Abstract Humanized immune system (HIS) mice, which can be engrafted with human cell line-derived or patient-derived tumors, have become essential tools for preclinical and IND-enabling development of cell therapies and biologics in oncology. However, selecting the appropriate HIS model remains challenging given the diversity of humanizable mouse strains and immune-engraftment protocols. We first compared immune profiles, clinical symptoms, body weight, and survival in severely immunodeficient mice engrafted with either cord blood-derived CD34+ hematopoietic stem cells (HSCs) or peripheral blood mononuclear cells (PBMCs). PBMC-engrafted mice demonstrated poor survival associated with early graft-versus-host disease (GvHD) and exhibited amplification of human T cells with a partially exhausted phenotype (Lag-3+, TIM-3+). In contrast, CD34-engrafted mice showed no health deterioration over 30 weeks and developed a complete human immune system comprising T, B, NK, and myeloid cells.These results place the CD34+ HSC engrafted HIS mice as overall superior model for drug assessment as it allows a longer, GvHD-free treatment window and a more complete immune system. We next implemented a universal, irradiation-free, chemoablation-based CD34+ HSC-engraftment protocol to compare the extent of immune humanization across several severely immunodeficient strains, including foundational models (NOG, NCG, BNDG, BRG, and next-generation strains (NOG-EXL, which overexpresses human GM-CSF and IL-3; and FcResolv NOG, which lacks murine Fcγ receptors). For each strain, we measured survival, overall humanization rate (percentage of human among total immune cells), and human immune-subset frequencies in blood. Finally, we demonstrate how hydrodynamic gene delivery of one or more human cytokines into HIS mice can boost certain immune populations when a transgenic strain overexpressing these cytokines is unavailable. Altogether, our findings provide a knowledge base for the selection of the humanized immune system mouse model with the most suitable immune reconstitution profile for assessing any drug candidate based on its mechanisms of action. Citation Format: Audrey Wetzel, Emilie Bayon, Sebastien Tabruyn, Dan Georgess. Developing the next generation of customized human immune system mice for preclinical oncology abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3376.
Wetzel et al. (Fri,) studied this question.
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