Cancer gene therapy with targeted adenoviruses

Bachtarzi, H.; Stevenson, Mark; Fisher, Kerry D.

doi:10.1517/17425240802507636

Cited by 42 publications

(24 citation statements)

References 81 publications

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“…31 In this study, the adenoviruses most likely infected pulmonary epithelial cells, and these cells do not produce IL-4 or IL-4d2 in health or disease. An alternative approach could be a transgenic model of T-cell-specific inducible expression of IL-4d2, but it would be difficult to ensure the expression of IL-4d2 in the lung only, because of the systemic presence of T cells and the unavailability of molecular markers distinguishing pulmonary T cells.…”

Section: Discussionmentioning

confidence: 70%

Splice isoforms of human interleukin-4 are functionally active in mice in vivo

et al. 2011

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Summary Interleukin‐4 (IL‐4) acts on cultured cells in a species‐specific fashion, although several reports have suggested that human (h) IL‐4 may be functionally active in rodents in vivo. The latter finding, if true, would not only offer possibilities for pre‐clinical testing of novel hIL‐4‐targeting therapies in animals, but also suggests new opportunities for mechanistic studies of IL‐4 and its receptors. Conventional IL‐4 is encoded by four exons, whereas its poorly studied alternatively spliced isoform is encoded by exons 1, 3 and 4 (IL‐4δ2). Replication‐deficient adenovirus‐mediated gene delivery of hIL‐4 isoforms (hIL‐4 or hIL‐4δ2) to mouse lungs caused similar pulmonary infiltration of T and B lymphocytes, but not eosinophils. There were significant differences in the changes of pulmonary cytokine milieu induced by hIL‐4 compared with hIL‐4δ2, with hIL‐4δ2 inducing higher levels of pro‐inflammatory (tumour necrosis factor‐α, IL‐1, and monocyte chemotactic protein‐1) and T helper type 1 (IL‐12 and interferon‐γ) cytokines. There was no elevation in endogenous mouse (m) IL‐4 or mIL‐4δ2 mRNAs, and germ‐line deficiency of mIL‐4 did not affect the degree of pulmonary infiltration. When combined with an ovalbumin model of asthma, hIL‐4δ2 stimulated a greater accumulation of lymphocytes than did hIL‐4. Pulmonary infiltration of lymphocytes induced by expression of hIL‐4 or hIL‐4δ2 was attenuated, but not completely abrogated, by germ‐line deficiency of mIL‐4Rα or murine signal transducer and activator of transcription 6, suggesting that these signalling molecules mediate the in vivo effects of hIL‐4 isoforms in mice. These findings suggest that splice isoforms of human IL‐4 are functionally active in vivo in mice, and partially share the effects of the corresponding species‐specific isoforms.

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Section: Discussionmentioning

confidence: 70%

Splice isoforms of human interleukin-4 are functionally active in mice in vivo

et al. 2011

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“…To reach this goal, several strategies have been explored including transcriptional targeting of tumors using tumorspecific promoters (24,27,28) and enhanced tumor tropism of both viral and nonviral vectors (29,30). Our efforts are quite similar to these exciting advancements, but instead of a therapeutic transgene for tumor treatment we propose the expression of a secretable reporter gene for the purposes of cancer detection.…”

Section: Discussionmentioning

confidence: 99%

Detecting cancers through tumor-activatable minicircles that lead to a detectable blood biomarker

Ronald

Chuang

Dragulescu-Andrasi

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Earlier detection of cancers can dramatically improve the efficacy of available treatment strategies. However, despite decades of effort on blood-based biomarker cancer detection, many promising endogenous biomarkers have failed clinically because of intractable problems such as highly variable background expression from nonmalignant tissues and tumor heterogeneity. In this work we present a tumor-detection strategy based on systemic administration of tumor-activatable minicircles that use the pan-tumorspecific Survivin promoter to drive expression of a secretable reporter that is detectable in the blood nearly exclusively in tumor-bearing subjects. After systemic administration we demonstrate a robust ability to differentiate mice bearing human melanoma metastases from tumor-free subjects for up to 2 wk simply by measuring blood reporter levels. Cumulative change in reporter levels also identified tumor-bearing subjects, and a receiver operator-characteristic curve analysis highlighted this test's performance with an area of 0.918 ± 0.084. Lung tumor burden additionally correlated (r 2 = 0.714; P < 0.05) with cumulative reporter levels, indicating that determination of disease extent was possible. Continued development of our system could improve tumor detectability dramatically because of the temporally controlled, high reporter expression in tumors and nearly zero background from healthy tissues. Our strategy's highly modular nature also allows it to be iteratively optimized over time to improve the test's sensitivity and specificity. We envision this system could be used first in patients at high risk for tumor recurrence, followed by screening high-risk populations before tumor diagnosis, and, if proven safe and effective, eventually may have potential as a powerful cancer-screening tool for the general population.cancer | minicircles | tumor-specific promoter | reporter gene | blood test

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“…Ad has several advantages for gene therapy application, including the ability to infect both dividing and nondividing cells, strong gene expression, the ability to produce high-titer viral stocks and no risk of insertional mutagenesis [12][13][14]. Replication-incompetent Ad, which lacks the Ad E1A gene essential for viral replication, has been widely used to transiently express therapeutic genes in a wide range of host cells [11].…”

Section: Adenovirusmentioning

confidence: 99%

Evolving Lessons on Nanomaterial-Coated Viral Vectors for Local and Systemic Gene Therapy

Kasala

Yoon

Hong

et al. 2016

Nanomedicine (Lond.)

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Viral vectors are promising gene carriers for cancer therapy. However, virus-mediated gene therapies have demonstrated insufficient therapeutic efficacy in clinical trials due to rapid dissemination to nontarget tissues and to the immunogenicity of viral vectors, resulting in poor retention at the disease locus and induction of adverse inflammatory responses in patients. Further, the limited tropism of viral vectors prevents efficient gene delivery to target tissues. In this regard, modification of the viral surface with nanomaterials is a promising strategy to augment vector accumulation at the target tissue, circumvent the host immune response, and avoid nonspecific interactions with the reticuloendothelial system or serum complement. In the present review, we discuss various chemical modification strategies to enhance the therapeutic efficacy of viral vectors delivered either locally or systemically. We conclude by highlighting the salient features of various nanomaterial-coated viral vectors and their prospects and directions for future research.

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Cancer gene therapy with targeted adenoviruses

Cited by 42 publications

References 81 publications

Splice isoforms of human interleukin-4 are functionally active in mice in vivo

Splice isoforms of human interleukin-4 are functionally active in mice in vivo

Detecting cancers through tumor-activatable minicircles that lead to a detectable blood biomarker

Evolving Lessons on Nanomaterial-Coated Viral Vectors for Local and Systemic Gene Therapy

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