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Background: Humanized immune system (HIS) mouse models are critical tools for evaluating immunotherapies, vaccines, and cell and gene therapies. While current models support robust human T and B cell reconstitution, they remain limited in generating functional innate immune compartments, particularly dendritic cells (DCs) and natural killer (NK) cells. DCs are essential for antigen presentation and T cell priming, yet their development is often impaired due to insufficient human cytokine support. Similarly, few platforms enable simultaneous reconstitution of NK, myeloid, DC, T, and B cell compartments, restricting studies of innate–adaptive crosstalk, anti-tumor immunity, and antibody-dependent cellular cytotoxicity. To address these limitations, we developed novel humanized NOG models incorporating either human Flt3 Ligand (hFlt3L) with murine Flt3 receptordisruption or physiologic expression of human IL-15/IL-15 receptor alpha chain (IL-15RA), with or without myeloid-supporting cytokines.

Methods: huNOG and huNOG-EXL mice expressing human Flt3L were engrafted with CD34⁺ human hematopoietic stem cells following busulfan conditioning. Donor-matched cohorts (2–3 donors) were longitudinally evaluated for immune reconstitution kinetics, including dendritic cell and NK cell development, chimerism, cytokine profiles, and survival). huNOG and huNOG-EXL expressing hIL-15/IL-15RA models were similarly engrafted and assessed for NK cell emergence,chimerism, T cell development,and cytokine expression. Additional endpoints included donor variability, persistence of immune subsets, and establishment of functional study windows.

Results: In IL-15RA NOG-EXL mice (4 WPE), human chimerism was unchanged versus controls; however, NK cells were markedly increased, alongside elevated myeloid populations. In IL-15RA NOG mice (6 WPE), NK cells and B cells were significantly increased, with no changes in T or myeloid compartments. In Flt3 NOG mice (4 WPE), human chimerism and NK cells were increased, with significant expansion of myeloid populations and murine dendritic cells despite Flt3 knockout, suggesting murine responsiveness to human Flt3L; human DCs were not yet elevated (however, published data suggests increase by 8WPE). In Flt3 NOG-EXL mice, early increases in chimerism and NK cells were observed; however, engraftment lagged by 10 WPE. Myeloid expansion persisted, while dendritic cell reconstitution was donor-dependent. B cells were reduced across Flt3-driven models.

Conclusions: Targeted cytokine modulation via Flt3L and IL-15/IL-15RA enhances key innate immune populations in humanized NOG models, enabling improved NK and myeloid/DC reconstitution relevant to immuno-oncology applications. These models represent promising platforms for evaluating therapies requiring coordinated innate and adaptive immunity. Ongoing longitudinal studies will define immune maturation, functional competency, durability of engraftment, and optimal study windows.

Background: Humanized immune system (HIS) models inadequately recapitulate human neutrophil biology. Neutrophils in current HIS models are rare, transient, or functionally immature, limiting their utility for immuno-oncology (10) and inflammatory disease research. To address this critical gap, the hG-CSF Kl NOG model incorporates human granulocyte colony-stimulating factor (G-CSF) into the murine G-CSF receptor locus, functionally disrupting murine granulopoiesis while enabling human neutrophil development. Following CD34+ hematopoietic stem cell engraftment in the hG-CSF Kl NOG (hG-CSF Kl huNOG), supports rapid generation of mature human neutrophils, enabling interrogation of human innate immune biology in vivo within a defined experimental window.

Methods: Humanized immune system (HIS) models inadequately recapitulate human neutrophil biology. Neutrophils in current HIS models are rare, transient, or functionally immature, limiting their utility for immuno-oncology (10) and inflammatory disease research. To address this critical gap, the hG-CSF Kl NOG model incorporates human granulocyte colony-stimulating factor (G-CSF) into the murine G-CSF receptor locus, functionally disrupting murine granulopoiesis while enabling human neutrophil development. Following CD34+ hematopoietic stem cell engraftment in the hG-CSF Kl NOG (hG-CSF Kl huNOG), supports rapid generation of mature human neutrophils, enabling interrogation of human innate immune biology in vivo within a defined experimental window.

Results: The hG-CSF Kl huNOG model achieved robust and reproducible human engraftment, with most animals exceeding 25% human chimerism by ~4 WPE. At 4 WPE, human chimerism reached ~ 70-90% depending on donor, significantly exceeding NOG-EXL controls. Critically, human neutrophils were significantly elevated relative to NOG-EXL, reaching ~5% of hCD45+ cells and ~22 cells/µL at peak compared to ~1 % and ~1 cell/µL in controls. Mature neutrophil subsets (CD16+CD89+) were present, and the human-to-murine granulocyte ratio was markedly increased, demonstrating effective suppression of murine granulopoiesis. Neutrophil reconstitution was sustained from 4-12WPE, defining a reproducible experimental window, with convergence toward control levels by 18WPE. Accelerated immune kinetics and consistent survival across donors further support model robustness, despite lower long-term chimerism relative to NOG-EXL.

Conclusions: The hG-CSF Kl huNOG model enables reproducible in vivo generation of mature human neutrophils, overcoming a major limitation of current HIS platforms. This model enables direct investigation of neutrophil-mediated mechanisms central to immuno-oncology, including tumor microenvironment remodeling, innate immune suppression, and cytokine-driven inflammation. A defined early study window (4-12WPE) supports translational study design for neutrophil-targeted therapeutics and combination strategies. These data position the hG-CSF Kl NOG/huNOG platform as a differentiated and clinically relevant model for advancing neutrophil-driven research.

Background: Humanized immune system (HIS) mouse models incorporating thymic tissue enable development of human MHC-restricted T cells and are critical for modeling adaptive immunity in vivo. The NeoThy platform uses neonatal thymic grafts as a non-fetal alternative to BLT models, enabling scalable, ethically accessible immune reconstitution. However, the impact of thymic donor, hematopoietic stem cell (HSC) donor, and HLA matching on tumor–immune interactions remains unclear.

Methods: NeoThy hIL-6 huNOG (NeoThy) mice were generated by co-transplanting HLA-typed cord blood-derived CD34⁺ HSCs and neonatal thymic tissue into IL-6 transgenic NOG mice. Control groups included CD34⁺-only (IL-6 huNOG) and non-humanized IL-6 NOG mice. Animals were implanted with a breast cancer PDX using combinations of two thymus donors and three CD34⁺ donors with varying HLA matching across four loci (HLA-A, -B, -C, -DRB1). Tumor growth, body weight, and immune profiling across peripheral blood, tumor, spleen, and lymph node were assessed. 

Results: Tumor growth and body weight were comparable across all cohorts, independent of HLA matching, confirming robust engraftment in NeoThy mice. Immune modulation was largely CD34+ donor-dependent. 

In peripheral blood, donors 1 and 3, thymus co-engraftment increased antigen-experienced (CD45RO⁺) CD4 and CD8 T cells, while donor 2 showed minimal changes. Only donor 3 demonstrated enhanced overall humanization. 

In tumors, donor 3 NeoThy mice exhibited the strongest immune activation signature, with increased NK/NKT cells, elevated antigen-experienced T cells, enrichment of CD8 and Treg populations, and reduced B cells. 

Lymph node data were variable; however, donor 3 showed a shift toward effector memory T cells and reduced myeloid/macrophage populations, while donor 1 demonstrated increased antigen-presenting myeloid cells.  

In spleen, donors 1 and 3 showed increased CD4⁺FOXP3⁺ Tregs. 

Conclusions: NeoThy mice support robust PDX growth independent of HLA matching, supporting their utility for oncology research. However, marked donor-dependent variability influences immune activation and differentiation. Thymus-driven education enhances antigen-experienced and functionally distinct immune populations, positioning NeoThy as a translational platform for evaluating cancer immunotherapies, including antigen-specific vaccines and combination approaches.