ITOC2 – 005. Humanized mouse models for preclinical testing of antitumour immune therapy

Abstract

The identification and validation of new targets for antitumour immune therapy is still a challenge for the preclinical research as the classical syngeneic tumour models are of limited translational value and the patient derived human tumour xenograft models (PDX) are growing on immunodeficient animals. Our aim is the development of PDX models on mice with a functional human immune system to improve predictability of drug efficacy and safety. We reconstituted a human immune system by engrafting human hematopoietic stem cells in immunodeficient mice. Twelve weeks later stable expression of lymphoid cell lineages in peripheral blood and secondary lymphoid tissues could be detected by flow cytometry and immunohistochemistry analysis. We investigated the co-application of cytokine treatment (IL-3, IL-2 and IL-15) on the differentiation of immune cells. Treatment with IL-3 increased the proliferation rate, however not the differentiation pattern. At the time when the human immune system is developed, established melanoma PDXs were transplanted on these humanized mice. Human tumours developed on humanized mice without evidence of rejection. Drug-sensitivity testing with various immunoconjugates in these tumour-bearing humanized mice will follow. Our humanized mouse models will enable a more appropriate preclinical assessment of immune-based therapeutic antitumour strategies especially when combining the humanized mouse with patient-derived xenografts.