Adenovector-mediated gene delivery of interleukin-2 in metastatic breast cancer and melanoma: results of a phase 1 clinical trial

Stewart, A. Keith; Lassam, Norman J.; Quirt, Ian; Bailey, Denis; Rotstein, Lorne; Krajden, Mel; Dessureault, Sophie; Gallinger, Steven; Cappe, D; Wan, Yong; Addison, Christina L.; Moen, Robert C.; Gauldie, Jack; Graham, Felicia L.

doi:10.1038/sj.gt.3300833

Cited by 121 publications

(73 citation statements)

References 31 publications

(39 reference statements)

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“…Based on the multiple functions of Ad5 E1B-55K it will be interesting to analyse the contribution of the shuttling activity for viral replication and adenovirus transforma-tion. These studies will provide valuable information allowing the rational design of optimized Ad vectors presently under active investigation as an anti-tumour therapy (Fujita et al, 1995;Kirn and Hermiston, 1999;Kirn et al, 1998;Stewart et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

The adenovirus type 5 E1B-55K oncoprotein is a highly active shuttle protein and shuttling is independent of E4orf6, p53 and Mdm2

et al. 2000

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The E1B-55K and E4orf6 oncoproteins of adenovirus type 5 are involved in the export of viral mRNAs. Previously, it was suggested that a complex composed of E1B-55K and E4orf6 serves as a nucleocytoplasmic transporter for viral mRNAs in which the E4orf6 protein directs both nuclear import and export. We now demonstrate that the E1B-55K protein itself shuttles e ciently in the absence of E4orf6. In addition, E1B-55K tra cking was independent of the de®ned shuttle proteins Mdm2 or p53, which interacts with E1B-55K. The identi®ed N-terminal E1B-55K leucine-rich nuclearexport signal (NES) conferred rapid nuclear export even in a heterologous system in contrast to the postulated E4orf6NES. Interestingly, although shuttling was blocked by inhibitors of the CRM1 mediated export pathway, E1B-55K inhibited neither the activity nor the tra cking of the retroviral shuttle proteins HIV-1 Rev and HTLV-1 Rex. In contrast, Rev or Rex blocked the nuclear export of E1B-55K, most likely by competing for essential export factors. Our results provide new insights into the regulation of the adenovirus mRNA export system and the processes of adenovirus mediated transformation. Oncogene (2000) 19, 850 ± 857.

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Section: Discussionmentioning

confidence: 99%

The adenovirus type 5 E1B-55K oncoprotein is a highly active shuttle protein and shuttling is independent of E4orf6, p53 and Mdm2

et al. 2000

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“…13,14 Clinical-grade AdCAIL-2 viral supernatant is packaged at 1 Â 10 10 PFU/ml (PFU: plaque forming unit) and contains 1-10 PFU of detectable wildtype virus in 1 Â 10 9 PFU of viral vector.…”

Section: Adenovirus and Vaccine Administrationmentioning

confidence: 99%

“…Safety testing for replication-competent adenovirus or shed adenovector in the blood, saliva or stool of patients was performed as in our previous studies and was negative for the entire study population. 13,14 Local immune responses Surgical specimens from all 12 patients taken at the time of prostatectomy (4 weeks after inoculation with Ad-CAIL-2) were characterized histologically by an infiltrate of CD3-positive T cells (Fig 1). Differential staining with CD4 and CD8 antibodies showed a preponderance of CD8-positive cells.…”

Section: Toxicitymentioning

confidence: 99%

“…12 In previous work we have demonstrated successful in vivo adenoviral-mediated gene transfer of immunostimulatory molecules into primary human tumors. 13,14 Furthermore, Phase I clinical trials of an adenovirus expressing IL-2 (AdCAIL-2) demonstrated safety of administration as well as bioactivity of the treatment. On the basis of these preclinical and clinical studies, we initiated a Phase I dose-escalation study of in situ AdCAIL-2 administration for patients with localized, high-risk prostate cancer.…”

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confidence: 99%

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A phase I trial of adenovector-mediated delivery of interleukin-2 (AdIL-2) in high-risk localized prostate cancer

et al. 2003

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Preclinical studies demonstrate that intratumoral delivery of adenovirus expressing IL-2 eradicates pre-established tumors in mice and confers immune protection from rechallenge. To explore the activity of AdCAIL-2 in prostate cancer, a Phase I clinical trial was conducted in patients with localized disease and Gleason score 47 or prostate-specific antigen (PSA) 410 plus Gleason score 7. A total of 12 patients were injected 4 weeks prior to prostatectomy in a dose-escalation study at doses of 10 9 , 5 Â 10 9 and 10 10 PFU of virus. No dose-limiting toxicity was observed. Side effects included perineal discomfort, hematuria, flu-like symptoms in two patients and urinary hesitancy in one patient. Pathology demonstrated an inflammatory response consisting predominantly of CD3+CD8+ T lymphocytes with areas of tumor necrosis. Intracellular cytokine staining of tumor-infiltrating lymphocytes demonstrated increases in both g-interferon and IL-4 secreting T cells after vaccination. PSA levels fell in five of five evaluable patients treated at the lowest dose (mean decline of 33.3%, range 17-69%). At higher doses, PSA values initially increased after injection, then fell to baseline prior to surgery. This trial demonstrates the feasibility and safety of intraprostatic adenovectormediated IL-2 gene delivery.

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“…This is probably due to the fact that gene delivery is only accomplished in a small portion of the tumour tissue and accompanying problems with the large vector doses then required to give significant gene transfer. Non-replicating vectors based on adenoviruses and retroviruses have been tested in the clinic for direct intra-tumoral delivery of potentially therapeutic genes such as p53 (reviewed by Fujiwara et al 8 ), various pro-drug activators such as thymidine kinase and nitroreductase (reviewed by Xu and McLeod 9 ), or immune stimulatory molecules such as IL2 (eg references 10,11) or various interferons (reviewed by Ferrantini and Belardelli 12 ). Significant efficacy has not, however, so far been demonstrated.…”

Section: Introductionmentioning

confidence: 99%

ICP34.5 deleted herpes simplex virus with enhanced oncolytic, immune stimulating, and anti-tumour properties

Liu¹,

Robinson²,

Han³

et al. 2003

Gene Ther

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624

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Adenovector-mediated gene delivery of interleukin-2 in metastatic breast cancer and melanoma: results of a phase 1 clinical trial

Cited by 121 publications

References 31 publications

The adenovirus type 5 E1B-55K oncoprotein is a highly active shuttle protein and shuttling is independent of E4orf6, p53 and Mdm2

The adenovirus type 5 E1B-55K oncoprotein is a highly active shuttle protein and shuttling is independent of E4orf6, p53 and Mdm2

A phase I trial of adenovector-mediated delivery of interleukin-2 (AdIL-2) in high-risk localized prostate cancer

ICP34.5 deleted herpes simplex virus with enhanced oncolytic, immune stimulating, and anti-tumour properties

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