate chimeric antigen receptor T-cell (CAR-T) therapy. We describe successful treatment of PML with Programmed death-1 (PD-1) blockade using pembrolizumab, 4 months following axicabtagene ciloleucel. Radiological features of immune reconstitution inflammatory syndrome without clinical deterioration were seen. Evidence of anti-viral immune reconstitution by in vitro detection of JC-specific T-cells and sustained neurological recovery in this patient suggest PD-1 blockade may be an effective treatment approach for PML post-CAR-T.

3.
Sci Rep ; 11(1): 21902, 2021 11 09.
Artigo em Inglês | MEDLINE | ID: mdl-34754016

RESUMO

Chimeric antigen receptor (CAR) T cells are a promising form of cancer immunotherapy, although they are often associated with severe toxicities. Here, we present a split-CAR design incorporating separate antigen recognition and intracellular signaling domains. These exploit the binding between the tetracycline repressor protein and a small peptide sequence (TIP) to spontaneously assemble as a functional CAR. Addition of the FDA-approved, small molecule antibiotic minocycline, acts as an "off-switch" by displacing the signaling domain and down-tuning CAR T activity. Here we describe the optimization of this split-CAR approach to generate a CAR in which cytotoxicity, cytokine secretion and proliferation can be inhibited in a dose-dependent and reversible manner. Inhibition is effective during on-going CAR T cell activation and inhibits activation and tumor control in vivo. This work shows how optimization of split-CAR structure affects function and adds a novel design allowing easy CAR inhibition through an FDA-approved small molecule.


Assuntos
Minociclina/farmacologia , Receptores de Antígenos Quiméricos/metabolismo , Linfócitos T/metabolismo , Animais , Técnicas de Cocultura , Feminino , Células HEK293 , Humanos , Camundongos , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Transdução de Sinais , Linfócitos T/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto
4.
J Clin Oncol ; 39(30): 3352-3363, 2021 10 20.
Artigo em Inglês | MEDLINE | ID: mdl-34464155

RESUMO

PURPOSE: Prognosis for adult B-cell acute lymphoblastic leukemia (B-ALL) is poor, and there are currently no licensed CD19 chimeric antigen receptor (CAR) therapeutics. We developed a novel second-generation CD19-CAR (CAT19-41BB-Z) with a fast off rate, designed for more physiologic T-cell activation to reduce toxicity and improve engraftment. We describe the multicenter phase I ALLCAR19 (NCT02935257) study of autologous CAT19-41BB-Z CAR T cells (AUTO1) in relapsed or refractory (r/r) adult B-ALL. METHODS: Patients age ≥ 16 years with r/r B-ALL were eligible. Primary outcomes were toxicity and manufacturing feasibility. Secondary outcomes were depth of response at 1 and 3 months, persistence of CAR-T, incidence and duration of hypogammaglobulinemia and B-cell aplasia, and event-free survival and overall survival at 1 and 2 years. RESULTS: Twenty-five patients were leukapheresed, 24 products were manufactured, and 20 patients were infused with AUTO1. The median age was 41.5 years; 25% had prior blinatumomab, 50% prior inotuzumab ozogamicin, and 65% prior allogeneic stem-cell transplantation. At the time of preconditioning, 45% had ≥ 50% bone marrow blasts. No patients experienced ≥ grade 3 cytokine release syndrome; 3 of 20 (15%) experienced grade 3 neurotoxicity that resolved to ≤ grade 1 within 72 hours with steroids. Seventeen of 20 (85%) achieved minimal residual disease-negative complete response at month 1, and 3 of 17 underwent allogeneic stem-cell transplantation while in remission. The event-free survival at 6 and 12 months was 68.3% (42.4%-84.4%) and 48.3% (23.1%-69.7%), respectively. High-level expansion (Cmax 127,152 copies/µg genomic DNA) and durable CAR-T persistence were observed with B-cell aplasia ongoing in 15 of 20 patients at last follow-up. CONCLUSION: AUTO1 demonstrates a tolerable safety profile, high remission rates, and excellent persistence in r/r adult B-ALL. Preliminary data support further development of AUTO1 as a stand-alone treatment for r/r adult B-ALL.


Assuntos
Antígenos CD19/imunologia , Imunoterapia Adotiva/efeitos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Receptores de Antígenos Quiméricos/imunologia , Linfócitos T/imunologia , Linfócitos T/transplante , Adolescente , Adulto , Agamaglobulinemia/etiologia , Linfócitos B/patologia , Medula Óssea/patologia , Síndrome da Liberação de Citocina/etiologia , Feminino , Doença Enxerto-Hospedeiro/etiologia , Humanos , Infecções/etiologia , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Doenças do Sistema Nervoso/etiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Intervalo Livre de Progressão , Recidiva , Retratamento , Taxa de Sobrevida , Transplante Autólogo/efeitos adversos , Resultado do Tratamento , Adulto Jovem
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