Engineered adenoviruses combine enhanced oncolysis with improved virus production by mesenchymal stromal carrier cells

Hammer, Katharina; Kazcorowski, Adam; Liu, Li; Behr, Michaël; Schemmer, Peter; Herr, Ingrid; Nettelbeck, Dirk M.

doi:10.1002/ijc.29442

Cited by 47 publications

(48 citation statements)

References 56 publications

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“…In recent years, MSCs have been studied as vehicles to deliver anti-cancer treatments because there is evidence that MSCs home to tumour sites. They can be induced to express anti-cancer proteins [e.g., interleukin (IL) 2], to produce pro-drug activating enzymes, which ensures that the active drug will only be localized in the tumour, or to deliver oncolytic viruses [20][21][22][23] . For these applications, the homing and persistence of MSCs in the target tissue are desirable [24] .…”

Section: Introductionmentioning

confidence: 99%

Homing and migration of mesenchymal stromal cells: How to improve the efficacy of cell therapy?

Becker¹,

Riet²

2016

WJSC

388

313

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Mesenchymal stromal cells (MSCs) are currently being investigated for use in a wide variety of clinical applications. For most of these applications, systemic delivery of the cells is preferred. However, this requires the homing and migration of MSCs to a target tissue. Although MSC homing has been described, this process does not appear to be highly efficacious because only a few cells reach the target tissue and remain there after systemic administration. This has been ascribed to low expression levels of homing molecules, the loss of expression of such molecules during expansion, and the heterogeneity of MSCs in cultures and MSC culture protocols. To overcome these limitations, different methods to improve the homing capacity of MSCs have been examined. Here, we review the current understanding of MSC homing, with a particular focus on homing to bone marrow. In addition, we summarize the strategies that have been developed to improve this process. A better understanding of MSC biology, MSC migration and homing mechanisms will allow us to prepare MSCs with optimal homing capacities. The efficacy of therapeutic applications is dependent on efficient delivery of the cells and can, therefore, only benefit from better insights into the homing mechanisms.

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Section: Introductionmentioning

confidence: 99%

Homing and migration of mesenchymal stromal cells: How to improve the efficacy of cell therapy?

Becker¹,

Riet²

2016

WJSC

388

313

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show abstract

“…We performed a global sensitivity analysis of the parameter space and model simulations with the current model and noticed that this is true. Experimental evidence from various tumor models with oAd support this conclusion 11,32,43 .…”

Section: Resultsmentioning

confidence: 78%

Mesenchymal stem cells used as carrier cells of oncolytic adenovirus results in enhanced oncolytic virotherapy

Mahasa

Pillis

Ouifki

et al. 2020

Sci Rep

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Mesenchymal stem cells (MScs) loaded with oncolytic viruses are presently being investigated as a new modality of advanced/metastatic tumors treatment and enhancement of virotherapy. MSCs can, however, either promote or suppress tumor growth. To address the critical question of how MSCs loaded with oncolytic viruses affect virotherapy outcomes and tumor growth patterns in a tumor microenvironment, we developed and analyzed an integrated mathematical-experimental model. We used the model to describe both the growth dynamics in our experiments of firefly luciferase-expressing Hep3B tumor xenografts and the effects of the immune response during the MSCs-based virotherapy. We further employed it to explore the conceptual clinical feasibility, particularly, in evaluating the relative significance of potential immune promotive/suppressive mechanisms induced by MSCs loaded with oncolytic viruses. We were able to delineate conditions which may significantly contribute to the success or failure of MSC-based virotherapy as well as generate new hypotheses. In fact, one of the most impactful outcomes shown by this investigation, not inferred from the experiments alone, was the initially counter-intuitive fact that using tumor-promoting MSCs as carriers is not only helpful but necessary in achieving tumor control. considering the fact that it is still currently a controversial debate whether MSCs exert a pro-or anti-tumor action, mathematical models such as this one help to quantitatively predict the consequences of using MSCs for delivering virotherapeutic agents in vivo. Taken together, our results show that MSC-mediated systemic delivery of oncolytic viruses is a promising strategy for achieving synergistic anti-tumor efficacy with improved safety profiles.

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“…Previous studies have utilized genetically engineered MSCs modified using various gene therapy methods, including delivery using adenoviral transfer (18,19), Lipofectamine (20), physical cell puncture (21), electroporation (22), soundwaves (23) and lentiviruses (4,24). The primary advantage of lentivirus transfection is the capacity of gene integration with high efficiency, which establishes a new cell line that expresses the target gene (25).…”

Section: Discussionmentioning

confidence: 99%

Differentiation of genetically modified canine bone mesenchymal stem cells labeled with superparamagnetic iron oxide into neural‑like cells

Liu

Wang

et al. 2018

Mol Med Report

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The use of mesenchymal stem cells (MSCs) has been reported to improve outcomes in various types of nervous system diseases, primarily based on their neural regenerative differentiation ability and paracrine effect on different neuroprotective cytokines. Genetically modified MSCs may enhance the paracrine effect and may further improve the cell‑based therapeutic outcome of nervous system diseases. Magnetic resonance imaging has been used to monitor distribution and migration of cells labeled with superparamagnetic iron oxide (SPIO) nanoparticles. However, few studies have described the neural differentiation ability of genetically modified and SPIO‑labeled MSCs, which is the foundation for cell tracking and cell therapy in vivo. In this study, canine bone marrow‑derived MSCs (BMSCs) were initially labeled with SPIO, by culturing with 20 µg/ml SPIO for 24 h, and transfected with the brain‑derived neurotrophic factor (BDNF) gene using lentivirus transfection at different multiplicities of infection (MOI) values. The optimized MOI value was demonstrated by cellular viability and enhanced green fluorescent protein (eGFP) rate. Subsequently, the BMSCs were induced to differentiate into neuron‑like cells by chemical induction. The results demonstrated that BDNF‑overexpressing BMSCs labeled with SPIO can be induced into neuron‑like cells with high efficiency and minimal effects on cell viability. Additionally, following neural differentiation, the cells transfected with BDNF and labeled with SPIO expressed significantly higher levels of BDNF and neural markers. The overexpression of BDNF may contribute to neural differentiation of BDNFs, and may have potential benefits for further BMSC‑based therapy in vivo.

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Engineered adenoviruses combine enhanced oncolysis with improved virus production by mesenchymal stromal carrier cells

Cited by 47 publications

References 56 publications

Homing and migration of mesenchymal stromal cells: How to improve the efficacy of cell therapy?

Homing and migration of mesenchymal stromal cells: How to improve the efficacy of cell therapy?

Mesenchymal stem cells used as carrier cells of oncolytic adenovirus results in enhanced oncolytic virotherapy

Differentiation of genetically modified canine bone mesenchymal stem cells labeled with superparamagnetic iron oxide into neural‑like cells

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