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Patient-Derived Xenografts (PDXs) – A Powerful Preclinical Tool for Immuno-Oncology Research

Jul 7, 2022 1:30:00 PM / by Champions Oncology

Cancer Cell and Lymphocytes

Patient-derived xenograft (PDX) mouse models have become an essential part of the preclinical immuno-oncology toolbox. These models implant patient-derived tumor tissue into immunocompromised mice and facilitate preclinical studies that characterize tumor biology and anti-tumor responses mediated by adoptive cell therapies or novel immuno-oncology drugs. Here we highlight how PDX models are generated and used, and which applications are most suitable for this type of model.

 

PDX models were developed in the early 2000s to address the gap between predicted, promising therapeutic responses based on evaluation in tumor cell lines versus the reality of poor responses observed in clinical trials. The genomes of passaged tumor cell lines were shown to vary dramatically compared with the original specimens and were lacking the cellular heterogeneity associated with normal tumor tissue. The development of different immunocompromised mouse lines beyond nude mice, particularly severely compromised immune deficient (SCID), NOD-SCID, or recombination-activating gene (Rag)-deficient mice paved the way for PDX models[1]. These immunocompromised models could tolerate transplantation with fragments of human tumors, which resulted in the growth of tumors with a heterogeneous cellular composition and phenotypic and genomic features that closely resembled the primary tumor[2]. These models have different types of immune defects: Nude mice have a mutation that prevents thymus development and thus lack T cells, and SCID and Rag-deficient mice have different mutations that results in B and T cell deficiency. Nude mice have been used commonly for rapidly growing tumors, where as SCID and Rag mice are more typically used for slower growing tumors. These models are not completely immunodeficient, so they were considered less than ideal hosts for PDX fragments. In recent years, several immunodeficient strains have been developed that carry additional mutations in the IL-2 receptor gamma chain, for which NSG and NRG mice have emerged as the most used strains for PDX studies. PDX models have been most successful in modeling solid tumors, including brain, breast, colorectal, lung, melanoma, pancreatic and ovarian tumors[3]. More recently, PDX models are being developed for hematological malignancies[4],[5].

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Several areas of immuno-oncology research have directly benefited from PDX models. In terms of tumor biology, PDX models can be used for tumor microenvironment studies and biomarker profiling, as well as working out mechanisms of tumor initiation and growth and metastasis[6]. Preclinical drug studies have been transformed by PDX models, as they have facilitated the screening of new drugs with respect to tumor genotype and have also provided a strategy for screening drug resistance[7]. Adoptive cell therapies have also been evaluated in PDX models, although evaluation of other immunotherapies is more limited given that these studies are best done in models with intact immune systems, particularly humanized mice[8].

 

The promising trends in personalized cancer therapies suggest that PDX mice will continue to be a critical tool for preclinical, and even diagnostic studies. PDX models can be challenging to develop, especially given the variables associated with patient tumor specimens. Most investigators prefer to work with experts in PDX models to assure that valuable patient tumor tissue samples are used correctly, and the resulting data can be used toward advancing research studies.

 

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[1] Shultz LD, Goodwin N, Ishikawa F, Hosur V, Lyons BL, Greiner DL. Human cancer growth and therapy in immunodeficient mouse models. Cold Spring Harb. Protoc. 2014;2014(7):694-708. Published 2014 Jul 1.

[2] Williams SA, Anderson WC, Santaguida MT, Dylla SJ. Patient-derived xenografts, the cancer stem cell paradigm, and cancer pathobiology in the 21st century. Lab. Invest. 2013 Sep;93(9):970-82.

[3] Tentler JJ, Tan AC, Weekes CD, et al. Patient-derived tumour xenografts as models for oncology drug development. Nat. Rev. Clin. Oncol. 2012;9(6):338-350.

[4] Chapuy B, Cheng H, Watahiki A, et al. Diffuse large B-cell lymphoma patient-derived xenograft models capture the molecular and biological heterogeneity of the disease. Blood. 2016;127(18):2203-2213.

[5] Richter-Pechańska P, Kunz JB, Bornhauser B, et al. PDX models recapitulate the genetic and epigenetic landscape of pediatric T-cell leukemia. EMBO Mol. Med. 2018;10(12):e9443.

[6] Cassidy JW, Caldas C, Bruna A. Maintaining Tumor Heterogeneity in Patient-Derived Tumor Xenografts. Cancer Res. 2015 Aug 1;75(15):2963-8.

[7] Gao, Hui, et al. High-throughput screening using patient-derived tumor xenografts to predict clinical trial drug response." Nat. Med. 2015 Nov; 21(11):1318-25.

[8] Jespersen H, Lindberg MF, Donia M, Söderberg EMV, Andersen R, Keller U, Ny L, Svane IM, Nilsson LM, Nilsson JA. Clinical responses to adoptive T-cell transfer can be modeled in an autologous immune-humanized mouse model. Nat. Commun. 2017 Sep 27;8(1):707.

 

 

Tags: Solid Tumor Oncology, Immuno-Oncology