Introduction to Patient-Derived Xenografts
Patient-derived xenograft (PDX) models represent a transformative platform in oncology research, providing a high-fidelity in vivo system for studying patient-specific tumor biology and therapeutic response. Unlike cell line-derived xenografts (CDX), which rely on immortalized and passaged tumor cells, PDX models are established by directly implanting freshly resected tumor tissue from cancer patients into immunodeficient mice. This method preserves the histopathological architecture, genetic heterogeneity, and molecular signatures of the original tumor with remarkable accuracy, enabling more clinically relevant investigations into tumor behavior, drug efficacy, resistance mechanisms, and biomarker development.
Biological Relevance and Tumor Heterogeneity
PDX models are particularly valuable in translational cancer research, where maintaining the native complexity of patient tumors is essential. Because they bypass the artificial selection pressures of in vitro culture, PDX tumors retain heterogeneous cellular subpopulations, including cancer stem-like cells, differentiated tumor cells, and stromal components. This allows researchers to evaluate therapeutic strategies against a microcosm of the patient’s cancer as it might behave in the clinic. Notably, the engrafted tumors often metastasize to sites that mimic human disease patterns, further enhancing the clinical translatability of PDX models.
Engraftment Procedure and Host Strains
The engraftment process typically involves subcutaneous implantation of small tumor fragments into severely immunodeficient mice such as NSG (NOD-scid IL2Rγnull) or NOG (NOD/Shi-scid IL2Rγnull) strains. These models lack T cells, B cells, and natural killer (NK) cells, creating a permissive environment for xenogeneic tissue engraftment. Upon successful engraftment, tumors are serially passaged into new mice for expansion and experimental use. Over time, researchers have developed large PDX biobanks representing a wide range of malignancies, including breast, lung, colorectal, pancreatic, prostate, ovarian, melanoma, and hematologic cancers. These biobanks have become invaluable resources for preclinical drug development, offering diverse genetic backgrounds and phenotypic characteristics for personalized therapy testing.
Role in Co-Clinical Trials and Precision Oncology
One of the most compelling uses of PDX models lies in co-clinical trials, wherein patient tumors are engrafted and treated in parallel with human clinical trials. This approach enables real-time evaluation of drug responses, resistance mechanisms, and predictive biomarkers. It also provides insight into differential drug efficacy across molecular subtypes, making PDX models a cornerstone of precision oncology. In particular, the ability to stratify PDX models by mutational status (e.g., EGFR, KRAS, BRAF, TP53) facilitates drug screening in genotype-specific cohorts, mirroring patient selection strategies used in clinical studies.
Limitations and the Emergence of Humanized PDX Models
Despite their many strengths, PDX models are not without limitations. The lack of a functional immune system in the host mice precludes meaningful evaluation of immune checkpoint inhibitors, adoptive cell therapies, and cancer vaccines. To overcome this, researchers have developed humanized PDX models by co-engrafting human hematopoietic stem cells or peripheral blood mononuclear cells (PBMCs), allowing partial reconstitution of human immunity. These hybrid models, although more complex and variable, are increasingly used in immuno-oncology to study tumor–immune interactions and immune-mediated mechanisms of drug resistance.
PDX models also present practical challenges. Establishment and expansion are time-intensive, often requiring several months per model. Engraftment rates vary by tumor type and aggressiveness, with hematologic and fast-growing solid tumors showing higher success rates than indolent or early-stage tumors. Furthermore, murine stromal components eventually replace the human tumor stroma during serial passaging, which can influence drug response and complicate interpretation of stromal-targeting therapies.
Predictive Value and Industrial Applications
The predictive power of PDX models for clinical drug response is well documented. Numerous studies have shown that PDX models replicate patient-specific responses to chemotherapy, targeted therapies, and investigational agents with high concordance. As a result, PDX platforms are widely used by pharmaceutical companies, contract research organizations (CROs), and academic cancer centers to conduct preclinical efficacy testing and biomarker validation prior to initiating Phase I/II clinical trials.