Artículo
Gene Therapy-Mediated Reprogramming Tumor Infiltrating T Cells Using IL-2 and Inhibiting NF-κB Signaling Improves the Efficacy of Immunotherapy in a Brain Cancer Model
Mineharu, Yohei; Muhammad, AKM Ghulam; Yagiz, Kader; Candolfi, Marianela
; Kroeger, Kurt M.; Xiong, Weidong; Puntel, Mariana
; Liu, Chunyan; Levy, Eva; Lugo, Claudia; Kocharian, Adrina; Allison, James P.; Curran, Michael A.; Lowenstein, Pedro R.; Castro, Maria G.


Fecha de publicación:
10/2012
Editorial:
Springer
Revista:
Neurotherapeutics
ISSN:
1933-7213
Idioma:
Inglés
Tipo de recurso:
Artículo publicado
Resumen
Immune-mediated gene therapy using adenovirus expressing Flt3 ligand and thymidine kinase followed by ganciclovir administration (Flt3/TK) effectively elicits tumor regression in preclinical glioma models. Herein, we assessed new strategies to optimize Flt3L/TK therapeutic efficacy in a refractory RG2 orthotopic glioblastoma model. Specifically, we aimed to optimize the therapeutic efficacy of Flt3L/TK treatment in the RG2 model by overexpressing the following genes within the brain tumor microenvironment: 1) a TK mutant with enhanced cytotoxicity (SR39 mutant TK), 2) Flt3L-IgG fusion protein that has a longer half-life, 3) CD40L to stimulate DC maturation, 4) T helper cell type 1 polarizing dendritic cell cytokines interleukin-12 or C-X-C motif ligand 10 chemokine (CXCL)-10, 5) C-C motif ligand 2 chemokine (CCL2) or C-C motif ligand 3 chemokine (CCL3) to enhance dendritic cell recruitment into the tumor microenvironment, 6) T helper cell type 1 cytokines interferon-γ or interleukin-2 to enhance effector T-cell functions, and 7) IκBα or p65RHD (nuclear factor kappa-B [NF-κB] inhibitors) to suppress the function of Foxp3+ Tregs and enhanced effector T-cell functions. Anti-tumor immunity and tumor specific effector T-cell functions were assessed by cytotoxic T lymphocyte assay and intracellular IFN-γ staining. Our data showed that overexpression of interferon-γ or interleukin-2, or inhibition of the nuclear factor kappa-B within the tumor microenvironment, enhanced cytotoxic T lymphocyte-mediated immune responses and successfully extended the median survival of rats bearing intracranial RG2 when combined with Flt3L/TK. These findings indicate that enhancement of T-cell functions constitutes a critical therapeutic target to overcome immune evasion and enhance therapeutic efficacy for brain cancer. In addition, our study provides novel targets to be used in combination with immune-therapeutic strategies for glioblastoma, which are currently being tested in the clinic.
Archivos asociados
https://dx.doi.org/10.1007/s13311-012-0144-7
https://link.springer.com/article/10.1007%2Fs13311-012-0144-7
https://link.springer.com/article/10.1007%2Fs13311-012-0144-7

Citación:
Mineharu, Yohei; Muhammad, AKM Ghulam; Yagiz, Kader; Candolfi, Marianela; Kroeger, Kurt M.; et al.; Gene Therapy-Mediated Reprogramming Tumor Infiltrating T Cells Using IL-2 and Inhibiting NF-κB Signaling Improves the Efficacy of Immunotherapy in a Brain Cancer Model; Springer; Neurotherapeutics; 9; 4; 10-2012; 827-843
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Articulos(BIOMED) [160]
Articulos de INSTITUTO DE INVESTIGACIONES BIOMEDICAS