Patient-derived tumor xenografts in humanized NSG-SGM3 mice: A new immuno-oncology platform.

Yao, Li‐Chin; Riess, Jonathan W.; Cheng, Mingshan; Wang, Minan; Banchereau, Jacques; Shultz, L D; Palucka, Karolina; Keck, James

doi:10.1200/jco.2016.34.15_suppl.3074

Cited by 4 publications

(6 citation statements)

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“…Importantly, taking into account the species specificity of the antibodies included in the assay, the presence of some circulating human cytokines detected in the nonhumanized NSG mice (e.g., granulocyte-macrophage colony-stimulating factor [GM-CSF], interleukin [IL]-6, and IL-8) were considered to have originated from the PDX because their levels, which were among the highest of the panel, were also clearly detected in the tumor collected from nonhumanized NSG mice. One of the recognized limitations of the hNSG mouse model resides in the absence of key cytokines that may support the stable engraftment of myeloid lineages, notably GM-CSF [ 40 ]. Interestingly, as the present results show, PDX-mediated production of GM-CSF may have contributed to this situation, as clearly evidenced by the fact that, despite the total levels of hCD45 + cells being similar between hNSG mice with/without PDXs, the percentage of the myeloid lineage subpopulation, represented by hCD33 + cells, was significantly increased in those mice harboring the tumors (Fig.…”

Section: Resultsmentioning

confidence: 99%

Evaluation of anti-PD-1-based therapy against triple-negative breast cancer patient-derived xenograft tumors engrafted in humanized mouse models

et al. 2018

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BackgroundBreast cancer has been considered not highly immunogenic, and few patients benefit from current immunotherapies. However, new strategies are aimed at changing this paradigm. In the present study, we examined the in vivo activity of a humanized anti-programmed cell death protein 1 (anti-PD-1) antibody against triple-negative breast cancer (TNBC) patient-derived xenograft (PDX) tumor models.MethodsTo circumvent some of the limitations posed by the lack of appropriate animal models in preclinical studies of immunotherapies, partially human leukocyte antigen-matched TNBC PDX tumor lines from our collection, as well as human melanoma cell lines, were engrafted in humanized nonobese diabetic/severe combined immunodeficiency IL2Rγnull (hNSG) mice obtained by intravenous injection of CD34+ hematopoietic stem cells into nonlethally irradiated 3–4-week-old mice. After both PDXs and melanoma cell xenografts reached ~ 150–200 mm3, animals were treated with humanized anti-PD-1 antibody or anti-CTLA-4 and evaluated for tumor growth, survival, and potential mechanism of action.ResultsHuman CD45+, CD20+, CD3+, CD8+, CD56+, CD68+, and CD33+ cells were readily identified in blood, spleen, and bone marrow collected from hNSG, as well as human cytokines in blood and engrafted tumors. Engraftment of TNBC PDXs in hNSG was high (~ 85%), although they grew at a slightly slower pace and conserved their ability to generate lung metastasis. Human CD45+ cells were detectable in hNSG-harbored PDXs, and consistent with clinical observations, anti-PD-1 antibody therapy resulted in both a significant reduction in tumor growth and increased survival in some of the hNSG PDX tumor lines, whereas no such effects were observed in the corresponding non-hNSG models.ConclusionsThis study provides evidence associated with anti-PD-1 immunotherapy against TNBC tumors supporting the use of TNBC PDXs in humanized mice as a model to overcome some of the technical difficulties associated with the preclinical investigation of immune-based therapies.Electronic supplementary materialThe online version of this article (10.1186/s13058-018-1037-4) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Evaluation of anti-PD-1-based therapy against triple-negative breast cancer patient-derived xenograft tumors engrafted in humanized mouse models

et al. 2018

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“…The aim of introducing these mutations is to reduce murine cells and increase the engraftment of human cells and tissues to better recapitulate human immune responses (Aryee et al 2014; Billerbeck et al 2011; Chen et al 2009; Rongvaux et al 2014; Yao et al 2016). …”

Section: Evolving History Of Humanized Micementioning

confidence: 99%

“…Even though this combination of genes supports human HSC engraftment, formation of myeloid leukocytes, and reduces B-lymphopoiesis post-BM transplantation this model lacks an improved red blood cell (RBC) reconstitution and the presence of SCF may destructively affect human stem cell compartments by supporting the growth and competitive repopulation of mouse cells (Billerbeck et al 2011; Yao et al 2016). …”

Section: Evolving History Of Humanized Micementioning

confidence: 99%

“…There has been a constant pursuit to engineer novel immunodeficient mouse models via gene deletion or backcrossing strains with mutations in essential molecular compartments such as, T cells, B cells, macrophages, natural killer (NK) cells, cytokines, TLRs, and transcription factors (Pearson et al 2008 ). The aim of introducing these mutations is to reduce murine cells and increase the engraftment of human cells and tissues to better recapitulate human immune responses (Aryee et al 2014 ; Billerbeck et al 2011 ; Chen et al 2009 ; Rongvaux et al 2014 ; Yao et al 2016 ).…”

Section: Evolving History Of Humanized Micementioning

confidence: 99%

“…Second, NOD.Cg- Prkdc scid Il2rg tm1Wjl Tg (CMV-IL3, CSF2, KITLG) 1Eav/MloySzJ (NSG-SGM3 mouse) are knock-in mice expressing IL-3, GM-CSF and stem cell factor (SCF) under the control of human-specific cytomegalovirus (CMV) (Billerbeck et al 2011 ; Yao et al 2016 ). Even though this combination of genes supports human HSC engraftment, formation of myeloid leukocytes, and reduces B-lymphopoiesis post-BM transplantation this model lacks an improved red blood cell (RBC) reconstitution and the presence of SCF may destructively affect human stem cell compartments by supporting the growth and competitive repopulation of mouse cells (Billerbeck et al 2011 ; Yao et al 2016 ).…”

Section: Evolving History Of Humanized Micementioning

confidence: 99%

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Humanized Mice as Unique Tools for Human-Specific Studies

Yong

Her

Chen

2018

Arch. Immunol. Ther. Exp.

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With an increasing human population, medical research is pushed to progress into an era of precision therapy. Humanized mice are at the very heart of this new forefront where it is acutely required to decipher human-specific disease pathogenesis and test an array of novel therapeutics. In this review, “humanized” mice are defined as immunodeficient mouse engrafted with functional human biological systems. Over the past decade, researchers have been conscientiously making improvements on the development of humanized mice as a model to closely recapitulate disease pathogenesis and drug mechanisms in humans. Currently, literature is rife with descriptions of novel and innovative humanized mouse models that hold a significant promise to become a panacea for drug innovations to treat and control conditions such as infectious disease and cancer. This review will focus on the background of humanized mice, diseases, and human-specific therapeutics tested on this platform as well as solutions to improve humanized mice for future clinical use.

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Development and Applications of Patient‐Derived Xenograft Models in Humanized Mice for Oncology and Immune‐Oncology Drug Discovery

2017

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With the recent approval of four novel immune oncology agents for the treatment of various cancers, the emerging power of this drug class has been substantiated. However, the full potential of such agents is yet to be realized, with only a fraction of the patient population responding to these drugs. A more advanced pre-clinical and translational research platform may increase our understanding of the mechanisms associated with immune-mediated cancer cell death, thereby facilitating the design and development of more generally efficacious agents and drug regimens. Described in this report are the nuances, advantages, and limitations of such a research approach. © 2017 by John Wiley & Sons, Inc.

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Patient-derived tumor xenografts in humanized NSG-SGM3 mice: A new immuno-oncology platform.

Cited by 4 publications

References 0 publications

Evaluation of anti-PD-1-based therapy against triple-negative breast cancer patient-derived xenograft tumors engrafted in humanized mouse models

Evaluation of anti-PD-1-based therapy against triple-negative breast cancer patient-derived xenograft tumors engrafted in humanized mouse models

Humanized Mice as Unique Tools for Human-Specific Studies

Development and Applications of Patient‐Derived Xenograft Models in Humanized Mice for Oncology and Immune‐Oncology Drug Discovery

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