An Improved Patient-Derived Xenograft Humanized Mouse Model for Evaluation of Lung Cancer Immune Responses

Meraz, Ismail M.; Majidi, Mourad; Feng, Ming; Shao, Ru; Ha, Min Jin; Neri, Shinya; Fang, Bingliang; Lin, Steven H.; Tinkey, Peggy T.; Shpall, Elizabeth J.; Morris, Jeffrey S.; Roth, Jack A.

doi:10.1158/2326-6066.cir-18-0874

Cited by 103 publications

(82 citation statements)

References 45 publications

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“…Moreover, Meraz and colleagues described the development of an improved Hu-PDX model that represent the human tumor microenvironment. Their results showed that approximately 60% to 80% of PDXs implanted in two different molecular types of Hu-PDX developed into tumors 69 . But current Hu-PDX model has several limitations: 1) the immune status and tumor microenvironment were not stable during Hu-PDX passage.…”

Section: Host Strainmentioning

confidence: 99%

The Essential Factors of Establishing Patient-derived Tumor Model

Chen¹,

Lin²,

Huang³

et al. 2021

J. Cancer

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Establishing an applicable preclinical model is vital for translational cancer research. Patient-derived xenograft has been important preclinical model systems and widely used for cancer research. Patient-derived xenograft models that represent the tumors of the patients are necessary to better translate research discoveries and to test potential therapeutic approaches. However, research in this field is hampered by the limited engraftment rate. In this review, we go over a large number of researches on patient-derived xenograft transplantation and firstly systematically summarize the main factors in methodology to successfully establish models. These results will be applied to the development of patient-derived xenograft leading to better preclinical research.

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Section: Host Strainmentioning

confidence: 99%

The Essential Factors of Establishing Patient-derived Tumor Model

Chen¹,

Lin²,

Huang³

et al. 2021

J. Cancer

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“…3 6 Despite this, the use of antibodies against PD-1 has shown efficacy in human xenograft and patient-derived xenograft tumors in these mice, demonstrating that these cells can generate antitumor responses. [7][8][9][10] Whereas checkpoint modulators have shown antitumor activity in humanized mice, there are limited data reporting characterization on human immune cell subsets within these tumors. To this end, we characterized several commonly used xenograft models across a range of tumor types in CD34 + humanized non-obese diabetic-scid gamma (NSG) mice.…”

Section: Introductionmentioning

confidence: 99%

Characterization of human cancer xenografts in humanized mice

Rios-Doria

Stevens

Maddage

et al. 2020

J Immunother Cancer

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BackgroundPreclinical evaluation of drugs targeting the human immune system has posed challenges for oncology researchers. Since the commercial introduction of humanized mice, antitumor efficacy and pharmacodynamic studies can now be performed with human cancer cells within mice bearing components of a human immune system. However, development and characterization of these models is necessary to understand which model may be best suited for different agents.MethodsWe characterized A375, A549, Caki-1, H1299, H1975, HCC827, HCT116, KU-19–19, MDA-MB-231, and RKO human cancer cell xenografts in CD34+humanized non-obese diabetic-scid gamma mice for tumor growth rate, immune cell profiling, programmed death ligand 1 (PD-L1) expression and response to anti-PD-L1 therapy. Immune cell profiling was performed using flow cytometry and immunohistochemistry. Antitumor response of humanized xenograft models to PD-L1 therapy was performed using atezolizumab.ResultsWe found that CD4+and CD8+T-cell composition in both the spleen and tumor varied among models, with A375, Caki-1, MDA-MB-231, and HCC827 containing higher intratumoral frequencies of CD4+and CD8+T cells of CD45+cells compared with other models. We demonstrate that levels of immune cell infiltrate within each model are strongly influenced by the tumor and not the stem cell donor. Many of the tumor models showed an abundance of myeloid cells, B cells and dendritic cells. RKO and MDA-MB-231 tumors contained the highest expression of PD-L1+tumor cells. The antitumor response of the models to atezolizumab was positively associated with the level of CD4+and CD8+tumor-infiltrating lymphocytes (TILs).ConclusionsThese data demonstrate that there are tumor-intrinsic factors that influence the immune cell repertoire within tumors and spleen, and that TIL frequencies are a key factor in determining response to anti-PD-L1 in tumor xenografts in humanized mice. These data may also aid in the selection of tumor models to test antitumor activity of novel immuno-oncology or tumor-directed agents.

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“…The HU-CD34 model has been successfully combined with several cell line-derived xenografts and PDXs of different cancer types (137)(138)(139). Although a perfect HLA match between CD34+ HSC donor and tumor patient is impossible, a partial HLA match did not negatively affect tumor growth in recent reports on PDXs (139,140).…”

Section: Hu-cd34 Modelmentioning

confidence: 99%

Glioblastoma Organoids: Pre-Clinical Applications and Challenges in the Context of Immunotherapy

et al. 2020

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Malignant brain tumors remain uniformly fatal, even with the best-to-date treatment. For Glioblastoma (GBM), the most severe form of brain cancer in adults, the median overall survival is roughly over a year. New therapeutic options are urgently needed, yet recent clinical trials in the field have been largely disappointing. This is partially due to inappropriate preclinical model systems, which do not reflect the complexity of patient tumors. Furthermore, clinically relevant patient-derived models recapitulating the immune compartment are lacking, which represents a bottleneck for adequate immunotherapy testing. Emerging 3D organoid cultures offer innovative possibilities for cancer modeling. Here, we review available GBM organoid models amenable to a large variety of pre-clinical applications including functional bioassays such as proliferation and invasion, drug screening, and the generation of patient-derived orthotopic xenografts (PDOX) for validation of biological responses in vivo. We emphasize advantages and technical challenges in establishing immunocompetent ex vivo models based on co-cultures of GBM organoids and human immune cells. The latter can be isolated either from the tumor or from patient or donor blood as peripheral blood mononuclear cells (PBMCs). We also discuss the challenges to generate GBM PDOXs based on humanized mouse models to validate efficacy of immunotherapies in vivo. A detailed characterization of such models at the cellular and molecular level is needed to understand the potential and limitations for various immune activating strategies. Increasing the availability of immunocompetent GBM models will improve research on emerging immune therapeutic approaches against aggressive brain cancer.

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An Improved Patient-Derived Xenograft Humanized Mouse Model for Evaluation of Lung Cancer Immune Responses

Cited by 103 publications

References 45 publications

The Essential Factors of Establishing Patient-derived Tumor Model

The Essential Factors of Establishing Patient-derived Tumor Model

Characterization of human cancer xenografts in humanized mice

Glioblastoma Organoids: Pre-Clinical Applications and Challenges in the Context of Immunotherapy

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