Background
The preclinical evaluation of novel immune therapies demands humanized mouse models with functional human immune cells. In previous studies we have established a humanized immune system in immunodecient mice by either transfer of hematopoietic stem cells (HSCs), PBMCs or NK cells. With the development of 2nd generation NOG mice a lineage specic dierentiation of immune sub-population of interest can be supported. By transplantation of cell-line-derived (CDX) or patient-derived (PDX) tumor xenografts on humanized mice, we successfully generated a full human tumor-immune-cell model for dierent tumor entities. Finally, we validated the functionality of these models using checkpoint inhibitors or anti-cancer antibodies.
Methods
HSC-humanized mice were generated by single i.v. transplantation of CD34+ stem cells to immunodeficient NOG mice. 1st and 2nd generation NOG mouse strains were used: NOG, NOG-EXL, NOGIL15, NOG-IL2, NOG-IL6 and FcResolv NOG were compared for their lineage specific differentiation to each other using single donors or a mixed HSC donor pool. Engraftment of immune cells was monitored by FACS analysis of blood samples. Partially HLA-matched PBMC were used to humanize tumor-bearing mice followed by treatment with checkpoint inhibitor. NK-cell humanization was done in hIL-15 NOG and FcResolv™ hIL-15 NOG mice. Here, a lung cancer PDX model was treated with cetuximab to analyse the effect of antibody-dependent cellular cytotoxicity
Conclusions
Next-generation NOG mouse strains are characterized by a lineage-specific differentiation of immune cells depending on integrated human cytokines. We established human tumor-immune cell models of different entities using CDX or PDX in combination with different donor derived immune cell subsets as effector cells. Our human tumor-immune-cell models allow preclinical, translational studies on tumor immune biology as well as evaluation of new therapies, drug combinations and biomarker identification and validation.
