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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...

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Autores principales: Yan, Chi, Nebhan, Caroline A., Saleh, Nabil, Shattuck-Brandt, Rebecca, Chen, Sheau-Chiann, Ayers, Gregory D., Weiss, Vivian, Richmond, Ann, Vilgelm, Anna E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
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
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author Yan, Chi
Nebhan, Caroline A.
Saleh, Nabil
Shattuck-Brandt, Rebecca
Chen, Sheau-Chiann
Ayers, Gregory D.
Weiss, Vivian
Richmond, Ann
Vilgelm, Anna E.
author_facet Yan, Chi
Nebhan, Caroline A.
Saleh, Nabil
Shattuck-Brandt, Rebecca
Chen, Sheau-Chiann
Ayers, Gregory D.
Weiss, Vivian
Richmond, Ann
Vilgelm, Anna E.
author_sort Yan, Chi
collection PubMed
description 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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spelling pubmed-103776522023-07-29 Generation of Orthotopic Patient-Derived Xenografts in Humanized Mice for Evaluation of Emerging Targeted Therapies and Immunotherapy Combinations for Melanoma Yan, Chi Nebhan, Caroline A. Saleh, Nabil Shattuck-Brandt, Rebecca Chen, Sheau-Chiann Ayers, Gregory D. Weiss, Vivian Richmond, Ann Vilgelm, Anna E. Cancers (Basel) Article 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. MDPI 2023-07-20 /pmc/articles/PMC10377652/ /pubmed/37509357 http://dx.doi.org/10.3390/cancers15143695 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Yan, Chi
Nebhan, Caroline A.
Saleh, Nabil
Shattuck-Brandt, Rebecca
Chen, Sheau-Chiann
Ayers, Gregory D.
Weiss, Vivian
Richmond, Ann
Vilgelm, Anna E.
Generation of Orthotopic Patient-Derived Xenografts in Humanized Mice for Evaluation of Emerging Targeted Therapies and Immunotherapy Combinations for Melanoma
title Generation of Orthotopic Patient-Derived Xenografts in Humanized Mice for Evaluation of Emerging Targeted Therapies and Immunotherapy Combinations for Melanoma
title_full Generation of Orthotopic Patient-Derived Xenografts in Humanized Mice for Evaluation of Emerging Targeted Therapies and Immunotherapy Combinations for Melanoma
title_fullStr Generation of Orthotopic Patient-Derived Xenografts in Humanized Mice for Evaluation of Emerging Targeted Therapies and Immunotherapy Combinations for Melanoma
title_full_unstemmed Generation of Orthotopic Patient-Derived Xenografts in Humanized Mice for Evaluation of Emerging Targeted Therapies and Immunotherapy Combinations for Melanoma
title_short Generation of Orthotopic Patient-Derived Xenografts in Humanized Mice for Evaluation of Emerging Targeted Therapies and Immunotherapy Combinations for Melanoma
title_sort generation of orthotopic patient-derived xenografts in humanized mice for evaluation of emerging targeted therapies and immunotherapy combinations for melanoma
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10377652/
https://www.ncbi.nlm.nih.gov/pubmed/37509357
http://dx.doi.org/10.3390/cancers15143695
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