Results of a phase I study of CN706, a replication-competent cytolytic adenovirus, for the treatment of adenocarcinoma of the prostate which is locally-recurrent following radiation therapy

DeWeese, Theodore L.; Drew, Roger; Li, S.; Goemann, Marti; Mikhak, Bahar; Rodríguez, Roberto; Hamper, Ulrike M.; DeJong, M; Detorie, Nick; Simons, J.W.

doi:10.1016/s0360-3016(00)80138-8

Cited by 44 publications

(52 citation statements)

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“…Based on diffusion, the maximum amount of disseminated viruses would be several orders of magnitude less than that retained in the tumour. This was inconsistent with the observations shown in Figures 1, 2, 4 and 5 and data in the literature (DeWeese et al, 2001;Nemunaitis et al, 2001;Sauthoff et al, 2003). Therefore, diffusion is negligible during the virus dissemination.…”

Section: Discussioncontrasting

confidence: 91%

“…Systemic virus dissemination after intratumoral infusion has been investigated in previous studies (DeWeese et al, 2001;Nemunaitis et al, 2001;Sauthoff et al, 2003). Sauthoff et al (2003) have detected a self-replicating adenoviral vector in mouse blood at 10 min after intratumoral infusion, based on the assay of virus titration on 293 cells.…”

Section: Discussionmentioning

confidence: 99%

“…Researchers often assume that viral vectors and transgene expression are confined to solid tumours after the infusion, thereby causing minimal toxicity in normal tissues (Lu et al, 1999;Paielli et al, 2000). On the other hand, researchers in some studies have observed that transgene expression in normal tissues can be as strong as that in tumours (Toloza et al, 1996;Bramson et al, 1997;Nasu et al, 1999;Tjuvajev et al, 1999;Lohr et al, 2001;Wang et al, 2003), that adenoviral vectors are present in systemic circulation of patients in clinical trials (DeWeese et al, 2001;Nemunaitis et al, 2001), and that some animals die within a short period after intratumoral infusion (Toloza et al, 1996;Tjuvajev et al, 1999). These observations indicate that viral vectors can escape from tumours during and/or after intratumoral infusion.…”

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confidence: 99%

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Characterisation of systemic dissemination of nonreplicating adenoviral vectors from tumours in local gene delivery

Wang

Yang

et al. 2005

Br J Cancer

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Systemic virus dissemination is a potential problem during local gene delivery in solid tumours. However, the kinetics and pathways of the dissemination have not been well characterised during the first 24 h after the infusion is started. To this end, we infused adenoviral vectors for luciferase or enhanced green fluorescence protein into three different tumour models in mice. During and/or after the infusion, we determined the amount of adenoviruses in the tumour, blood, and liver, and examined the transgene expression in the liver, lung, blood, and tumour. In addition, we intravenously injected tumour cells expressing luciferase and examined the biodistribution of these cells in the body. We observed transgene expression in the liver and tumour at 24 h after the infusion, but could not detect transgene expression in the blood and lung. The peak concentration of viral vectors in the plasma occurred during the intratumoral infusion. At 10 min after the infusion, few viral vectors remained in the blood and the ratio of copy numbers of adenoviruses between liver and tumour was 42 in 80% and X10 in 40% of the mice. Most tumour cells injected intravenously accumulated in the lung within the first 24 h. Taken together, these data indicated that systemic virus dissemination occurred mainly during the first 10 min after the intratumoral infusion was started, and that the dissemination was due to infusion-induced convective transport of viral vectors into leaky tumour microvessels.

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Section: Discussioncontrasting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Characterisation of systemic dissemination of nonreplicating adenoviral vectors from tumours in local gene delivery

Wang

Yang

et al. 2005

Br J Cancer

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“…Although KD1 and KD3 performed well in tissue culture as well as in tumor xenotransplant experiments, 13,22 a review of the literature suggested that in in vitro experiments 15,[27][28][29][30] and especially in a clinical setting 31,32 the oncolytic effect of tumor-selective replicating Ads can be augmented by the use of concomitant radiation and/or chemotherapy. In this paper, we have examined whether the combination of radiation with Ad5-based vectors that overexpress ADP has an advantage over any of these treatments used alone.…”

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confidence: 99%

Radiation increases the activity of oncolytic adenovirus cancer gene therapy vectors that overexpress the ADP (E3-11.6K) protein

et al. 2003

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We have described three potential adenovirus type 5 (Ad5)-based replication-competent cancer gene therapy vectors named KD1, KD3, and VRX-007. All three vectors overexpress an Ad5 protein named Adenovirus Death Protein (ADP, also named E3-11.6 K protein). ADP is required for efficient lysis of Ad5-infected cells and spread of virus from cell to cell, and thus its overexpression increases the oncolytic activity of the vectors. KD1 and KD3 contain mutations in the Ad5 E1A gene that knock out binding of the E1A proteins to cellular p300/CBP and pRB; these mutations allow KD1 and KD3 to grow well in cancer cells but not in normal cells. VRX-007 has wild-type E1A. Here we report that radiation increases the oncolytic activity of KD1, KD3, and VRX-007. This increased activity was observed in cultured cells, and it was not because of radiation-induced replication of the vectors. The combination of radiation plus KD3 suppressed the growth of A549 lung adenocarcinoma xenografts in nude mice more efficiently than radiation alone or KD3 alone. The combination of ADP-overexpressing vectors and radiation may have potential in treating cancer.

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“…to humans without dose-limiting side effects. 37 The most difficult form of cervical cancer to treat is disseminated disease. For such applications, systemic administration is necessary.…”

Section: Effect Of Rgd-4c Modification On Infectivity and Killing Of mentioning

confidence: 99%

Evaluation of a selectively oncolytic adenovirus for local and systemic treatment of cervical cancer

Bauerschmitz

Kanerva

Wang

et al. 2004

Intl Journal of Cancer

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Treatment options for disseminated cervical cancer remain inadequate. Here, we investigated a strategy featuring Ad5-⌬24RGD, an oncolytic adenovirus replication-competent selectively in cells defective in the Rb-p16 pathway, such as most cervical cancer cells. The viral fiber contains an ␣ v ␤ 3 and ␣ v ␤ 5 integrin-binding RGD-4C motif, allowing coxsackieadenovirus receptor-independent infection. These integrins have been reported to be frequently upregulated in cervical cancer. Oncolysis of cervical cancer cells was similar to a wild-type control in vitro. In an animal model of cervical cancer, the therapeutic efficacy of Ad5-⌬24RGD could be demonstrated for both intratumoral and intravenous application routes. Biodistribution was determined following intravenous administration to mice. Further preclinical safety data were obtained by demonstrating lack of replication of the agent in human peripheral blood mononuclear cells. These results suggest that Ad5-⌬24RGD could be useful for local or systemic treatment of cervical cancer in patients with disease resistant to currently available modalities.

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Results of a phase I study of CN706, a replication-competent cytolytic adenovirus, for the treatment of adenocarcinoma of the prostate which is locally-recurrent following radiation therapy

Cited by 44 publications

References 0 publications

Characterisation of systemic dissemination of nonreplicating adenoviral vectors from tumours in local gene delivery

Characterisation of systemic dissemination of nonreplicating adenoviral vectors from tumours in local gene delivery

Radiation increases the activity of oncolytic adenovirus cancer gene therapy vectors that overexpress the ADP (E3-11.6K) protein

Evaluation of a selectively oncolytic adenovirus for local and systemic treatment of cervical cancer

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