Application of Highly Immunocompromised Mice for the Establishment of Patient-Derived Xenograft (PDX) Models

Abstract

Patient-derived xenograft (PDX) models are created by engraftment of patient tumor tissues into immunocompetent mice. Since a PDX model retains the characteristics of the primary patient tumor including gene expression profiles and drug responses, it has become the most reliable in vivo human cancer model. The engraftment rate increases with the introduction of Non-obese diabetic Severe combined immunodeficiency (NOD/SCID)-based immunocompromised mice, especially the NK-deficient NOD strains NOD/SCID/interleukin-2 receptor gamma chain(IL2Rγ)null (NOG/NSG) and NOD/SCID/Jak3(Janus kinase 3)null (NOJ). Success rates differ with tumor origin: gastrointestinal tumors acquire a higher engraftment rate, while the rate is lower for breast cancers. Subcutaneous transplantation is the most popular method to establish PDX, but some tumors require specific environments, e.g., orthotropic or renal capsule transplantation. Human hormone treatment is necessary to establish hormone-dependent cancers such as prostate and breast cancers. PDX mice with human hematopoietic and immune systems (humanized PDX) are powerful tools for the analysis of tumor–immune system interaction and evaluation of immunotherapy response. A PDX biobank equipped with patients’ clinical data, gene-expression patterns, mutational statuses, tumor tissue architects, and drug responsiveness will be an authoritative resource for developing specific tumor biomarkers for chemotherapeutic predictions, creating individualized therapy, and establishing precise cancer medicine.

Antitumor Activity of Amivantamab (JNJ-61186372), an EGFR–MET Bispecific Antibody, in Diverse Models of EGFR Exon 20 Insertion–Driven NSCLC

“…In this study, we used two different xenograft models, NOG mice and BALB/c nude mice for in vivo study. As demonstrated in many studies, NOG mice have impaired innate immunity and extremely low NK-cell activity, whereas BALB/c nude mice have intact innate immunity and active NK cells (43,44). For this reason, more potent ADCC activity was expected in BALB/c nude mice than NOG mice.…”

Patient-Derived Xenograft Models in Urological Malignancies: Urothelial Cell Carcinoma and Renal Cell Carcinoma

“…They are athymic, and their reduction in T cell production inhibits the adaptive immune response. However, their intact innate immunity can limit utility for human tumor grafting, particularly in less aggressive, slower growing tumor types, or in more immunogenic malignancies such as RCC and urothelial carcinoma [15]. The scid mice are a strain with severe combined immunodeficiency developed in C.B17 mice, which prevents the development of mature T cells and B cells.…”

“…Though initially thought to be resistant to the spontaneous thymic lymphomas that limit the lifespan of NOD scid mice, various labs have reported low rates of both thymic lymphomas and other non-human tumors following engraftment. Development of spontaneous thymic lymphomas has been reported in up to 15% of C.B17 scid mice and 67% of NOD-scid mice, while the incidence of spontaneous lymphoma is much lower in Il2rg-deficient mouse models (NSG/NOG/NRG), with reported rates of 0.7% in NSG and NOG mice [15,[20][21][22].…”

Current methods in translational cancer research

“…Lastly, in order to establish standard PDX models, a key requirement is that the mice cannot have an intact immune system. This has impeded the use of PDX mice in studies assessing immune checkpoint-blocking agents [148,149]. This is also driven, in part, by gradual replacement of engrafted stromal cells (and immune cells found in the tumor) with mouse cells leading to a more murine-like tumor microenvironment [131].…”