Clinical trials of gene therapy, virotherapy, and immunotherapy for malignant gliomas

Barzon, Luisa; Zanusso, Mariano; Colombo, Federico; Palù, Giorgio

doi:10.1038/sj.cgt.7700930

Cited by 42 publications

(34 citation statements)

References 82 publications

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“…These therapeutic strategies have been translated into clinical trials. 3,4 Unfortunately, to date, the results achieved from most clinical trials have not shown substantial therapeutic efficacy.…”

Section: Introductionmentioning

confidence: 99%

Targeted-simultaneous expression of Gas1 and p53 using a bicistronic adenoviral vector in gliomas

et al. 2007

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The targeted expression of transgenes is one of the principal goals of gene therapy, and it is particularly relevant for the treatment of brain tumors. In this study, we examined the effect of the overexpression of human gas1 (growth arrest specific 1) and human p53 cDNAs, both under the transcriptional control of a promoter of the human glial fibrillary acidic protein (gfa2), employing adenoviral expression vectors, in glioma cells. We showed that the targeted overexpression of gas1 and p53 (AdSGas1 and AdSp53, respectively) in rat glioma cells (C6) reduced the number of viable cells and induced apoptosis. Moreover, the adenovirally targeted expression of these genes also reduced tumor growth in vivo. Unexpectedly, there was no additive effect when both gas1 and p53 were simultaneously expressed in the same cells using a bicistronic adenoviral vector. We suggest that Gas1 does not act in combination with p53 in the C6 and U373 glioma cell lines, inducing apoptosis and cell cycle arrest. Our results indicate that the targeted expression of tumor suppressor genes (gas1 and p53) regulated by the gfa2 promoter, together with adenoviral vectors may provide an interesting approach for adjuvant selective glioma gene therapy.

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Section: Introductionmentioning

confidence: 99%

Targeted-simultaneous expression of Gas1 and p53 using a bicistronic adenoviral vector in gliomas

et al. 2007

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“…However, for brain-related gene therapy strategies, such as brain cancer gene therapy, and gene therapy for genetic diseases involving central nervous system pathology, current protocols under development are mainly based on intra-cranial injections. [1][2][3] This is not only clinically difficult because it requires high risk surgical procedures, but also inefficient in gene delivery, as localized injections do not allow Ad5 vectors to access all diseased cells. Therefore, it is essential to develop a strategy that allows systemically administered Ad5 vectors to infect the brain cells.…”

Section: Introductionmentioning

confidence: 99%

Directing adenovirus across the blood–brain barrier via melanotransferrin (P97) transcytosis pathway in an in vitro model

et al. 2006

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Adenovirus serotype 5 (Ad5) is widely used in the development of gene therapy protocols. However, current gene therapy strategies involving brain are mostly based on intracranial injection. A major obstacle for systemically administered vectors to infect brain tissue is the blood-brain barrier (BBB). One strategy to cross the BBB is transcytosis, a transcellular transport process that shuttles a molecule from one side of the cell to the other side. Recently, melanotransferrin (MTf)/P97 was found to be able to cross the BBB and accumulate in brain. We thus hypothesize that re-directing Ad5 vectors to the MTf transcytosis pathway may facilitate Ad5 vectors to cross the BBB. To test this hypothesis, we constructed a bi-specific adaptor protein containing the extracellular domain of the coxsackie-adenovirus receptor (CAR) and the full-length melanotransferrin (sCAR-MTf), and investigated its ability to re-direct Ad5 vectors to the MTf transcytosis pathway. We found this adaptor protein could redirect Ad5 to the MTf transcytosis pathway in an in vitro BBB model, and the transcytosed Ad5 viral particles retained their native infectivity. The sCAR-MTf-mediated Ad5 transcytosis was temperature-and dose dependent. In addition, we examined the directionality of sCAR-MTf-mediated Ad5 transcytosis, and found the efficiency of apical-to-basal transcytosis was much higher than that of basal-to-apical direction, supporting a role of this strategy in transporting Ad5 vectors towards the brain. Taken together, our study demonstrated that re-directing Ad5 to the MTf transcytosis pathway could facilitate gene delivery across the BBB.

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“…This prompts attempts of delivery of suicidal genes into gliomas. It is often accomplished by targeted delivery by viral and non-viral vectors targeting over-expressed (e.g., EGFR) or uniquely mutated (e.g., EGFRvIII) receptors [14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31]. A spectrum of the targeted biomarkers is expanded with those being displayed on cancer initiating cells including CD133 and its variants [11,12].…”

Section: Cancers Treated With Cell Suicide Inducing Genesmentioning

confidence: 99%

Frontiers in Suicide Gene Therapy of Cancer

Malecki¹

2012

J Genet Syndr Gene Ther

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The National Cancer Institute (NCI) and the American Cancer Society (ACS) predict that 1,638,910 men and women will be diagnosed with cancer in the USA in 2012. Nearly 577,190 patients will die of cancer of all sites this year. Patients undergoing current systemic therapies will suffer multiple side effects from nausea to infertility. Potential parents, when diagnosed with cancer, will have to deposit oocytes and sperms prior to starting systemic radiation or chemo-therapy for the future genetic testing and in vitro fertilization, while trying to avoid risks of iatrogenic mutations in their germ cells. Otherwise, children of parents treated with systemic therapies, will be at high risk of developing genetic disorders. According to these predictions, this year will carry another, very poor therapeutic record again.The ultimate goal of cancer therapy is the complete elimination of all cancer cells, while leaving all healthy cells unharmed. One of the most promising therapeutic strategies in this regard is cancer suicide gene therapy (CSGT), which is rapidly progressing into new frontiers.The therapeutic success, in CSGT, is primarily contingent upon precision in delivery of the therapeutic transgenes to the cancer cells only. This is addressed by discovering and targeting unique or / and over-expressed biomarkers displayed on the cancer cells and cancer stem cells. Specificity of cancer therapeutic effects is further enhanced by designing the DNA constructs, which put the therapeutic genes under the control of the cancer cell specific promoters. The delivery of the suicidal genes to the cancer cells involves viral, as well as synthetic vectors, which are guided by cancer specific antibodies and ligands. The delivery options also include engineered stem cells with tropisms towards cancers. Main mechanisms inducing the cancer cells' deaths include: transgenic expression of thymidine kinases, cytosine deaminases, intracellular antibodies, telomeraseses, caspases, DNases. Precautions are undertaken to eliminate the risks associated with transgenesis.Progress in genomics and proteomics should help us in identifying the cancer specific biomarkers and metabolic pathways for developing new strategies towards clinical trials of targeted and personalized gene therapy of cancer.

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Clinical trials of gene therapy, virotherapy, and immunotherapy for malignant gliomas

Cited by 42 publications

References 82 publications

Targeted-simultaneous expression of Gas1 and p53 using a bicistronic adenoviral vector in gliomas

Targeted-simultaneous expression of Gas1 and p53 using a bicistronic adenoviral vector in gliomas

Directing adenovirus across the blood–brain barrier via melanotransferrin (P97) transcytosis pathway in an in vitro model

Frontiers in Suicide Gene Therapy of Cancer

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