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Humanized Immune System Mice and Cell-Line Derived Xenografts

Dec 16, 2021 1:30:00 PM / by Champions Oncology

3D rendering of the tumor microenvironment

Humanized immune system (HIS) mice are valuable models for preclinical oncology research because they can tolerate tumor xenografts and can be used to assess responses to novel drugs, biologics, or adaptive cell therapies. Cell-line derived xenografts (CDX) are commonly used in HIS mice for these preclinical studies because they have defined properties and genomic sequences and are ideal for screening targeted therapies. Here we highlight features of HIS models that use CDX and compare this approach with patient-derived xenografts (PDX).

 

Cancer cell lines exist for nearly every known solid tumor or hematologic malignancy and can be grown in culture for in vitro drug screening. These cell lines can be transplanted into immunodeficient or HIS mice for in vivo studies as well. Hundreds of cancer cell lines have been sequenced and characterized for mutations that contribute to tumorigenesis, and these cell lines can be readily used for both in vitro and in vivo screens[1]. HIS models can be made in different immunodeficient mice that are reconstituted with either CD34+ human hematopoietic stem cells (HSCs) or peripheral blood mononuclear cells (PBMCs). After the immune system has been reconstituted with these human cells, which can take several weeks, CDX cells are injected either subcutaneously or into target tissues, which is then typically followed by evaluation of preclinical drug candidates[2]. CDX are ideal for evaluating drug candidates that target specific mutations in a tumor cell line. CDX tend to grow predictably and are well-characterized in different mouse models, including metastasis and tumor budding, thus making them appropriate for evaluating of drugs that can target specific pathways in tumors and for gaining insights into tissue penetration and distribution.

SEM (TEM) macroscope image. DNA mutations.Although CDX cell lines are useful for preclinical screens, they behave differently than bona fide tumors or patient-derived xenografts (PDX) and often do not recapitulate the tumor microenvironment. Thus, CDX models are considered more appropriate for early preclinical studies in which in vitro work is being carried over to HIS models. CDX models can use paired tumor cell lines that carry or lack specific mutations to validate a drug target, which is critical issue to address in preclinical studies. Later stage clinical studies with leading drug or biologic candidates typically use PDX models to better evaluate responses in humans.

 

CDX models have emerged as a tool to study early steps related to the spread of circulating tumor cells (CTCs). CTCs are released from tumor masses and have phenotypic properties that allow them to survive in circulation and seed new tumor metastases. In most tumor models, CTCs circulate at very low frequencies and can be difficult to detect. CTC-derived CDX models use engineered tumor cell lines that allow for their detection, and this approach has been critical to understanding the metastatic cascade that occurs during CTC dissemination[3]. These models can also be used to evaluate drugs that target CTCs or disseminated tumors.

 

Although PDX models are widely used now, CDX models in HIS mice have a place in preclinical research for identifying drug candidates, determining mechanisms of action, and validating drug targets. CDX models in HIS mice continue to be a key player in preclinical oncology research.

 

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[1] Yu C, Mannan AM, Yvone GM, et al. High-throughput identification of genotype-specific cancer vulnerabilities in mixtures of barcoded tumor cell lines. Nature Biotechnol. 2016 Apr;34(4):419-23.

[2] Lin S, Huang G, Cheng L, et al. Establishment of peripheral blood mononuclear cell-derived humanized lung cancer mouse models for studying efficacy of PD-L1/PD-1 targeted immunotherapy. MAbs. 2018 Nov-Dec;10(8):1301-1311.

[3] Tayoun T, Faugeroux V, Oulhen M, Aberlenc A, Pawlikowska P, Farace F. CTC-Derived Models: A Window into the Seeding Capacity of Circulating Tumor Cells (CTCs). Cells. 2019 Sep 25;8(10):1145.

 

Tags: Humanized Models