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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.
- Source :
-
Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics [Neurotherapeutics] 2012 Oct; Vol. 9 (4), pp. 827-43. - Publication Year :
- 2012
-
Abstract
- 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.
- Subjects :
- Adenoviridae genetics
Animals
Antiviral Agents therapeutic use
Brain Neoplasms genetics
Brain Neoplasms immunology
Dendritic Cells immunology
Disease Models, Animal
Ganciclovir therapeutic use
Genetic Vectors
Glioblastoma genetics
Glioblastoma immunology
Humans
Interleukin-2 immunology
Lymphocytes, Tumor-Infiltrating immunology
Membrane Proteins therapeutic use
NF-kappa B immunology
Rats
Recombinant Proteins therapeutic use
Thymidine Kinase therapeutic use
Tumor Microenvironment immunology
Brain Neoplasms therapy
Genetic Therapy methods
Glioblastoma therapy
Immunotherapy methods
Signal Transduction
T-Lymphocytes immunology
Subjects
Details
- Language :
- English
- ISSN :
- 1878-7479
- Volume :
- 9
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics
- Publication Type :
- Academic Journal
- Accession number :
- 22996231
- Full Text :
- https://doi.org/10.1007/s13311-012-0144-7