Humanized NOD-SCID IL2rg –/– mice as a preclinical model for cancer research and its potential use for individualized cancer therapies

Zhou, Quan; Facciponte, John G.; Jin, Min; Shen, Qiang; Lin, Qiang

doi:10.1016/j.canlet.2013.10.015

Cited by 83 publications

(66 citation statements)

References 66 publications

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“…1 presents a simplified overview of the development of various immonodeficient mice for humanized mouse models. A remarkable improvement was obtained by introducing the mutated IL-2 receptor gamma chain (IL-2Ry) into the parent NOD/SCID and RAG1/2 -/-immunodeficient mouse strains [28,29]. These strains feature multiple immunodeficiencies, including defects in T-, B-and natural killer cells, reduced macrophage and dendritic cell function.…”

Section: Mice With Humanized Immune Systemmentioning

confidence: 97%

Animal models in translational medicine: Validation and prediction

Denayer¹,

Stöhr²,

Roy³

2014

European Journal of Molecular &Amp; Clinical Medicine

309

283

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a b s t r a c tDespite large investments in drug development, the overall success rate of drugs during clinical development remains low. One prominent explanation is flawed preclinical research, in which the use and outcome of animal models is pivotal to bridge the translational gap to the clinic. Therefore, the selection of a validated and predictive animal model is essential to address the clinical question. In this review, the current challenges and limitations of animal models are discussed, with a focus on the fit-forpurpose validation. Moreover, guidance is provided on the selection, design and conduct of an animal model, including the recommendation of assessing both efficacy and safety endpoints. In order to improve the clinical translation, the use of humanized mouse models and preclinical applications of clinical features are discussed. On top, the translational value of animal models could be further enhanced when combined with emerging alternative translational approaches. Focal points:Bedside Animal models are essential for translation of drug findings from bench to bedside. Hence, critical evaluation of the face and predictive validity of these models is important. Reversely, clinical bedside findings that were not predicted by animal testing should be back translated and used to refine the animal models. BenchsideProper design, execution and reporting of animal model results help to make preclinical data more reproducible and translatable to the clinic. IndustryDesign of an animal model strategy is part of the translational plan rather than (a) single experiment (s). Data from animal models are essential in predicting the clinical outcome for a specific drug in development. CommunityReview, standardization and refinement of animal models by disease expert groups helps to improve rigor of animal model testing. It is important that the applied animal models are validated fit-forpurpose according to stringent criteria and reproducible. GovernmentsAs during drug development fit-for-purpose animal models are key for success in clinical translation, financial investments and support from the government to develop, optimize, validate and run such translation tools are important. Over time, this will be of benefit for patients and healthcare institutions. Regulatory agenciesPreclinical testing of a drug in an animal model is not a prerequisite for regulatory agencies before entering clinical trials, but does unquestionably provide valuable data on the expected clinical performance of the drug. Hence, testing in animal models is largely recommended from both a business and patient perspective. In addition, inclusion of safety parameters in animal models will help to build the required safety data package of drugs in development.

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Section: Mice With Humanized Immune Systemmentioning

confidence: 97%

Animal models in translational medicine: Validation and prediction

Denayer¹,

Stöhr²,

Roy³

2014

European Journal of Molecular &Amp; Clinical Medicine

309

283

View full text Add to dashboard Cite

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“…gamma chain (γc)-deficient mice, nonobese diabetic (NOD)-severed combined immunodeficiency (SCID)-IL-2 receptor gamma (IL2rg)-deficient mice are commonly used host for xenograft implantation (Aparicio, Hidalgo, & Kung, 2015;Holzapfel et al, 2015;Legrand et al, 2009;Rongvaux et al, 2013). Mouse models xenografted with human tumor tissues are also widely used for immune-based targeted therapy studies, such as anti-VEGF and anti-EGFR mAbs, and adoptive-transferred engineered T cells (Holzapfel et al, 2015;Zhou, Facciponte, Jin, Shen, & Lin, 2014). However, it is notable that an assessment of these classes of therapy is flawed by the lack of intact adaptive immunity in the recipients, including important regulatory T and B cells.…”

Section: Humanized Mouse Tumor Modelsmentioning

confidence: 99%

Mouse Models of Tumor Immunotherapy

Ngiow

Loi

Thomas

et al. 2016

Advances in Immunology

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“…The breakthrough in the field of human cell engraftment came with the creation of the NOD-SCID mouse with either a deletion of the IL-2R common chain (NSG mouse) or a truncated mutation of the IL-2R (NOG mouse), which both allow the engraftment of human cells to a previously unachievable level [52]. The NSG mouse was found to support greater engraftment of human cells than any of the other available strains [53].…”

Section: Development Of Humanized Mouse Modelsmentioning

confidence: 99%

Chimeric Antigen Receptor T Cells for the Treatment of Cancer and the Future of Preclinical Models for Predicting their Toxicities

Wegner

2017

Immunotherapy

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CAR-T cell therapy has achieved highly promising results in clinical trials, particulary in B-cell malignancies. However, reports of Serious adverse events (SAE) including a number of patient deaths has raised concerns about safety of this treatment.Presently available pre-clinical models are not designed for predicting toxicities seen in human patients. Besides choosing the right animal model, careful considerations must be taken in CAR T-cell design and the amount of T-cells infused. The development of more sophisticated in vitro models and humanized mouse models for preclinical modeling and toxicity tests will help us to improve the design of clinical trials in cancer immunotherapy.

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Humanized NOD-SCID IL2rg –/– mice as a preclinical model for cancer research and its potential use for individualized cancer therapies

Cited by 83 publications

References 66 publications

Animal models in translational medicine: Validation and prediction

Animal models in translational medicine: Validation and prediction

Mouse Models of Tumor Immunotherapy

Chimeric Antigen Receptor T Cells for the Treatment of Cancer and the Future of Preclinical Models for Predicting their Toxicities

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