Tumor Anti-angiogenic Gene Therapy with Microencapsulated Recombinant CHO Cells

Zhang, Ying; Wang, Wei; Zhou, Jing; Wu, Yu; Zhang, Xulang; Guo, Xin; Ma, Xiaojun

doi:10.1007/s10439-007-9255-4

Cited by 15 publications

(4 citation statements)

References 43 publications

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“…The implantation of ES-expressing cells encapsulated in alginate microcapsules into the peritoneal cavity of mice has also been described. The articles reported lower levels of heterologous ES, namely 0.257 μg/ml (22), 0.194 μg/ml (21), and 0.017 μg/ml (10), compared with the levels of up to 2.98 μg/ml described here.…”

Section: Discussioncontrasting

confidence: 57%

“…The treatment of solid tumors using local ES delivery by implantation of alginate microcapsules containing genetically engineered cells that produce ES at the vicinity of the tumor site (10,16) or by transplantation of ES-producer cells into the peritoneal cavity of model animals (18,21,22) has been described. However, there is no possibility of withdrawing the alginate microcapsules containing the genetically engineered cells in the case of undesired side effects.…”

Section: Introductionmentioning

confidence: 99%

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Continuous and High-Level in Vivo Delivery of Endostatin from Recombinant Cells Encapsulated in TheraCyte® Immunoisolation Devices

et al. 2010

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Endostatin (ES) is a potent inhibitor of angiogenesis and tumor growth. Continuous ES delivery of ES improves the efficacy and potency of the antitumoral therapy. The TheraCyte system is a polytetrafluoroethylene (PTFE) semipermeable membrane macroencapsulation system for implantation of genetically engineered cells specially designed for the in vivo delivery of therapeutic proteins, such as ES, which circumvents the problem of limited half-life and variation in circulating levels. In order to enable neovascularization at the tissues adjacent to the devices prior to ES secretion by the cells inside them, we designed a scheme in which empty TheraCyte devices were preimplanted SC into immunodeficient mice. Only after healing (17 days later) were Chinese hamster ovary cells expressing ES injected into the preimplanted devices. In another model for device implantation, the cells expressing ES where loaded into the immunoisolation devices prior to implantation into the animals, and the TheraCyte were then immediately implanted SC into the mice. Throughout the 2-month study, constant high ES levels of up to 3.7 microg/ml were detected in the plasma of the mice preimplanted with the devices, while lower but also constant levels of ES (up to 2.1 microg/ml plasma) were detected in the mice that had received devices preloaded with the ES-expressing cells. Immunohistochemistry using anti-ES antibody showed reaction within the device and outside it, demonstrating that ES, secreted by the confined recombinant cells, permeated through the membrane and reached the surrounding tissues.

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Section: Discussioncontrasting

confidence: 57%

Section: Introductionmentioning

confidence: 99%

Continuous and High-Level in Vivo Delivery of Endostatin from Recombinant Cells Encapsulated in TheraCyte® Immunoisolation Devices

et al. 2010

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“…Regarding the comparison between treatment using non-encapsulated cells or cells wrapped up in alginate microcapsules [6,7,9,10], the advantages of the use of macroencapsulated cells are: (1) the possibility of removing the devices in the case of adverse reactions or at the end of the treatment; (2) escape of potentially tumorigenic endostatin producing cells from the macrocapsules is virtually impossible; (3) the system described herein allows the use of universal allogeneic endostatin producer cells, avoiding the host's immune rejection.…”

Section: Discussionmentioning

confidence: 99%

Anti-tumor therapy with macroencapsulated endostatin producer cells

et al. 2010

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BackgroundTheracyte is a polytetrafluoroethylene membrane macroencapsulation system designed to induce neovascularization at the tissue interface, protecting the cells from host's immune rejection, thereby circumventing the problem of limited half-life and variation in circulating levels. Endostatin is a potent inhibitor of angiogenesis and tumor growth. Continuous delivery of endostatin improves the efficacy and potency of the antitumoral therapy. The purpose of this study was to determine whether recombinant fibroblasts expressing endostatin encapsulated in Theracyte immunoisolation devices can be used for delivery of this therapeutic protein for treatment of mice bearing B16F10 melanoma and Ehrlich tumors.ResultsMice were inoculated subcutaneously with melanoma (B16F10 cells) or Ehrlich tumor cells at the foot pads. Treatment began when tumor thickness had reached 0.5 mm, by subcutaneous implantation of 107 recombinant encapsulated or non-encapsulated endostatin producer cells. Similar melanoma growth inhibition was obtained for mice treated with encapsulated or non-encapsulated endostatin-expressing cells. The treatment of mice bearing melanoma tumor with encapsulated endostatin-expressing cells was decreased by 50.0%, whereas a decrease of 56.7% in tumor thickness was obtained for mice treated with non-encapsulated cells. Treatment of Ehrlich tumor-bearing mice with non-encapsulated endostatin-expressing cells reduced tumor thickness by 52.4%, whereas lower tumor growth inhibition was obtained for mice treated with encapsulated endostatin-expressing cells: 24.2%. Encapsulated endostatin-secreting fibroblasts failed to survive until the end of the treatment. However, endostatin release from the devices to the surrounding tissues was confirmed by immunostaining. Decrease in vascular structures, functional vessels and extension of the vascular area were observed in melanoma microenvironments.ConclusionsThis study indicates that immunoisolation devices containing endostatin-expressing cells are effective for the inhibition of the growth of melanoma and Ehrlich tumors.Macroencapsulation of engineered cells is therefore a reliable platform for the refinement of innovative therapeutic strategies against tumors.

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“…The relatively new human Expi293F cell line, however, is mostly used for transient transgene expression. Since transient biotherapeutics expression is not always an attractive option from an industrial or cell-therapeutic perspective, an Expi293F platform should entail transgenic master cell lines with modular features as a basis for biopharmaceutical testing/production and innovative therapeutic applications such as transplantable cell-encapsulated mini bioreactors ( Zhang et al, 2007 ; Lathuilière et al, 2015 ; Bose et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

A versatile genomic transgenesis platform with enhanced λ integrase for human Expi293F cells

Siddiqui

Peter

Ngoh

et al. 2023

Front. Bioeng. Biotechnol.

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Reliable cell-based platforms to test and/or produce biologics in a sustainable manner are important for the biotech industry. Utilizing enhanced λ integrase, a sequence-specific DNA recombinase, we developed a novel transgenesis platform involving a fully characterized single genomic locus as an artificial landing pad for transgene insertion in human Expi293F cells. Importantly, transgene instability and variation in expression were not observed in the absence of selection pressure, thus enabling reliable long-term biotherapeutics testing or production. The artificial landing pad for λ integrase can be targeted with multi-transgene constructs and offers future modularity involving additional genome manipulation tools to generate sequential or nearly seamless insertions. We demonstrated broad utility with expression constructs for anti PD-1 monoclonal antibodies and showed that the orientation of heavy and light chain transcription units profoundly affected antibody expression levels. In addition, we demonstrated encapsulation of our PD-1 platform cells into bio-compatible mini-bioreactors and the continued secretion of antibodies, thus providing a basis for future cell-based applications for more effective and affordable therapies.

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Tumor Anti-angiogenic Gene Therapy with Microencapsulated Recombinant CHO Cells

Cited by 15 publications

References 43 publications

Continuous and High-Level in Vivo Delivery of Endostatin from Recombinant Cells Encapsulated in TheraCyte® Immunoisolation Devices

Continuous and High-Level in Vivo Delivery of Endostatin from Recombinant Cells Encapsulated in TheraCyte® Immunoisolation Devices

Anti-tumor therapy with macroencapsulated endostatin producer cells

A versatile genomic transgenesis platform with enhanced λ integrase for human Expi293F cells

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