Oncolytic viral therapies – the clinical experience

Aghi, Manish K.; Martuza, Robert L.

doi:10.1038/sj.onc.1209037

Cited by 258 publications

(265 citation statements)

References 51 publications

(36 reference statements)

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“…Adenoviruses controlling E1A under the wild-type promoter and containing the wild-type fiber or the KKTK-RGDK-modified fiber (wild-type adenovirus (Adwt) and Adwt-RGDK) were also included in this study as controls. Animals were weighed daily and common toxicity events reported in clinical trials after high-dose systemic injection of adenoviruses, such as liver enzymes elevation and hematological alterations, 17 were determined. For oncolytic viruses, these parameters were measured at day 5 after injection as at this time point it is described to occur a toxicity peak of inflammatory response.…”

Section: Resultsmentioning

confidence: 99%

Improved systemic antitumor therapy with oncolytic adenoviruses by replacing the fiber shaft HSG-binding domain with RGD

et al. 2011

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Retargeting oncolytic adenoviruses from their systemic preeminent liver tropism to disseminated tumor foci would highly improve the efficacy of these agents at eradicating tumors. We have replaced the KKTK fiber shaft heparan sulfate glycosaminoglycan-binding domain with an RGDK motif in order to achieve simultaneously liver detargeting and tumor targeting. When inserted into a wild-type backbone, this mutation palliated liver transaminase elevation and hematological alterations in mice. Importantly, when tested in a backbone that redirects E1A transcription towards pRB pathway deregulation, RGD at this novel shaft location also improved significantly systemic antitumor therapy compared with the broadly used RGD location at the HI-loop of the fiber knob domain. Gene Therapy (2012) Keywords: oncolytic adenovirus; fiber shaft; HSG-binding domain; RGD motif; antitumor efficacy INTRODUCTION Oncolytic adenoviruses are promising therapies for cancer treatment owing to their ability to self-amplify at the tumor site. However, systemic delivery of Ad5 results in a rapid clearance from the bloodstream and the sequestration of the virus in the liver, which causes toxicity and a drop in virus bioavailability. 1 As the success of adenoviral therapy depends on the ability of adenoviruses to reach disseminated cancer cells, this liver tropism limits the efficacy of the therapy upon systemic administration. To overcome this limitation, capsid retargeting mutations are under study.To retarget Ad5 to tumor sites, it is necessary to abrogate liver transduction (liver detargeting) and to expose new ligands specific for tumor cells on capsid proteins (tumor targeting). To achieve liver detargeting, several mutations on capsid proteins, such as the double ablation of CAR and integrin binding, have failed to reduce hepatocyte transduction in vivo owing to the role of blood factors in adenovirus liver transduction. 2,3 Recently, ablation of Factor X binding by the hexon has resulted in successful liver-detargeting, 4,5 although this might be at the expense of lower tumor targeting. 6 Alternatively, the mutation of the heparan sulfate glycosaminoglycan (HSG) putative-binding site KKTK of the Ad5 fiber shaft domain detargets liver transduction, probably because of affectation of the bending or structure of the fiber. 2,7,8 On the other hand, the HI-loop of the fiber knob domain has been used to accommodate a broad range of tumor-selective peptides for tumor targeting 9-11 Among all peptides incorporated into the HI loop, the CDCRGDCFC motif (known as RGD-4C) has been broadly used and confers on Ad5 a CAR-independent entry mechanism by using aV-b3 and aV-b5 integrins as primary receptors. 12,13 As integrins are a large family of adhesive receptors involved in the spread and adhesion

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Section: Resultsmentioning

confidence: 99%

Improved systemic antitumor therapy with oncolytic adenoviruses by replacing the fiber shaft HSG-binding domain with RGD

et al. 2011

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“…22,23 A dose of 5 Â 10 10 viral particles of AdwtRGD caused up to an 80-fold elevation of both AST and ALT compared with non-treated animals ( Figure 2a). In contrast, the injection of the same dose of ICOVIR-7 did not increase transaminase levels significantly.…”

Section: Icovir-7 Replication Is Restricted In Normal Cellsmentioning

confidence: 98%

A modified E2F-1 promoter improves the efficacy to toxicity ratio of oncolytic adenoviruses

et al. 2009

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The E2F-1 promoter has been used to confer tumorselective E1A expression in oncolytic adenoviruses. Tumor specificity is mainly conferred by a unique structure of E2F-responsive sites organized in palindromes. Binding of the E2F-pRb complex to these palindromes results in repression of transcription in normal cells. Owing to deregulation of the Rb/p16 pathway in tumor cells, binding of free E2F activates transcription and initiates an autoactivation loop involving E1A and E4-6/7. ICOVIR-7 is a new oncolytic adenovirus designed to increase the E2F dependency of E1A gene expression. It incorporates additional palindromes of E2F-responsive sites in an insulated E2F-1 promoter controlling E1A-D24. The E2F palindromes inhibited replication in normal cells, resulting in a low systemic toxicity at high doses in immunocompetent mice. The D24 deletion avoids a loop of E2F-mediated selfactivation in nontumor cells. Importantly, the additional E2F-binding hairpins boost the positive feedback loop on the basis of E1A-mediated transcriptional regulation of E4-6/7 turned on in cancer cells and increased antitumoral potency as shown in murine subcutaneous xenograft models treated by intravenous injection. These results suggest that the unique genetic combination featured in ICOVIR-7 may be promising for treating disseminated neoplasias.

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“…1 The feasibility and safety of oncolytic adenoviruses in human patients have been demonstrated in clinical trials with multiple modes of delivery, and the combination with standard chemotherapy or radiotherapy has the potential to further increase the antitumor activity of oncolytic adenoviruses. 2,3 However, a significant therapeutic effect has not been clearly demonstrated to date. Therefore, improvements in the efficacy of oncolytic adenoviruses are required to obtain clear benefits in cancer patients.…”

Section: Introductionmentioning

confidence: 99%

GALV expression enhances the therapeutic efficacy of an oncolytic adenovirus by inducing cell fusion and enhancing virus distribution

et al. 2011

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The limitations of the current oncolytic adenoviruses for cancer therapy include insufficient potency and poor distribution of the virus throughout the tumor mass. To address these problems, we generated an oncolytic adenovirus expressing the hyperfusogenic form of the gibbon-ape leukemia virus (GALV) envelope glycoprotein under the control of the adenovirus major late promoter. The oncolytic properties of the new fusogenic adenovirus, ICOVIR16, were analyzed both in vitro and in vivo, and compared with that of its non-fusogenic counterpart, ICOVIR15. Our results indicate that GALV expression by ICOVIR16 induced extensive syncytia formation and enhanced tumor cell killing in a variety of tumor cell types. When injected intratumorally or intravenously into mice with large pre-established melanoma or pancreatic tumors, ICOVIR16 rapidly reduced tumor burden, and in some cases, resulted in complete eradication of the tumors. Importantly, GALV expression induced tumor cell fusion in vivo and enhanced the spreading of the virus throughout the tumor. Taken together, these results indicate that GALV expression can improve the antitumoral potency of an oncolytic adenovirus and suggest that ICOVIR16 is a promising candidate for clinical evaluation in patients with cancer.

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Oncolytic viral therapies – the clinical experience

Cited by 258 publications

References 51 publications

Improved systemic antitumor therapy with oncolytic adenoviruses by replacing the fiber shaft HSG-binding domain with RGD

Improved systemic antitumor therapy with oncolytic adenoviruses by replacing the fiber shaft HSG-binding domain with RGD

A modified E2F-1 promoter improves the efficacy to toxicity ratio of oncolytic adenoviruses

GALV expression enhances the therapeutic efficacy of an oncolytic adenovirus by inducing cell fusion and enhancing virus distribution

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