TNFerade Biologic, an Adenovector With a Radiation-Inducible Promoter, Carrying the Human Tumor Necrosis Factor Alpha Gene: A Phase I Study in Patients With Solid Tumors

Senzer, Neil; Mani, Sridhar; Rosemurgy, Alexander S.; Nemunaitis, John; Cunningham, Casey; Guha, Chandan; Bayol, Natalia; Gillen, Michelle; Chu, Karen; Rasmussen, Camilla; Rasmussen, Henrik; Küfe, Donald; Weichselbaum, Ralph R.; Hanna, Nader

doi:10.1200/jco.2004.01.227

Cited by 180 publications

(107 citation statements)

References 38 publications

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“…4 Thus, combination treatment has great potential for translation into effective clinic therapy in the immediate future. [14][15][16] In the case of CG7870, the alterations in vector design (relative to earlier adenovirus-based therapeutic agents) presented an unknown material impact on the efficacy of a treatment regimen combining the vector and radiation. Namely, CG7870 is transcriptionally regulated by dual, heterologous promoters and retains the Ad5, wild-type E3 region.…”

Section: Discussionmentioning

confidence: 99%

Oncolytic adenovirus CG7870 in combination with radiation demonstrates synergistic enhancements of antitumor efficacy without loss of specificity

Dilley

Reddy

et al. 2005

Cancer Gene Ther

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Conditionally replicating adenoviruses that selectively replicate in tumor cells, but not in normal cells, are being explored as virotherapeutic agents for cancer. A prostate-specific oncolytic adenovirus, CG7870 is currently being evaluated in phase 1/2 clinical trials for the treatment of prostate cancer. To decrease the effective dose and further increase the therapeutic efficacy of CG7870, the combination of virotherapy with radiation therapy was explored in this study. CG7870 is an oncolytic adenovirus in which tumor-specific promoters are driving the expression of E1A and E1B proteins. The effects of combined treatment with CG7870 and radiation on cultured cells were determined in cytotoxicity and virus yield assays. The antitumor efficacy of CG7870 (1 Â 10 7 particles/mm 3 of tumor), 10 Gy of local radiation or both was evaluated in established subcutaneous LNCaP xenografts in nude mice. In vitro, the dual agent treatment resulted in synergistically enhanced potency at suboptimal doses of radiation and virus. Virus yield in irradiated cells increased relative to yield in nonirradiated cells without compromising the specificity of the vector for its target cell types. In vivo, CG7870 treatment alone suppressed tumor growth and extended tumor nonprogression time. The average tumor-volume of the groups treated with CG7870 only and radiation only was 121 and 126% of baseline, respectively, 39 days after treatment. The average tumor-volume of the combination group was 34% of baseline 39 days after a single dose of treatment. No significant body weight loss was observed in any treatment group. There was a significant drop in serum level of prostate-specific antigen (PSA) in the combination group compared to the group treated with either agent alone. In mice treated with CG7870 only or radiation only, serum PSA levels changed to 26 and 383% of baseline, respectively, by study day 46. In contrast, PSA levels in mice treated with CG7870 plus radiation decreased to less than 11% of baseline by study day 46. Histological analysis of tumor sections collected from the combination group revealed enhanced necrosis and more apoptotic cells. Combination of CG7870 with radiotherapy significantly increased antitumor efficacy compared to either agent alone. These results suggest that CG7870 in combination with radiation has improved antitumor efficacy at lower doses and with no additional side effects.

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Section: Discussionmentioning

confidence: 99%

Oncolytic adenovirus CG7870 in combination with radiation demonstrates synergistic enhancements of antitumor efficacy without loss of specificity

Dilley

Reddy

et al. 2005

Cancer Gene Ther

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“…15 For in-vitro studies, the Tf-lipoplex was prepared in serum-free culture media to achieve the ratio of Tf:liposome:DNA at 12.5:10:1 (mg:nmol:mg), respectively. Tf (5 mg ml À1 , iron-saturated holo-transferrin; Sigma, St Louis, MO) and was first incubated with liposome in 100 ml of media for 5 min followed by mixing with 100 ml of media containing plasmid DNA cytomegalovirus-green fluorescent protein (CMV-GFP).…”

Section: Cell Line and Tf-lipoplex Formationmentioning

confidence: 99%

“…To measure cell uptake of Tf-lipoplex, WB and LLC1 cells were plated on 24-well plates at a density of 1 Â 10 5 cells per well overnight and were irradiated with 2 or 4 Gy followed by immediate incubation with Tf-lipoplex containing 30 ng of plasmid DNA (CMV-LacZ) for various times (15,30, 60 and 120 min). After washing, cells were lysed in 200 ml of 1 Â Reporter Lysis Buffer (Promega, Madison, WI) for measurement of DNA content by real-time PCR.…”

Section: Real-time Pcr Analysismentioning

confidence: 99%

“…One of such advance is TNFerade, which uses radiation to induce tumor necrosis factor-a expression spatially and temporally in tumors by replication-deficient adenovirus vector containing a radiation-inducible promoter from the egr-1 gene. 14,15 Our own study has demonstrated that radiation induces adenovirus uptake in tumors, contributing to enhanced transgene expression. 16,17 For liposome-mediated delivery, radiation has been shown to increase drug delivery to tumor blood vessels 18 and to sustain an enhanced transgene expression in human breast cancer cells.…”

Section: Introductionmentioning

confidence: 99%

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Radiation improves gene delivery by a novel transferrin-lipoplex nanoparticle selectively in cancer cells

Abela

Qian

et al. 2008

Cancer Gene Ther

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Selective gene transfer to tumor is critical in cancer gene therapy. We previously used ionizing radiation to improve adenovirus uptake in intrahepatic tumors but liver cytotoxicity associated with the viral administration still occurred. Here, we explore the potential of radiation for improving gene delivery by a virus-mimicking nanoparticle, transferrin (Tf)-cationic liposome-DNA complex (Tf-lipoplex). Transduction by Tf-lipoplex was highly efficient in various cell lines and further increased by radiation in a dose-and time-dependent manner. This radiation induction, which was associated with an increase in Tf-lipoplex uptake (3-to 4-folds in hepatocytes WB and lung cancer cells, LLC1), was absent when a Tf-deficient complex was used or abolished by the presence of free Tf, suggesting that Tf receptor (TfR) interaction is required for radiation induction. Radiation (10-20 Gy) markedly induced transgene (LacZ) expression in LLC1 xenografts (3.5-to 7.4-folds), correlating with increased plasmid content and TfR expression in irradiated tumors. Moreover, Tf-lipoplex-mediated gene expression was not observed in the liver or other normal tissues regardless of radiation treatment. We conclude that radiation improves Tf-lipoplex gene delivery selectively to tumor cells both in vitro and in vivo. Our findings may provide insight in developing ligand-specific lipoplex for molecularly targeted cancer gene therapy.

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“…[10][11][12] Recently, in a phase I clinical trial, an adenoviral vector containing the Egr1 gene promoter controlling the expression of the cytotoxin tumor necrosis factor a (Ad-Egr1-TNFa) has shown no increase in toxicity and some enhancement in tumor response, compared with radiation alone. 13 The mechanism of Egr1 activation after radiation and other cytotoxic agents is still unknown. However, radiation inducibility was pinpointed to 10 nucleotide motifs of consensus sequence CC(A/T) 6 GG, known as CArG elements, within the 490 nucleotide Egr1 promoter region.…”

mentioning

confidence: 99%

Gene therapy vectors containing CArG elements from the Egr1 gene are activated by neutron irradiation, cisplatin and doxorubicin

et al. 2005

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TNFerade Biologic, an Adenovector With a Radiation-Inducible Promoter, Carrying the Human Tumor Necrosis Factor Alpha Gene: A Phase I Study in Patients With Solid Tumors

Cited by 180 publications

References 38 publications

Oncolytic adenovirus CG7870 in combination with radiation demonstrates synergistic enhancements of antitumor efficacy without loss of specificity

Oncolytic adenovirus CG7870 in combination with radiation demonstrates synergistic enhancements of antitumor efficacy without loss of specificity

Radiation improves gene delivery by a novel transferrin-lipoplex nanoparticle selectively in cancer cells

Gene therapy vectors containing CArG elements from the Egr1 gene are activated by neutron irradiation, cisplatin and doxorubicin

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