INVESTIGADORES
PUNTEL Mariana
artículos
Título:
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
Autor/es:
MINEHARU; MUHAMMAD; YAGIZ; CANDOLFI; KROEGER; XIONG; PUNTEL; LIU; LEVY; LUGO; KOCHARIAN; ALLISON; CURRAN; LOWENSTEIN; CASTRO
Revista:
NEUROTHERAPEUTICS
Editorial:
ELSEVIER SCIENCE INC
Referencias:
Lugar: Amsterdam; Año: 2012 vol. 9 p. 827 - 843
ISSN:
1933-7213
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.