A heparan sulfate-targeted conditionally replicative adenovirus, Ad5.pk7-Δ24, for the treatment of advanced breast cancer

Ranki, Tuuli; Kanerva, Anna; Ristimäki, Ari; Hakkarainen, Tanja; Särkioja, Merja; Kangasniemi, Lotta; Raki, Mari; Laakkonen, Pirjo; Goodison, Steve; Hemminki, Akseli

doi:10.1038/sj.gt.3302830

Cited by 44 publications

(30 citation statements)

References 38 publications

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“…Ad5LacZ and Ad5F/K21 21 have a b-galactosidase expression cassette inserted in the place of deleted E1 region. Ad5-D24E3, Ad5/3-D24, Ad5-D24RGD 22 , and Ad5.pK7-D24 23 have a 24-bp deletion in the CR2 region of the E1A. Replication-deficient viruses were propagated in 293 and CRAds in A549 cells.…”

Section: Recombinant Adenovirusesmentioning

confidence: 99%

Noninvasive imaging for evaluation of the systemic delivery of capsid‐modified adenoviruses in an orthotopic model of advanced lung cancer

Särkioja

Kanerva

Salo

et al. 2006

Cancer

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BACKGROUND.Variable expression of the coxsackie and adenovirus receptor (CAR) has limited gene transfer efficacy to many types of tumors. Consequently, tropism‐modified adenoviruses have been developed for enhanced infectivity. To the authors' knowledge, targeting approaches for nonsmall cell lung cancer (NSCLC) have not been comprehensively evaluated. The current hypothesis was that modified adenoviruses could be used for increasing gene transfer to and killing of NSCLC cells in vitro and in vivo.METHODS.Ten NSCLC cell lines were analyzed to represent the different NSCLC histologies. Because clinical tumors may differ from established cell lines, 6 clinical specimens fresh from patients were analyzed. For in vivo studies, a novel orthotopic murine model of advanced lung cancer was developed. Because tumor response is difficult to quantitate in orthotopic models, noninvasive imaging of green fluorescent protein (GFP) was utilized as a surrogate for tumor size measurements.RESULTS.Adenoviruses whose capsids were modified with RGD‐4C, the serotype 3 knob, or polylysine displayed increased gene transfer to NSCLC cell lines and clinical samples in comparison to serotype 5 viruses. Conditionally replicating oncolytic adenoviruses (CRAds) with the same modifications showed enhanced therapeutic efficiency in vitro and in vivo. The median survival of mice treated with Ad5.pK7‐Δ24 or Ad5‐Δ24RGD increased 37% (P<.01). GFP imaging allowed noninvasive individualized detection of response and recurrence.CONCLUSIONS.Targeting of adenovirus to heterologous receptors can improve killing of NSCLC cells. Utilization of clinical samples and an orthotopic model of advanced lung cancer may provide clinically relevant translational data. Cancer 2006. © 2006 American Cancer Society.

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Section: Recombinant Adenovirusesmentioning

confidence: 99%

Noninvasive imaging for evaluation of the systemic delivery of capsid‐modified adenoviruses in an orthotopic model of advanced lung cancer

Särkioja

Kanerva

Salo

et al. 2006

Cancer

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“…8 Although RGD motif and polylysine residues have been incorporated into the adenovirus fiber knob to enhance the gene transduction efficacy of a tumor, because the loss of coxsackievirus and adenovirus receptor (CAR) expression is sometimes associated with malignant progression, 9 those motifs also significantly enhanced gene transduction of normal tissues. 6,10 Proper targeting ligands on the cells of interest are still generally not known, which impedes the application of fiber-modified adenovirus vectors for oncolytic virus therapies.…”

Section: Introductionmentioning

confidence: 99%

Oncolytic virus therapy for pancreatic cancer using the adenovirus library displaying random peptides on the fiber knob

Nishimoto

Yoshida²,

Miura³

et al. 2009

Gene Ther

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A conditionally replicative adenovirus is a novel anticancer agent designed to replicate selectively in tumor cells. However, a leak of the virus into systemic circulation from the tumors often causes ectopic infection of various organs. Therefore, suppression of naive viral tropism and addition of tumor-targeting potential are necessary to secure patient safety and increase the therapeutic effect of an oncolytic adenovirus in the clinical setting. We have recently developed a direct selection method of targeted vector from a random peptide library displayed on an adenoviral fiber knob to overcome the limitation that many cell type-specific ligands for targeted adenovirus vectors are not known. Here we examined whether the addition of a tumor-targeting ligand to a replication-competent adenovirus ablated for naive tropism enhances its therapeutic index. First, a peptide-display adenovirus library was screened on a pancreatic cancer cell line (AsPC-1), and particular peptide sequences were selected. The replication-competent adenovirus displaying the selected ligand (AdDCAR-SYE) showed higher oncolytic potency in several other pancreatic caner cell lines as well as AsPC-1 compared with the untargeted adenovirus (AdDCAR). An intratumoral injection of AdDCAR-SYE significantly suppressed the growth of AsPC-1 subcutaneous tumors, and an analysis of adenovirus titer in the tumors revealed an effective replication of the virus in the tumors. Ectopic liver gene transduction following the intratumoral injection of AdDCAR-SYE was not increased compared with the AdDCAR. The results showed that a tumor-targeting strategy using an adenovirus library is promising for optimizing the safety and efficacy of oncolytic adenovirus therapy.

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“…RGD-4C binds to the avh class of integrins (24,25), and polylysine chains give the virus tropism toward heparan sulfate proteoglycans (HSPG; ref. 26). We hypothesized that these capsid modifications would enhance transduction of renal cancer cells, which would subsequently lead to an increased oncolytic effect and antitumor efficacy with the respective oncolytic viruses in vitro and in vivo.…”

Section: Introductionmentioning

confidence: 99%

Treatment of metastatic renal cancer with capsid-modified oncolytic adenoviruses

Guse

Ranki

Ala‐Opas

et al. 2007

Molecular Cancer Therapeutics

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Renal cancer is a common and deadly disease that lacks curative treatments when metastatic. Here, we have used oncolytic adenoviruses, a promising developmental approach whose safety has recently been validated in clinical trials. Although preliminary clinical efficacy data exist for selected tumor types, potency has generally been less than impressive. One important reason may be that expression of the primary receptor, coxsackie-adenovirus receptor, is often low on many or most advanced tumors, although not evaluated in detail with renal cancer. Here, we tested if fluorescence-assisted cell sorting could be used to predict efficacy of a panel of infectivity-enhanced capsid-modified marker gene expressing adenoviruses in renal cancer cell lines, clinical specimens, and subcutaneous and orthotopic murine models of peritoneally metastatic renal cell cancer. The respective selectively oncolytic adenoviruses were tested for killing of tumor cells in these models, and biodistribution after locoregional delivery was evaluated. In vivo replication was analyzed with noninvasive imaging. Ad5/3-#24, Ad5-#24RGD, and Ad5.pK7-#24 significantly increased survival of mice compared with mock or wild-type virus and 50% of Ad5/3-#24 treated mice were alive at 320 days. Because renal tumors are often highly vascularized, we investigated if results could be further improved by adding bevacizumab, a humanized antivascular endothelial growth factor antibody. The combination was well tolerated but did not improve survival, suggesting that the agents may be best used in sequence instead of together. These results set the stage for clinical testing of oncolytic adenoviruses for treatment of metastatic renal cancer currently lacking other treatment options. [Mol Cancer Ther 2007;6(10):2728 -36]

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A heparan sulfate-targeted conditionally replicative adenovirus, Ad5.pk7-Δ24, for the treatment of advanced breast cancer

Cited by 44 publications

References 38 publications

Noninvasive imaging for evaluation of the systemic delivery of capsid‐modified adenoviruses in an orthotopic model of advanced lung cancer

Noninvasive imaging for evaluation of the systemic delivery of capsid‐modified adenoviruses in an orthotopic model of advanced lung cancer

Oncolytic virus therapy for pancreatic cancer using the adenovirus library displaying random peptides on the fiber knob

Treatment of metastatic renal cancer with capsid-modified oncolytic adenoviruses

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