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

Verma, Bhavna; Ritchie, Michael; Mancini, Maria

doi:10.1002/cpph.26

Cited by 10 publications

(9 citation statements)

References 40 publications

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“…More recently, the generation of humanized PDX models offers a more sophisticated alternative. In this model, irradiated immune-deficient mice are reconstituted with a human immune system (Rongvaux et al 2014;Verma et al 2017)). As an example, human hepatocellular carcinoma (HCC) PDX tumors implanted in irradiated NOD-SCID Il2rg −/− (NSG) mice reconstituted with human CD34 + hematopoietic stem cells exhibit human leukocytes infiltrated in tumors, phenotypes associated with immune exhaustion, and therapeutic response to pembrolizumab and ipilimumab (Zhao et al 2018).…”

Section: Challenges In Studying Cancer-associated Inflammatory Cellsmentioning

confidence: 99%

Roles of the immune system in cancer: from tumor initiation to metastatic progression

2018

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The presence of inflammatory immune cells in human tumors raises a fundamental question in oncology: How do cancer cells avoid the destruction by immune attack? In principle, tumor development can be controlled by cytotoxic innate and adaptive immune cells; however, as the tumor develops from neoplastic tissue to clinically detectable tumors, cancer cells evolve different mechanisms that mimic peripheral immune tolerance in order to avoid tumoricidal attack. Here, we provide an update of recent accomplishments, unifying concepts, and future challenges to study tumor-associated immune cells, with an emphasis on metastatic carcinomas.

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Section: Challenges In Studying Cancer-associated Inflammatory Cellsmentioning

confidence: 99%

Roles of the immune system in cancer: from tumor initiation to metastatic progression

2018

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“…PDX models, which preserve the histology of patient tumors and exhibit similar gene expression patterns, represent an asset for testing therapeutic agents in development (Izumchenko et al., 2017). A comprehensive review of PDX model generation and use in humanized mouse models was published earlier by our group (see Current Protocols article; Verma et al., 2017).…”

Section: Commentarymentioning

confidence: 99%

“…The PBMC‐HIS model (Basic Protocol 2) has an abbreviated timeline as compared to the huCD34+ HSC‐HIS model (Basic Protocol 1). The timing of PBMC implantation is dictated by the study design and the tumor model selected (see Current Protocols article; Verma et al., 2017). A PDX tumor study requires subcutaneous PDX implantation prior to PBMC implantation, followed by randomization and dosing, whereas in a CDX study, PBMCs can be implanted before or after tumor cell engraftment.…”

Section: Commentarymentioning

confidence: 99%

Establishment of Humanized Mice from Peripheral Blood Mononuclear Cells or Cord Blood CD34+ Hematopoietic Stem Cells for Immune‐Oncology Studies Evaluating New Therapeutic Agents

Verma

Wesa

2020

CP Pharmacology

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The clinical success of immune checkpoint modulators and the development of next-generation immune-oncology (IO) agents underscore the need for robust preclinical models to evaluate novel IO therapeutics. Human immune system (HIS) mouse models enable in vivo studies in the context of the HIS via a human tumor. The immunodeficient mouse strains NOG (Prkdc scid Il2rg tm1Sug ) and triple-transgenic NOG-EXL [Prkdc scid Il2rg tm1Sug Tg (SV40/HTLV-IL3, CSF2)], which expresses human IL-3 and GM-CSF, allow for human CD34+ hematopoietic stem cell (huCD34+ HSC) engraftment and multilineage immune cell development by 12 to 16 weeks post-transplant and facilitate studies of immunomodulatory agents. A more rapid model of human immune engraftment utilizes peripheral blood mononuclear cells (PBMCs) transplanted into immunodeficient murine hosts, permitting T-cell engraftment within 2 to 3 weeks without outgrowth of other human immune cells. The PBMC-HIS model can be limited due to onset of xenogeneic graft-versus-host disease (xGVHD) within 3 to 5 weeks post-implantation. Host deficiency in MHC class I, as occurs in beta-2 microglobulin knockout in either NOG or NSG mice, results in resistance to xGVHD, which permits a longer therapeutic window. In this article, detailed processes for generating humanized mice by transplantation of HSCs from cord blood-derived huCD34+ HSCs or PBMCs into immunodeficient mouse strains to respectively generate HSC-HIS and PBMC-HIS mouse models are provided. In addition, the co-engraftment and growth kinetics of patient-derived and cell line-derived xenograft tumors in humanized mice and recovery of tumor-infiltrating lymphocytes from growing tumors to evaluate immune cell subsets by flow cytometry are described. © 2020 The Authors.Basic Protocol 1: Establishment of patient-derived xenograft tumors in CD34+ hematopoietic stem cell-humanized mice Basic Protocol 2: Establishment of patient-derived xenograft tumors in peripheral blood mononuclear cell-humanized mice Support Protocol 1: Flow cytometry assessment of humanization in mice Support Protocol 2: Flow cytometry assessment of tumor-infiltrating lymphocytes in tumor-bearing humanized mouse models Keywords: humanized mouse model r immune oncology r patient-derived xenograft (PDX) models r tumor-infiltrating lymphocytes

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“…40,41 However, creating a humanized mouse requires a very involved technique and has difficulties in carefully fine-tune many experiment variables with low success rate. 8,42 Moreover, the unavailability of a large number of autologous CD34+ HSCs to generate cohorts for study purposes limits the applicability of humanized mouse as a standard preclinical cancer model.…”

Section: Pdx As a Model For Drug Responsementioning

confidence: 99%

Patient-derived cancer modeling for precision medicine in colorectal cancer: beyond the cancer cell line

Pyo

Hong

Lee

et al. 2020

Cancer Biology & Therapy

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Since effective immunotherapeutic agents such as immune checkpoint blockade to treat cancer have emerged, the need for reliable preclinical cancer models that can evaluate and discover such drugs became stronger than ever before. The traditional preclinical cancer model using a cancer cell line has several limitations to recapitulate intra-tumor heterogeneity and in-vivo tumor activity including interactions between tumor-microenvironment. In this review, we will go over various preclinical cancer models recently discovered including patient-derived xenografts, humanized mice, organoids, organotypic-tumor spheroids, and organ-on-a-chip models. Moreover, we will discuss the future directions of preclinical cancer research.

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

Cited by 10 publications

References 40 publications

Roles of the immune system in cancer: from tumor initiation to metastatic progression

Roles of the immune system in cancer: from tumor initiation to metastatic progression

Establishment of Humanized Mice from Peripheral Blood Mononuclear Cells or Cord Blood CD34+ Hematopoietic Stem Cells for Immune‐Oncology Studies Evaluating New Therapeutic Agents

Patient-derived cancer modeling for precision medicine in colorectal cancer: beyond the cancer cell line

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