Human adenovirus type 35 vector for gene therapy of brain cancer: improved transduction and bypass of pre-existing anti-vector immunity in cancer patients

Brouwer, Eric; Havenga, Menzo; Ophorst, Olga; Leeuw, Bertie de; Gijsbers, Linda; Gillissen, Gert; Hoeben, Rob C.; Horst, Maarten ter; Nanda, Dharmin; Dirven, Clemens; Avezaat, C. J. J.; Goudsmit, Jaap; Smitt, Peter Sillevis

doi:10.1038/sj.cgt.7701010

Cited by 39 publications

(34 citation statements)

References 30 publications

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“…The differences in adenovirus transduction efficiency and promoter studies emphasize the importance to use short-term cultures of glioblastoma cells. In the meantime, Brouwer et al have demonstrated that recombinant Ad5/35 has a significantly higher transduction efficiency of primary glioblastoma cells than Ad5 [53]. However, the authors did not analyze the effects on treatment efficacy.…”

Section: Introductionmentioning

confidence: 91%

Improved glioblastoma treatment with Ad5/35 fiber chimeric conditionally replicating adenoviruses

Hoffmann

Meyer

Wildner

2007

The Journal of Gene Medicine

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Adenovirus type 5 (Ad5)-based vectors have been used in clinical trials for glioblastoma treatment, but the capacity of Ad5 to infect human glioma cells was questioned. Seeking to improve the adenovirus transduction, we tested four Ad5-based vectors differing only in their fiber gene on permanent and short-term cultures of glioblastoma cells. A wild-type fiber Ad5 vector (Ad5.Luc) was compared to an RGD integrin-binding motif-containing fiber adenovirus (AdlucRGD) and the two fiber chimeras Ad5/3 and Ad5/35, with vector binding redirected to the Ad3 or Ad35 receptor, respectively. Compared to Ad5, the transduction of the tested short-term glioblastoma cultures with the vector Ad5/35.Luc, AdlucRGD and Ad5/3.Luc was enhanced by approximately 72%, approximately 13% and approximately 2%, respectively. To limit adenovirus spread, we aimed to develop conditionally replicative Ad5/35 vectors by targeting the expression of the essential E1 and E4 genes; in addition, some vectors had the E1Delta24 deletion. We analyzed eleven promoters for their activity in glioblastoma cells and determined the specificity of eight replicative adenovirus vectors in vitro. We evaluated the most promising vectors with E1/E4 under the control of the GFAP/Ki67 or E2F-1/COX-2 promoters, and the native Ad5 or the chimeric Ad5/35 fiber for their antineoplastic activity in a subcutaneous and intracranial glioblastoma xenograft model. Animals treated with the Ad5/35-based vectors showed significantly smaller tumors and longer survival than those treated with the homologous Ad5 vectors; no significant toxicity was observed in the intracranial model. Our data suggest that Ad5/35-based vectors are promising tools for glioblastoma treatment.

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Section: Introductionmentioning

confidence: 91%

Improved glioblastoma treatment with Ad5/35 fiber chimeric conditionally replicating adenoviruses

Hoffmann

Meyer

Wildner

2007

The Journal of Gene Medicine

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“…22 Ad35, a chimeric vector was found to have lower antigenic properties, but increased ability to transfer a gene to primary glioma cells compared with Ad5 depicting it as an interesting candidate vector for gene therapy of malignant glioma. 23 However, although genetic strategies to circumvent Coxsackie-adenovirus receptor deficiency in glioma cells could reproducibly expand the cellular entry mechanisms of Ad vectors in cultured and primary glioma cells, these approaches were insufficient to confer in vivo significant infectivity enhancement over unmodified Ad vectors, suggesting that other factors, such as extracellular matrix, stromal cells and the three-dimensional tumor architecture, have important roles in vivo and interfere with Ad-based gene delivery into gliomas. 24 Invasive tumors, including gliomas, utilize proteinases to degrade extracellular matrix components and diffuse into the adjacent tissues or migrate toward distant ones.…”

Section: Adenovirus Retrovirusmentioning

confidence: 99%

“…35 A conditionally replication-competent Ad5-based vector with the Ad35 fiber shaft and knob domains (Ad5/35) had a potent antiglioma effect suggesting that Ad35-based vectors may be useful for the treatment of glioma. 36 A replication-selective adenovirus (CB1) having a double deletion of the 24 bp Rb-binding region in the E1a gene, and a 903 bp deleted region in the E1b gene that abrogates the expression of the p53-binding E1B-55 kDa protein, exerted a potent anticancer effect in vitro in U-251 MG, U-373 MG and D-54 MG human glioma cell lines. In vivo experiments using intracranially implanted D-54 MG glioma xenografts improved survival of nude mice.…”

Section: Oncolytic Virusesmentioning

confidence: 99%

Viruses, gene therapy and stem cells for the treatment of human glioma

2009

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“…67 Examples include an Ad3 fiber knob (binds to CD80, CD86, and unknown receptor) and Ad5 fiber chimera (Ad5/3), which had greatly increased glioma infectivity and cytotoxicity in vitro 68,69 ; Ad5 with canine Ad1 (CK1) or porcine Ad (PK) fiber was more efficient than Ad5/3 70 ; and Ad16p (binds to CD46) and chimpanzee CV23 efficiently infected GSCs. 71 A screen of 16 Ad5 fiber chimeras on primary glioma cell cultures identified B-group viruses (Ad11, Ad35, Ad50 [bind to CD46, overexpressed in GBM]) as having greatly increased infectivity compared with Ad5, 72 with Ad5/35 extending survival in vivo. 68 These same strategies can be used for targeting replication-defective Ad vectors.…”

Section: Adenovirusesmentioning

confidence: 99%

Current Status of Gene Therapy for Brain Tumors∗

Ning

Rabkin

2015

Translating Gene Therapy to the Clinic

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Glioblastoma (GBM) is the most common and deadliest primary brain tumor in adults, with current treatments having limited impact on disease progression. Therefore the development of alternative treatment options is greatly needed. Gene therapy is a treatment strategy that relies on the delivery of genetic material, usually transgenes or viruses, into cells for therapeutic purposes, and has been applied to GBM with increasing promise. We have included selectively replicationcompetent oncolytic viruses within this strategy, although the virus acts directly as a complex biologic anti-tumor agent rather than as a classic gene delivery vehicle. GBM is a good candidate for gene therapy because tumors remain locally within the brain and only rarely metastasize to other tissues; the majority of cells in the brain are post-mitotic, which allows for specific targeting of dividing tumor cells; and tumors can often be accessed neurosurgically for administration of therapy. Delivery vehicles used for brain tumors include nonreplicating viral vectors, normal adult stem/progenitor cells, and oncolytic viruses. The therapeutic transgenes or viruses are typically cytotoxic or express prodrug activating suicide genes to kill glioma cells, immunostimulatory to induce or amplify anti-tumor immune responses, and/or modify the tumor microenvironment such as blocking angiogenesis. This review describes current preclinical and clinical gene therapy strategies for the treatment of glioma.Treating malignant gliomas, of which glioblastoma (GBM) is the most common and least curable, remains a daunting challenge even after substantial efforts to develop alternative therapies. The current standard of care is maximal surgical resection followed by radiation and temozolomide chemotherapy; however, the median survival still remains less than 15 months. 1,2 This poor survival is due to the aggressive and invasive nature of the tumor cells, resistance to treatment, and the challenges of delivering therapeutics into the brain. 3 GBM is thought to be derived from a small population of glioblastoma stem cells (GSCs), so-called because of their stem cell-like properties of self-renewal and multilineage differentiation while being highly tumorigenic. [4][5][6] GSCs have become an important model for studying GBM because their xenografts mimic the heterogeneous histopathology of the patient's tumor from which they were derived 7,8 and they remain genotypically similar to the patient's tumor, in contrast to serum-cultured cell lines. 9 These cells have provided insights into the origin of tumor-initiating cells and new targets for therapy. Other GBM animal models include established glioma cell lines (human and rodent) implanted intracranially into immunodeficient or immunocompetent animals, and genetically engineered mice that spontaneously develop brain tumors or are induced with viral vectors. 10 GENE DELIVERY VEHICLES FOR GLIOBLASTOMAMost gene therapies for GBM use biologic vectors such as viruses or cells. Replicationdefective or non-repli...

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Human adenovirus type 35 vector for gene therapy of brain cancer: improved transduction and bypass of pre-existing anti-vector immunity in cancer patients

Cited by 39 publications

References 30 publications

Improved glioblastoma treatment with Ad5/35 fiber chimeric conditionally replicating adenoviruses

Improved glioblastoma treatment with Ad5/35 fiber chimeric conditionally replicating adenoviruses

Viruses, gene therapy and stem cells for the treatment of human glioma

Current Status of Gene Therapy for Brain Tumors∗

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