Heat shock phenocopies E1B-55K late functions and selectively sensitizes refractory tumor cells to ONYX-015 oncolytic viral therapy

O’Shea, Clodagh C.; Soria, Conrado; Bagus, Bridget; McCormick, Frank

doi:10.1016/j.ccr.2005.06.009

Cited by 102 publications

(92 citation statements)

References 59 publications

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“…7 The therapeutic index of oncolytic adenovirus could also be increased by fever and the concomitant induction of a heat shock response could significantly improve ONYX-015 cancer therapy. 26,27 In the current trial of H103, an association between fever and clinical benefit was not found. Mild-to-moderate hematological toxicities have generally been observed in the trials of adenoviruses using the virus as a gene therapy vector or oncolytic virus.…”

Section: Discussionmentioning

confidence: 58%

“…Although HSPs may have potential protective roles in cancer as molecular chaperones toward proteins damaged by extreme environmental stress, 20 as capacitors of phenotypic mutations due to the cancer cell's genetic instability 21 or as multiple pathway transductors in self-sufficient survival signaling, 22 HSPs may also play assistant functions to oncolytic virus by greatly enhancing oncolytic virus's efficacy on the other hand. 23 In the competition between cancer cells and oncolytic viruses, we prefer the assumption that HSPs may be more helpful to oncolytic virus compared with cancer cells, because HSP-armed oncolytic adenovirus experienced more cytotoxicity to tumor cells than the oncolytic virus without HSP gene in our earlier study. 19 In addition, given the transient expression of transgenes delivered by adenovirus, which seldom integrates into the cell's genome, 24 HSP expression induced by H103 will be abolished after the clearance of the virus from cancer cells and may have no long-lasting effect on the survival of cancer cells.…”

Section: Introductionmentioning

confidence: 99%

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A phase I trial of intratumoral administration of recombinant oncolytic adenovirus overexpressing HSP70 in advanced solid tumor patients

Li¹,

Liu

Xr³

et al. 2008

Gene Ther

105

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Our pre-clinical studies demonstrated that intratumoral vaccination with a recombinant oncolytic type 2 adenovirus overexpressing the heat shock protein (HSP)70 protein, designated as H103, can inhibit primary and metastatic tumors through enhanced oncolytic activity and HSPmediated immune responses against shared and mutated tumor antigens. In the pre-clinical studies of local H103 administration, no significant toxicity was observed in the animal trials with mice, cavy or rhesus monkeys. A phase I clinical trial of intratumoral injection of H103 was conducted in the patients with advanced solid tumors. A total of 27 patients were injected intratumorally with H103 in a dose-escalation study from a dose of 2.5 Â 10 7 to 3.0 Â 10 12 viral particles (VPs). The maximum tolerated dose of H103 was not defined. Two patients developed dose-limiting toxicities of grade III fever at the dose of 1.5 Â 10 12 VP and transient grade IV thrombocytopenia at the dose of 3.0 Â 10 12 VP. The common adverse events were mainly mild to moderate (grade I/II) in nature, including fever, mild injection-site reaction, leucopenia, lymphopenia, thrombocytopenia and hypochromia. The objective response (complete response+partial response) to H103-injected tumors was 11.1% (3/27), and the clinical benefit rate (complete response+partial response+minor response+stable disease) was 48.1%. Interestingly, transient and partial regression of distant, uninjected tumors was observed in three patients. The numbers of immune cells (CD4 + and CD8 + T cells, and natural killer cells) were elevated after H103 administration, but without statistical significance. This phase I trial demonstrates that intratumoral administration of H103 can be safely applied to cancer patients and shows promising clinical antitumor activity, warranting a further clinical investigation.

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Section: Discussionmentioning

confidence: 58%

Section: Introductionmentioning

confidence: 99%

A phase I trial of intratumoral administration of recombinant oncolytic adenovirus overexpressing HSP70 in advanced solid tumor patients

Li¹,

Liu

Xr³

et al. 2008

Gene Ther

105

View full text Add to dashboard Cite

show abstract

“…33 Heat shock response rescues late viral RNA export and renders refractory tumor cells permissive to dl1520. 53 A specific question that we investigated in this study is how dl1520 can efficiently replicate in some cancer cells, but its replication is limited in other cancer cells. In order to study this question in a cellular environment that excludes effect of p53 factor, we used p53-null Hep3B and Saos2 cells as models.…”

Section: Adenoviruses-induced Cell Cycle Changes In Hep3b and Saos2 Cmentioning

confidence: 99%

Selective replication of E1B55K-deleted adenoviruses depends on enhanced E1A expression in cancer cells

Zheng

et al. 2005

Cancer Gene Ther

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E1B55K-deleted dl1520 could selectively replicate in cancer cells and has been used in clinical trials as an antitumor agent. The mechanism of virus selective replication in cancer cells, including a possible role of p53, is unclear. Studies with established cancer cell lines have demonstrated that some cancer cells are resistant to dl1520 replication, regardless of the p53 status. Hep3B cells supported the E1b-deleted adenoviruses to replicate, whereas Saos2 cells were resistant to viral replication. We applied p53-null Hep3B and Saos2 cells as models to clarify the replication ability of E1B55K-deleted adenoviruses with different expression levels of E1a. We show that lower E1A expression in Saos2 may be the reason for the poor replication in some cancer cells due to the fact that E1a promoter was less activated in Saos2 than in Hep3B. We also demonstrate that the E1B55K protein can increase E1A expression in Saos2 cells for efficient virus replication. In addition, the upstream regions of the E1a promoter have transcriptional activity in Hep3B cells but not in Saos2 cells. The viral E1B55K protein may activate cancer cellular factor(s) that targets the upstream regions of the E1a gene to increase its expression. This is the first study demonstrating that E1B55K protein affects the E1A production levels that is related to cancer selective replication. Our studies have suggested that increase of E1A expression from E1b-deleted adenoviruses may enhance killing cancer cells that otherwise are resistant to viral replication.

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“…Detailed analysis demonstrated that the loss of the mRNA transport function provided by E1b-55k could be complimented in tumor cell lines, suggesting a novel mechanism of tumor-selective viral replication. 8 However, complementation of lost functions due to the deletion of E1b-55k was incomplete in most tumor cells. Consequently, the titer and cytolytic activity of dl1520 in tumor cells was often one to two logs lower than wild-type Ad5 in the same tumor cells.…”

Section: Introductionmentioning

confidence: 99%

Deletion analysis of Ad5 E1a transcriptional control region: impact on tumor-selective expression of E1a and E1b

Hedjran¹,

Shantanu²,

Tony³

2011

Cancer Gene Ther

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The regulatory sequences upstream of E1a, the first viral protein expressed upon infection of cells with adenovirus, have binding sites for multiple transcription factors including two binding sites for E2f and five binding sites for Pea3. We evaluated the impact of deletions, which remove one or more of these transcription factor-binding sites on the expression of E1a in a panel of tumor cells and non-transformed cells. We demonstrated that specific deletions in the E1a enhancer markedly reduced the expression of E1a in growth-arrested cells while having a minimal impact on the expression of E1a in a panel of tumor cells. In particular, deletion of a 50-bp region located from À305 to À255 upstream of the E1a initiation site resulted in marked reduction of E1a and E1b expression and cytolytic activity in growth-arrested cells, while retaining near wild-type of expression of E1a and E1b and cytolytic activity in tumor cells. This deletion removed two Pea3 sites and one E2f site. The characteristics of this vector, TAV-255, was compared with dl1520 (Onyx-015) and demonstrated restricted cytolytic activity in growth-arrested cells similar to dl1520 and superior cytolytic activity in a panel of tumor cell lines. In this current study, we demonstrate that TAV-255, an E1a enhancer deletion vector, possesses tumor selective expression of both E1a and E1b along with potent tumor-selective oncolytic activity.

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Heat shock phenocopies E1B-55K late functions and selectively sensitizes refractory tumor cells to ONYX-015 oncolytic viral therapy

Cited by 102 publications

References 59 publications

A phase I trial of intratumoral administration of recombinant oncolytic adenovirus overexpressing HSP70 in advanced solid tumor patients

A phase I trial of intratumoral administration of recombinant oncolytic adenovirus overexpressing HSP70 in advanced solid tumor patients

Selective replication of E1B55K-deleted adenoviruses depends on enhanced E1A expression in cancer cells

Deletion analysis of Ad5 E1a transcriptional control region: impact on tumor-selective expression of E1a and E1b

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