{
  "abstract": "Background Cell humanized mouse models that reconstitute the human immune system are valuable in the field of immuno-oncology (IO) and IO drug development. Importantly, the development of cell humanized mouse models that recapitulate a comprehensive immune system is critical for the study of the interplay between T, myeloid, dendritic, and natural killer cells in the context of cancer. In the present study, we have developed a novel NOD-scid IL2rg null (NSG) mouse variant (NSG-FLT3-IL15) that transgenically expresses human IL-15 and human FLT3 ligand to enhance maturation of functional innate immune cells including human CD56+CD16+ NK cells, CD33+ myeloid cells, CD141+ and CD1c+ conventional DC subsets, CD123+ pDCs, and CD14+ monocytes alongside adaptive immune cells such as CD4+ regulatory T cells and CD4+ and CD8+ effector T cells over a 28-week period.Methods NSG-FLT3-IL15 mice, along with control strains NSG, NSG-IL15, and NSG-FLT3, were engrafted with human umbilical cord blood-derived CD34 + hematopoietic stem cells from three different donors, and blood samples were collected until week 28 post-transplantation. Flow cytometry revealed that hCD45+ cell engraftment and T cell subpopulations (CD3+, CD4+, and CD8+) in NSG-FLT3-IL15 mice were comparable to parental control strains. For functional IO studies, CD34 huNSG-FLT3-IL15 mice were engrafted with various PDX and CDX tumors and evaluated against various IO therapies such as CAR T, Trispecific NK cell engagers, and antibody-drug conjugates.Results CD34 NSG-FLT3-IL15 mice exhibited enhanced CD56 +/dim CD16+ NK cells compared to the control strains. Furthermore, levels of myeloid sub-lineage cells such as monocytes, macrophages (M1), granulocytes, dendritic cells, and neutrophils, were higher than in NSG or NSG-IL15 strains but comparable to NSG-FLT3 strain mice. Current growth kinetic studies with human patient derived tumors will assess human immune cell infiltration across NSG variants. In vivo efficacy studies demonstrate the successful engraftment of a wide array of PDX/CDX tumors and demonstrate therapy induced tumor killing by the enhanced innate human immune cells developed in NSG-FLT3-IL15 mice.Conclusions Overall, these results demonstrate that the NSG-IL15-FLT3 model supports enhanced development of functional human innate immune cells and serves as a novel comprehensive immune model for studying human IO.Ethics Approval Animal experiments were conducted at University of Minnesota under AUS#2207-40255A and the Jackson Laboratory under AUS#18002-1.",
  "authors": [
    {
      "affiliations": [
        "The Jackson Laboratory, Sacramento, CA, USA"
      ],
      "name": "Peter Deng"
    },
    {
      "affiliations": [
        "The Jackson Laboratory, Sacramento, CA, USA"
      ],
      "name": "Pali Kaur"
    },
    {
      "affiliations": [
        "The Jackson Laboratory, Sacramento, CA, USA"
      ],
      "name": "Brian Soper"
    },
    {
      "affiliations": [
        "The Jackson Laboratory, Sacramento, CA, USA"
      ],
      "name": "Shuang Hu"
    },
    {
      "affiliations": [
        "The Jackson Laboratory, Sacramento, CA, USA"
      ],
      "name": "Voot Yin"
    }
  ],
  "title": "2 CD34 huNSG-FLT3-IL15, a novel mouse strain with improved development of T, myeloid, dendritic, and natural killer cells for immuno-oncology therapeutic applications",
  "uid": "1574a621-b5f6-545b-b212-85e667c2f30e"
}