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 Journal Article
| Authors: | Mineharu, Y.; Muhammad, A. G.; Yagiz, K.; Candolfi, M.; Kroeger, K. M.; Xiong, W.; Puntel, M.; Liu, C.; Levy, E.; Lugo, C.; Kocharian, A.; Allison, J. P.; Curran, M. A.; Lowenstein, P. R.; Castro, M. G. |
| Article Title: | 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 |
| 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. © 2012 The American Society for Experimental NeuroTherapeutics, Inc. |
| Keywords: | immunohistochemistry; nonhuman; tumor associated leukocyte; animal tissue; gene overexpression; interleukin 2; cancer immunotherapy; dendritic cell; animal experiment; animal model; immunoglobulin enhancer binding protein; in vivo study; cytotoxicity; in vitro study; hybrid protein; immunotherapy; gamma interferon; immunoglobulin g; glioma cell; glioblastoma; rat; gene therapy; tumor immunity; thymidine kinase; adenovirus vector; flt3 ligand; ganciclovir; stereotactic procedure; monocyte chemotactic protein 1; helper cell; hsv1-tk; nuclear reprogramming; cancer transplantation; cancer gene therapy; tumor microenvironment; macrophage inflammatory protein 1alpha; adenoviral vectors |
| Journal Title: | Neurotherapeutics |
| Volume: | 9 |
| Issue: | 4 |
| ISSN: | 1933-7213 |
| Publisher: | The American Society for Experimental Neurotherapeutics, Inc |
| Date Published: | 2012-10-01 |
| Start Page: | 827 |
| End Page: | 843 |
| Language: | English |
| DOI: | 10.1007/s13311-012-0144-7 |
| PROVIDER: | scopus |
| PMCID: | PMC3480576 |
| PUBMED: | 22996231 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 3 December 2012" - "Source: Scopus" |
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