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1.
Clin Cancer Res ; 30(11): 2545-2557, 2024 Jun 03.
Artículo en Inglés | MEDLINE | ID: mdl-38551501

RESUMEN

PURPOSE: Medulloblastoma (MB), the most common childhood malignant brain tumor, has a poor prognosis in about 30% of patients. The current standard of care, which includes surgery, radiation, and chemotherapy, is often responsible for cognitive, neurologic, and endocrine side effects. We investigated whether chimeric antigen receptor (CAR) T cells directed toward the disialoganglioside GD2 can represent a potentially more effective treatment with reduced long-term side effects. EXPERIMENTAL DESIGN: GD2 expression was evaluated on primary tumor biopsies of MB children by flow cytometry. GD2 expression in MB cells was also evaluated in response to an EZH2 inhibitor (tazemetostat). In in vitro and in vivo models, GD2+ MB cells were targeted by a CAR-GD2.CD28.4-1BBζ (CAR.GD2)-T construct, including the suicide gene inducible caspase-9. RESULTS: GD2 was expressed in 82.68% of MB tumors. The SHH and G3-G4 subtypes expressed the highest levels of GD2, whereas the WNT subtype expressed the lowest. In in vitro coculture assays, CAR.GD2 T cells were able to kill GD2+ MB cells. Pretreatment with tazemetostat upregulated GD2 expression, sensitizing GD2dimMB cells to CAR.GD2 T cells cytotoxic activity. In orthotopic mouse models of MB, intravenously injected CAR.GD2 T cells significantly controlled tumor growth, prolonging the overall survival of treated mice. Moreover, the dimerizing drug AP1903 was able to cross the murine blood-brain barrier and to eliminate both blood-circulating and tumor-infiltrating CAR.GD2 T cells. CONCLUSIONS: Our experimental data indicate the potential efficacy of CAR.GD2 T-cell therapy. A phase I/II clinical trial is ongoing in our center (NCT05298995) to evaluate the safety and therapeutic efficacy of CAR.GD2 therapy in high-risk MB patients.


Asunto(s)
Gangliósidos , Inmunoterapia Adoptiva , Meduloblastoma , Receptores Quiméricos de Antígenos , Ensayos Antitumor por Modelo de Xenoinjerto , Humanos , Meduloblastoma/terapia , Meduloblastoma/inmunología , Meduloblastoma/patología , Meduloblastoma/genética , Meduloblastoma/metabolismo , Animales , Ratones , Gangliósidos/metabolismo , Gangliósidos/inmunología , Receptores Quiméricos de Antígenos/inmunología , Receptores Quiméricos de Antígenos/genética , Receptores Quiméricos de Antígenos/metabolismo , Inmunoterapia Adoptiva/métodos , Inmunoterapia Adoptiva/efectos adversos , Línea Celular Tumoral , Niño , Femenino , Linfocitos T/inmunología , Linfocitos T/metabolismo , Neoplasias Cerebelosas/terapia , Neoplasias Cerebelosas/inmunología , Neoplasias Cerebelosas/patología , Neoplasias Cerebelosas/metabolismo , Morfolinas/farmacología , Masculino , Preescolar , Benzamidas , Compuestos de Bifenilo , Piridonas
2.
Nat Commun ; 14(1): 3423, 2023 06 09.
Artículo en Inglés | MEDLINE | ID: mdl-37296093

RESUMEN

Chimeric antigen receptor T (CAR-T) cell therapy may achieve long-lasting remission in patients with B-cell malignancies not responding to conventional therapies. However, potentially severe and hard-to-manage side effects, including cytokine release syndrome (CRS), neurotoxicity and macrophage activation syndrome, and the lack of pathophysiological experimental models limit the applicability and development of this form of therapy. Here we present a comprehensive humanized mouse model, by which we show that IFNγ neutralization by the clinically approved monoclonal antibody, emapalumab, mitigates severe toxicity related to CAR-T cell therapy. We demonstrate that emapalumab reduces the pro-inflammatory environment in the model, thus allowing control of severe CRS and preventing brain damage, characterized by multifocal hemorrhages. Importantly, our in vitro and in vivo experiments show that IFNγ inhibition does not affect the ability of CD19-targeting CAR-T (CAR.CD19-T) cells to eradicate CD19+ lymphoma cells. Thus, our study provides evidence that anti-IFNγ treatment might reduce immune related adverse effect without compromising therapeutic success and provides rationale for an emapalumab-CAR.CD19-T cell combination therapy in humans.


Asunto(s)
Neoplasias , Receptores Quiméricos de Antígenos , Ratones , Animales , Humanos , Inmunoterapia Adoptiva/efectos adversos , Linfocitos B , Interferón gamma , Neoplasias/etiología , Síndrome de Liberación de Citoquinas , Antígenos CD19 , Tratamiento Basado en Trasplante de Células y Tejidos
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