B7.1 expression eliminates tumor resistance to IL-12 gene therapy

Heise, Charles P.; Shi, Fushun; Albertini, Mark R.; Mahvi, David M.

doi:10.1038/sj.cgt.7700283

Cited by 9 publications

(5 citation statements)

References 21 publications

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“…Although both IL‐12 gene therapy and agonistic 4‐1BB antibody therapy have been shown to induce tumor regression in some murine models when administered as single agents, in many poorly immunogenic models a single agent was not effective and resulted in tumor growth inhibition rather than cure 48, 49, 50. We previously achieved eradication and long‐term remission of hepatic metastases in both mouse colon (MCA 26) and breast (JC) tumor models using the combination of intra‐tumoral delivery of the IL‐12 gene and systemic administration of agonistic antibody against 4‐1BB (the combination therapy) 51, 52.…”

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confidence: 99%

Self‐Aggregated Dinuclear Lanthanide(III) Complexes as Potential Bimodal Probes for Magnetic Resonance and Optical Imaging

Regueiro‐Figueroa

Nonat

Rolla

et al. 2013

Chemistry A European J

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Homodinuclear lanthanide complexes (Ln = La, Eu, Gd, Tb, Yb and Lu) derived from a bis-macrocyclic ligand featuring two 2,2',2''-(1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid chelating sites linked by a 2,6-bis(pyrazol-1-yl)pyridine spacer (H2L(3)) were prepared and characterized. Luminescence lifetime measurements recorded on solutions of the Eu(III) and Tb(III) complexes indicate the presence of one inner-sphere water molecule coordinated to each metal ion in these complexes. The overall luminescence quantum yields were determined (ϕ H2O = 0.01 for [Eu2(L(3))] and 0.50 for [Tb2(L(3))] in 0.01 M TRIS/HCl, pH 7.4; TRIS = tris(hydroxymethyl)aminomethane), pointing to an effective sensitization of the metal ion by the bispyrazolylpyridyl unit of the ligand, especially with Tb. The nuclear magnetic relaxation dispersion (NMRD) profiles recorded for [Gd2(L(3))] are characteristic of slowly tumbling systems, showing a low-field plateau and a broad maximum around 30 MHz. This suggests the occurrence of aggregation of the complexes giving rise to slowly rotating species. A similar behavior is observed for the analogous Gd(III) complex containing a 4,4'-dimethyl-2,2'-bipyridyl spacer ([Gd2(L(1))]). The relaxivity of [Gd2(L(3))] recorded at 0.5 T and 298 K (pH 6.9) amounts to 13.7 mM(-1) s(-1). The formation of aggregates has been confirmed by dynamic light scattering (DLS) experiments, which provided mean particle sizes of 114 and 38 nm for [Gd2(L(1))] and [Gd2(L(3))], respectively. TEM images of [Gd2(L(3))] indicate the formation of nearly spherical nanosized aggregates with a mean diameter of about 41 nm, together with some nonspherical particles with larger size.

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confidence: 99%

Self‐Aggregated Dinuclear Lanthanide(III) Complexes as Potential Bimodal Probes for Magnetic Resonance and Optical Imaging

Regueiro‐Figueroa

Nonat

Rolla

et al. 2013

Chemistry A European J

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“…The central dogma of this model is that exogenous B7.1 plays a direct role in activation of CD8 T cells and inhibition of tumor growth. This conventional model is supported by the fact that more than 50% of B7.1‐expressing tumor cells in the total population are needed for sensitizing IL‐12 treatment,31 demonstrating a direct involvement of exogenous B7.1 in IL‐12‐mediated tumor growth inhibition. However, the conventional model cannot explain why less than 5% transfection efficiency of exogenous B7.1 and IL‐12 gene via electroporation as demonstrated in this study can lead to a superior CTL activity and tumor regression for up to 80% of mice (Figs.…”

Section: Discussionmentioning

confidence: 95%

The mechanism of exogenous B7.1‐enhanced IL‐12‐mediated complete regression of tumors by a single electroporation delivery

Liu

Xia

Torrero

et al. 2006

Intl Journal of Cancer

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Electroporation-based mono-gene therapy has received great interest in recent years but coadministration of different therapeutic genes for treatment of tumors has not been well explored. We hypothesize that electroporation is capable of delivering multiple genes that induce an additive or synergistic antitumor effect. To test this hypothesis, we used mice that were bearing SCCVII or TRAMP tumors. Established tumors with a diameter of 4-5 mm were injected with control plasmid DNA or plasmid DNA encoding B7.1, IL-12 or both via electroporation. Tumor regression, CTL activity and the level of B7.1, IL-12 and Stat1 expression were determined in both wild-type mice and in mice with a knockout of the Stat1 gene. Remarkably, a single coadministration of the plasmids that encoded IL-12 and B7.1 eradicated tumors in 80% of mice. The therapeutic effect was associated with high levels of endogenous B7.1 expression, activity of cytotoxic lymphocytes, and activation of Stat1. Both exogenous B7.1 and IL-12 were required for inducing a high level of Stat1 activation in tumors, which occurred through a mechanism that was independent of the host Stat1. Both stimulators were also required for inducing the strong cytotoxic lymphocyte activity and for increasing the level and extending the duration of endogenous B7.1 expression. We therefore propose a 2-signal stimulation model to explain the synergistic effect of the coadministration of IL-12 and B7.1 on the regression of the tumors. ' 2006 Wiley-Liss, Inc.

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“…In our study, we found significantly increased concentrations of IL-12 in the serum of Ad-B7-H3-GFP treated animals. IL-12 has been shown to act synergistically with members of the B7-family against various tumors (15)(16)(17). When present at the site of antigen presentation, IL-12 favours the development of a Th1type immune response leading to the induction of cytotoxic T-cells (18,19), the main effectors of an antitumor immune response.…”

Section: Discussionmentioning

confidence: 99%

Adenoviral B7-H3 therapy induces tumor specific immune responses and reduces secondary metastasis in a murine model of colon cancer

Eisenbach¹,

Lupu²,

Lupu³

et al. 2007

Z Gastroenterol

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Current cancer gene therapies aim at the induction of systemic antitumor immune responses. Tumors may deliver antigens to T-cells, but may lack the costimulatory signals necessary for mounting an effective response. The purpose of this study was to evaluate the efficacy of an adenoviral delivery of the B7-H3 costimulatory molecule in mice to induce antitumor immune responses. Colon cancers were established by orthotopic injection of syngeneic colon cancer cells into the cecum on Balb/c mice. After two weeks, these mice were treated by intratumoral injection of an adenovirus expressing mouse B7-H3 (Ad-B7-H3-GFP) or a control virus (Ad-GFP). Ad-B7-H3-GFP treatment resulted in a reduction of tumor size compared to the controls. In addition, the occurrence of secondary metastasis was significantly reduced in B7-H3 treated mice compared to control animals (lymph node 7/10 vs. 10/10; liver 2/10 vs. 8/10, p≤0.05). Ad-B7-H3-GFP treated animals showed significantly higher frequencies of tumor-specific interferon-γ producing CD8 + T-cells (p≤0.05) and higher interleukin-12 levels (p≤0.01) than control animals. This study demonstrates that adenoviral B7-H3 transfer is able to induce a specific cellular antitumor immune response leading to primary tumor regression and reduction of secondary metastasis in vivo.

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B7.1 expression eliminates tumor resistance to IL-12 gene therapy

Cited by 9 publications

References 21 publications

Self‐Aggregated Dinuclear Lanthanide(III) Complexes as Potential Bimodal Probes for Magnetic Resonance and Optical Imaging

Self‐Aggregated Dinuclear Lanthanide(III) Complexes as Potential Bimodal Probes for Magnetic Resonance and Optical Imaging

The mechanism of exogenous B7.1‐enhanced IL‐12‐mediated complete regression of tumors by a single electroporation delivery

Adenoviral B7-H3 therapy induces tumor specific immune responses and reduces secondary metastasis in a murine model of colon cancer

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