Bacterial glucuronidase as general marker for oncolytic virotherapy or other biological therapies

Heß, Michael; Stritzker, Jochen; Härtl, Barbara; Sturm, Julia; Gentschev, Ivaylo; Szalay, Aladar A.

doi:10.1186/1479-5876-9-172

Cited by 14 publications

(19 citation statements)

References 30 publications

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“…Oncolytic activities of GL-ONC1 were quantified by the detection of b-gluc. Dilutions of PF and EDTA plasma samples were analyzed as described previously (27).…”

Section: B-gluc Assaymentioning

confidence: 99%

Phase I Study of Oncolytic Vaccinia Virus GL-ONC1 in Patients with Peritoneal Carcinomatosis

Lauer¹,

Schell²,

Beil³

et al. 2018

Clinical Cancer Research

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Peritoneal carcinomatosis is common in advanced tumor stages or disease recurrence arising from gastrointestinal cancers, gynecologic malignancies, or primary peritoneal carcinoma. Because current therapies are mostly ineffective, new therapeutic approaches are needed. Here, we report on a phase I study designed to assess safety, MTD, and antitumor activity of intraperitoneal administration of oncolytic vaccinia virus GL-ONC1 in advanced stage peritoneal carcinomatosis patients. GL-ONC1 was administered intraperitoneally every 4 weeks for up to four cycles at three different dose levels (10-10 pfu) following a standard 3+3 dose escalation design. GL-ONC1 was infused via an indwelling catheter that enabled repetitive analyses of peritoneal fluid biopsies. The primary study objective was safety of GL-ONC1 according to Common Terminology Criteria for Adverse Events, version 4.0 (CTCAEv4.0). Patients with advanced-stage peritoneal carcinomatosis ( = 7) or advanced peritoneal mesothelioma ( = 2) received 24 doses of GL-ONC1. Adverse events were limited to grades 1-3, including transient flu-like symptoms and increased abdominal pain, resulting from treatment-induced peritonitis. No DLT was reported, and the MTD was not reached. Furthermore, no signs of viral shedding were observed. Importantly, in 8 of 9 study patients, effective intraperitoneal infections, in-patient replication of GL-ONC1, and subsequent oncolysis were demonstrated in cycle 1. All patients developed neutralizing activities against GL-ONC1. GL-ONC1 was well tolerated when administered into the peritoneal cavity of patients with advanced stage peritoneal carcinomatosis. Efficient tumor cell infection, in-patient virus replication, and oncolysis were limited to treatment cycle 1 (ClinicalTrials.gov number, NCT01443260). .

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“…Oncolytic activities of GL-ONC1 were quantified by the detection of b-gluc. Dilutions of PF and EDTA plasma samples were analyzed as described previously (27).…”

Section: B-gluc Assaymentioning

confidence: 99%

Phase I Study of Oncolytic Vaccinia Virus GL-ONC1 in Patients with Peritoneal Carcinomatosis

Lauer¹,

Schell²,

Beil³

et al. 2018

Clinical Cancer Research

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“…The quantitative β-glucuronidase assay using this GusA enzyme is a very promising and well established in our laboratory reporter system 27, 28, 29. It is very accurate, requires very small sample volume, uses inexpensive substrates, and could be carried out in a very short time.…”

Section: Discussionmentioning

confidence: 99%

Humanized Mice with Subcutaneous Human Solid Tumors for Immune Response Analysis of Vaccinia Virus-Mediated Oncolysis

Tsoneva

Minev

Frentzen

et al. 2017

Molecular Therapy - Oncolytics

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Oncolytic vaccinia virus (VACV) therapy is an alternative cancer treatment modality that mediates targeted tumor destruction through a tumor-selective replication and an induction of anti-tumor immunity. We developed a humanized tumor mouse model with subcutaneous human tumors to analyze the interactions of VACV with the developing tumors and human immune system. A successful systemic reconstitution with human immune cells including functional T cells as well as development of tumors infiltrated with human T and natural killer (NK) cells was observed. We also demonstrated successful in vivo colonization of such tumors with systemically administered VACVs. Further, a new recombinant GLV-1h376 VACV encoding for a secreted human CTLA4-blocking single-chain antibody (CTLA4 scAb) was tested. Surprisingly, although proving CTLA4 scAb’s in vitro binding ability and functionality in cell culture, beside the significant increase of CD56bright NK cell subset, GLV-1h376 was not able to increase cytotoxic T or overall NK cell levels at the tumor site. Importantly, the virus-encoded β-glucuronidase as a measure of viral titer and CTLA4 scAb amount was demonstrated. Therefore, studies in our “patient-like” humanized tumor mouse model allow the exploration of newly designed therapy strategies considering the complex relationships between the developing tumor, the oncolytic virus, and the human immune system.

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“…6D). Regarding the higher activity of bacterial β-glucuronidase at pH 7.4, it should be noted that since micelles are poorly internalized 50 and virus-encoded β-glucuronidase is released from the tumor cells upon tumor cell lysis 40 , it is expected that part of the prodrug is activated in the extracellular space having a pH close to neutral.…”

Section: Resultsmentioning

confidence: 99%

“…Determination of glucuronidase activity was performed with minor variations according to Hess et al 40 . Briefly, tumors were isolated 26 days after the first DOX treatment, weighted, snap-frozen in liquid nitrogen and stored at −80°C.…”

Section: Glucuronidase Assaymentioning

confidence: 99%

PEG-pHPMAm-based polymeric micelles loaded with doxorubicin-prodrugs in combination antitumor therapy with oncolytic vaccinia viruses

et al. 2014

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An enzymatically activatable prodrug of doxorubicin was covalently coupled, using clickchemistry, to the hydrophobic core of poly(ethylene glycol)-b-poly[N-(2-hydroxypropyl)-methacrylamide-lactate] micelles. The release and cytotoxic activity of the prodrug was evaluated in vitro in A549 non-small-cell lung cancer cells after adding β-glucuronidase, an enzyme which is present intracellularly in lysosomes and extracellularly in necrotic areas of tumor lesions. The prodrug-containing micelles alone and in combination with standard and β-glucuronidaseproducing oncolytic vaccinia viruses were also evaluated in vivo, in mice bearing A549 xenograft tumors. When combined with the oncolytic viruses, the micelles completely blocked tumor growth. Moreover, a significantly better antitumor efficacy as compared to virus treatment alone was observed when β-glucuronidase virus treated tumor-bearing mice received the prodrugcontaining micelles. These findings show that combining tumor-targeted drug delivery systems with oncolytic vaccinia viruses holds potential for improving anticancer therapy.

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Bacterial glucuronidase as general marker for oncolytic virotherapy or other biological therapies

Cited by 14 publications

References 30 publications

Phase I Study of Oncolytic Vaccinia Virus GL-ONC1 in Patients with Peritoneal Carcinomatosis

Phase I Study of Oncolytic Vaccinia Virus GL-ONC1 in Patients with Peritoneal Carcinomatosis

Humanized Mice with Subcutaneous Human Solid Tumors for Immune Response Analysis of Vaccinia Virus-Mediated Oncolysis

PEG-pHPMAm-based polymeric micelles loaded with doxorubicin-prodrugs in combination antitumor therapy with oncolytic vaccinia viruses

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