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1.
Nature ; 629(8010): 201-210, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38600376

RESUMEN

Chimeric antigen receptor (CAR) T cell therapy has transformed the treatment of haematological malignancies such as acute lymphoblastic leukaemia, B cell lymphoma and multiple myeloma1-4, but the efficacy of CAR T cell therapy in solid tumours has been limited5. This is owing to a number of factors, including the immunosuppressive tumour microenvironment that gives rise to poorly persisting and metabolically dysfunctional T cells. Analysis of anti-CD19 CAR T cells used clinically has shown that positive treatment outcomes are associated with a more 'stem-like' phenotype and increased mitochondrial mass6-8. We therefore sought to identify transcription factors that could enhance CAR T cell fitness and efficacy against solid tumours. Here we show that overexpression of FOXO1 promotes a stem-like phenotype in CAR T cells derived from either healthy human donors or patients, which correlates with improved mitochondrial fitness, persistence and therapeutic efficacy in vivo. This work thus reveals an engineering approach to genetically enforce a favourable metabolic phenotype that has high translational potential to improve the efficacy of CAR T cells against solid tumours.


Asunto(s)
Proteína Forkhead Box O1 , Inmunoterapia Adoptiva , Neoplasias , Receptores Quiméricos de Antígenos , Células Madre , Linfocitos T , Humanos , Ratones , Línea Celular Tumoral , Proteína Forkhead Box O1/metabolismo , Proteína Forkhead Box O1/genética , Mitocondrias/metabolismo , Fenotipo , Receptores Quiméricos de Antígenos/inmunología , Receptores Quiméricos de Antígenos/metabolismo , Linfocitos T/inmunología , Linfocitos T/metabolismo , Linfocitos T/citología , Microambiente Tumoral/inmunología , Células Madre/citología , Células Madre/inmunología , Células Madre/metabolismo , Neoplasias/inmunología , Neoplasias/patología , Neoplasias/terapia
2.
Cancer Res ; 74(9): 2412-21, 2014 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-24556719

RESUMEN

Tumor-induced immunosuppression remains one of the major obstacles to many potentially effective cancer therapies and vaccines. Host interleukin (IL)-23 suppresses the immune response during tumor initiation, growth, and metastases, and neutralization of IL-23 causes IL-12-dependent antitumor effects. Here, we report that combining agonistic anti-CD40 monoclonal antibodies (mAb) to drive IL-12 production and anti-IL-23 mAbs to counter the tumor promoting effects of IL-23 has greater antitumor activity than either agent alone. This increased antitumor efficacy was observed in several experimental and spontaneous lung metastases models as well as in models of de novo carcinogenesis. The combination effects were dependent on host IL-12, perforin, IFN-γ, natural killer, and/or T cells and independent of host B cells and IFN-αß sensitivity. Interestingly, in the experimental lung metastases tumor models, we observed that intracellular IL-23 production was specifically restricted to MHC-II(hi)CD11c(+)CD11b(+) cells. Furthermore, an increase in proportion of these IL-23-producing cells was detected only in tumor models where IL-23 neutralization was therapeutic. Overall, these data suggest the clinical potential of using anti-CD40 (push) and anti-IL-23 mAbs (pull) to tip the IL-12/23 balance in established tumors.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Antígenos CD40/inmunología , Interleucina-23/inmunología , Neoplasias Pulmonares/tratamiento farmacológico , Melanoma Experimental/tratamiento farmacológico , Animales , Anticuerpos Monoclonales/administración & dosificación , Antineoplásicos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Antígenos CD40/metabolismo , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Fibrosarcoma/tratamiento farmacológico , Interleucina-12/metabolismo , Interleucina-23/metabolismo , Neoplasias Pulmonares/secundario , Masculino , Melanoma Experimental/patología , Metilcolantreno , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Trasplante de Neoplasias , Proteínas Citotóxicas Formadoras de Poros/metabolismo
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