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Generation of Orthotopic Patient-Derived Xenografts in Humanized Mice for Evaluation of Emerging Targeted Therapies and Immunotherapy Combinations for Melanoma
SIMPLE SUMMARY: Patient-derived xenografts (PDX) are valuable models in preclinical oncology drug development. However, they are not well suited for testing immune-based therapies. In contrast, when humanized mice are developed by xenotransplantation of irradiated mice with human CD34+ stem cells to...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10377652/ https://www.ncbi.nlm.nih.gov/pubmed/37509357 http://dx.doi.org/10.3390/cancers15143695 |
Sumario: | SIMPLE SUMMARY: Patient-derived xenografts (PDX) are valuable models in preclinical oncology drug development. However, they are not well suited for testing immune-based therapies. In contrast, when humanized mice are developed by xenotransplantation of irradiated mice with human CD34+ stem cells to allow for the growth of human tumor tissue in the context of a humanized immune system, it is possible to evaluate the response to both targeted therapy and immune therapy. Unfortunately, humanized mice transplanted with human PDX tissue frequently develop graft-versus-host disease (GVHD). Here, we optimized a protocol for generating humanized PDX mouse models with considerably reduced development of GVHD, making preclinical trials with immune checkpoint inhibitors possible. ABSTRACT: Current methodologies for developing PDX in humanized mice in preclinical trials with immune-based therapies are limited by GVHD. Here, we compared two approaches for establishing PDX tumors in humanized mice: (1) PDX are first established in immune-deficient mice; or (2) PDX are initially established in humanized mice; then established PDX are transplanted to a larger cohort of humanized mice for preclinical trials. With the first approach, there was rapid wasting of PDX-bearing humanized mice with high levels of activated T cells in the circulation and organs, indicating immune-mediated toxicity. In contrast, with the second approach, toxicity was less of an issue and long-term human melanoma tumor growth and maintenance of human chimerism was achieved. Preclinical trials from the second approach revealed that rigosertib, but not anti-PD-1, increased CD8/CD4 T cell ratios in spleen and blood and inhibited PDX tumor growth. Resistance to anti-PD-1 was associated with PDX tumors established from tumors with limited CD8+ T cell content. Our findings suggest that it is essential to carefully manage immune editing by first establishing PDX tumors in humanized mice before expanding PDX tumors into a larger cohort of humanized mice to evaluate therapy response. |
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