Effects of Onyx-015 among metastatic colorectal cancer patients that have failed prior treatment with 5-FU/leucovorin

Reid, Tony; Freeman, Scott; Post, Leonard; McCormick, Frank; Sze, Daniel Y.

doi:10.1038/sj.cgt.7700819

Cited by 89 publications

(72 citation statements)

References 35 publications

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“…12 Despite evidence of ongoing replication of Onyx-015, there were no clinical symptoms of infection of normal tissues such as cough, conjunctivitis or diarrhea; however, necrosis of tumor masses was demonstrated radiographically. 12,17 Taken together, these findings are consistent with tumor-selective replication of Onyx-015.…”

Section: Introductionsupporting

confidence: 62%

“…17 The objective response rate for patients in this study was 8% and the median survival was 11 months, exceeding the expected response rate of 2-5% and survival of 4-6 months for patients with refractory colorectal cancer. [18][19][20][21][22] Although the objective response rate was encouraging, standard radiographic response criteria may not have captured important clinical responses with this biologically active agent.…”

Section: Introductioncontrasting

confidence: 61%

“…[18][19][20][21][22] Although the objective response rate was encouraging, standard radiographic response criteria may not have captured important clinical responses with this biologically active agent. 12,17,23 Forty-six percent of the patients in the phase II study demonstrated transient enlargement of the tumor masses 3 weeks after administration of Onyx-015 followed by regression of the tumors starting 2-3 months after initiation of therapy. 17 Transient enlargement is consistent with inflammation of the tumor masses and this effect, coupled with extensive necrosis and slow resolution of the tumor, may have obscured the actual response rate in this study.…”

Section: Introductionmentioning

confidence: 99%

“…12,17,23 Forty-six percent of the patients in the phase II study demonstrated transient enlargement of the tumor masses 3 weeks after administration of Onyx-015 followed by regression of the tumors starting 2-3 months after initiation of therapy. 17 Transient enlargement is consistent with inflammation of the tumor masses and this effect, coupled with extensive necrosis and slow resolution of the tumor, may have obscured the actual response rate in this study. Because of the biphasic response curve, patients with clinical benefit as shown by prolonged survival, were not classified as responders by standard radiographic response criteria.…”

Section: Introductionmentioning

confidence: 99%

“…Finally, in patients with cancer, we demonstrated that transient enlargement of tumor masses occurs in the first few weeks after treatment with Onyx-015. 17,23 Enlargement of the tumor masses could cause increased intrahepatic pressure resulting in bile duct obstruction and a rise in blood levels of bilirubin and alkaline phosphatase. We reviewed the data from the Onyx-015 hepatic artery infusion study to determine if repeated infusions of adenovirus into the hepatic artery of patients with metastatic colorectal cancer caused increased or idiosyncratic hepatic toxicity.…”

Section: Introductionmentioning

confidence: 99%

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Minimal hepatic toxicity of Onyx-015: spatial restriction of coxsackie-adenoviral receptor in normal liver

Thorne

Korn

et al. 2006

Cancer Gene Ther

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We administered an adenoviral vector, Onyx-015, into the hepatic artery of patients with metastatic colorectal cancer involving the liver. Thirty-five patients enrolled in this multi-institutional phase I/II trial received up to eight arterial infusions of up to 2 Â 10 12 viral particles. Hepatic toxicity was the primary dose-limiting toxicity observed in preclinical models. However, nearly 200 infusions of this adenoviral vector were administered directly into the hepatic artery without significant toxicity. Therefore, we undertook this analysis to determine the impact of repeated adenoviral exposure on hepatic function. Seventeen patients were treated at our institution, providing a detailed data set on the changes in hepatic function following repeated exposure to adenovirus. No changes in hepatic function occurred with the first treatment of Onyx-015 among these patients. Transient increases in transaminase levels occurred in one patient starting with the second infusion and transient increases in bilirubin was observed in two patients starting with the fifth treatment. These changes occurred too early to be explained by viral-mediated lysis of hepatocytes. In addition, viremia was observed starting 3-5 days after the viral infusion in half of the patient, but was not associated with hepatic toxicity. To further understand the basis for the minimal hepatic toxicity of adenoviral vectors, we evaluated the replication of adenovirus in primary hepatocytes and tumor cells in culture and the expression of the coxsackie-adenoviral receptor (CAR) in normal liver and colon cancer metastatic to the liver. We found that adenovirus replicates poorly in primary hepatocytes but replicates efficiently in tumors including tumors derived from hepatocytes. In addition, we found that CAR is localized at junctions between hepatocytes and is inaccessible to hepatic blood flow. CAR is not expressed on tumor vasculature but is expressed on tumor cells. Spatial restriction of CAR to the intercellular space in normal liver and diminished replication of adenovirus in hepatocytes may explain the minimal toxicity observed following repeated hepatic artery infusions with Onyx-015.

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Section: Introductionsupporting

confidence: 62%

Section: Introductioncontrasting

confidence: 61%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Minimal hepatic toxicity of Onyx-015: spatial restriction of coxsackie-adenoviral receptor in normal liver

Thorne

Korn

et al. 2006

Cancer Gene Ther

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Gene and Viral Therapy

Spurrell¹

2007

The Cancer Handbook

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The aim of gene therapy is to treat cancer by the introduction of genes that will sensitize tumour cells to other therapies, replace a mutated gene with a wild‐type copy, or activate an antitumour host immune response. Viruses can be used as vectors for carrying therapeutic transgenes, as well as being oncolytic in their own right. Using viruses to treat tumours derives from the inherent ability of a replicating virus to eventually destroy its host cell. Oncolytic viruses are tumour specific, causing lysis of tumour cells and not normal cells. There are viruses that are naturally tumour specific and viruses that have been engineered to become tumour specific. More recently, there has been increasing interest in the development of non‐viral vectors as gene therapy carriers. The benefits of using non‐viral vectors is that they are less likely to elicit an unwanted immune response, there is no risk of recombination, and they are easier to produce on a large scale. There are two main types of non‐viral gene delivery method—physical and via a chemical carrier. Both viral and non‐viral vectors have entered human phase I and II clinical trials in patients with a variety of solid tumour malignancies.

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Oncolytic viral therapy for human cancer: Challenges revisited

Tong

2005

Drug Dev. Res.

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Conditional replicative, oncolytic adenoviruses are genetically modified to replicate primarily in malignant cells with oncogenetic defects, selectively killing cancer cells in the process. Viral progenies released within the tumor microenvironment can penetrate, infect, and destroy additional cell layers of the solid tumor mass. Much excitement has been generated over the clinical successes of ONYX-015 adenovirus treatment for advanced head and neck cancer, pancreatic carcinoma, and metastatic colorectal carcinoma at the locoregional level. However, follow-up trials with systemic viral administration have not met initial expectations. This review examines recent basic science developments that may potentially overcome the two key limitations of systemic virotherapy, namely, suboptimal tumor oncolysis and pharmacokinetic shortcomings due to rapid viral clearance. Late-generation constructs incorporate alternative viral backbone modifications and antitumor transgenes to enhance oncolytic potency. Furthermore, altered viral tropism, through masking or substitution of viral surface components, is likely to promote tumor-selective targeting and safety. Merits of these approaches in the clinical arena are discussed. Drug Dev.

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Effects of Onyx-015 among metastatic colorectal cancer patients that have failed prior treatment with 5-FU/leucovorin

Cited by 89 publications

References 35 publications

Minimal hepatic toxicity of Onyx-015: spatial restriction of coxsackie-adenoviral receptor in normal liver

Minimal hepatic toxicity of Onyx-015: spatial restriction of coxsackie-adenoviral receptor in normal liver

Gene and Viral Therapy

Oncolytic viral therapy for human cancer: Challenges revisited

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