Preclinical platform for long-term evaluation of immuno-oncology drugs using hCD34+ humanized mouse model
Background Well-characterized preclinical models are essential for immune-oncology research. We investigated the feasibility of our humanized mouse model for evaluating the long-term efficacy of immunotherapy and biomarkers.Methods Humanized mice were generated by injecting human fetal cord blood-de...
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BMJ Publishing Group
2020-10-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/8/2/e001513.full |
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| author | Yong Wha Moon Nahee Park Kamal Pandey Sei Kyung Chang Ah-Young Kwon Young Bin Cho Jin Hur Nar Bahadur Katwal Seung Ki Kim Seung Ah Lee Gun Woo Son Jong Min Jo Hee Jung Ahn |
| author_facet | Yong Wha Moon Nahee Park Kamal Pandey Sei Kyung Chang Ah-Young Kwon Young Bin Cho Jin Hur Nar Bahadur Katwal Seung Ki Kim Seung Ah Lee Gun Woo Son Jong Min Jo Hee Jung Ahn |
| author_sort | Yong Wha Moon |
| collection | DOAJ |
| description | Background Well-characterized preclinical models are essential for immune-oncology research. We investigated the feasibility of our humanized mouse model for evaluating the long-term efficacy of immunotherapy and biomarkers.Methods Humanized mice were generated by injecting human fetal cord blood-derived CD34+ hematopoietic stem cells to NOD-scid IL2rγnull (NSG) mice myeloablated with irradiation or busulfan. The humanization success was defined as a 25% or higher ratio of human CD45+ cells to mice peripheral blood mononuclear cells.Results Busulfan was ultimately selected as the appropriate myeloablative method because it provided a higher success rate of humanization (approximately 80%) and longer survival time (45 weeks). We proved the development of functional T cells by demonstrating the anticancer effect of the programmed cell death-1 (PD-1) inhibitor in our humanized mice but not in non-humanized NSG mice. After confirming the long-lasting humanization state (45 weeks), we further investigated the response durability of the PD-1 inhibitor and biomarkers in our humanized mice. Early increase in serum tumor necrosis factor α levels, late increase in serum interleukin 6 levels and increase in tumor-infiltrating CD8+ T lymphocytes correlated more with a durable response over 60 days than with a non-durable response.Conclusions Our CD34+ humanized mouse model is the first in vivo platform for testing the long-term efficacy of anticancer immunotherapies and biomarkers, given that none of the preclinical models has ever been evaluated for such a long duration. |
| format | Article |
| id | doaj-art-d8f5bfe7a6a840658a1bb4ecf9245bb2 |
| institution | OA Journals |
| issn | 2051-1426 |
| language | English |
| publishDate | 2020-10-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-d8f5bfe7a6a840658a1bb4ecf9245bb22025-08-20T02:13:20ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262020-10-018210.1136/jitc-2020-001513Preclinical platform for long-term evaluation of immuno-oncology drugs using hCD34+ humanized mouse modelYong Wha Moon0Nahee Park1Kamal Pandey2Sei Kyung Chang3Ah-Young Kwon4Young Bin Cho5Jin Hur6Nar Bahadur Katwal7Seung Ki Kim8Seung Ah Lee9Gun Woo Son10Jong Min Jo11Hee Jung Ahn121 Hematology and Oncology, Department of Internal Medicine, CHA Bundang Medical Center, Seongnam, South Korea1 Hematology and Oncology, Department of Internal Medicine, CHA Bundang Medical Center, Seongnam, South Korea1 Hematology and Oncology, Department of Internal Medicine, CHA Bundang Medical Center, Seongnam, South Korea3 Department of Radiation Oncology, CHA Bundang Medical Center, Seongnam, South Korea4 Department of Pathology, CHA Bundang Medical Center, Seongnam, South Korea1 Hematology and Oncology, Department of Internal Medicine, CHA Bundang Medical Center, Seongnam, South Korea1 Hematology and Oncology, Department of Internal Medicine, CHA Bundang Medical Center, Seongnam, South Korea1 Hematology and Oncology, Department of Internal Medicine, CHA Bundang Medical Center, Seongnam, South Korea5 Department of Surgery, CHA Bundang Medical Center, Seongnam, South Korea5 Department of Surgery, CHA Bundang Medical Center, Seongnam, South Korea1 Hematology and Oncology, Department of Internal Medicine, CHA Bundang Medical Center, Seongnam, South Korea1 Hematology and Oncology, Department of Internal Medicine, CHA Bundang Medical Center, Seongnam, South Korea4 Department of Pathology, CHA Bundang Medical Center, Seongnam, South KoreaBackground Well-characterized preclinical models are essential for immune-oncology research. We investigated the feasibility of our humanized mouse model for evaluating the long-term efficacy of immunotherapy and biomarkers.Methods Humanized mice were generated by injecting human fetal cord blood-derived CD34+ hematopoietic stem cells to NOD-scid IL2rγnull (NSG) mice myeloablated with irradiation or busulfan. The humanization success was defined as a 25% or higher ratio of human CD45+ cells to mice peripheral blood mononuclear cells.Results Busulfan was ultimately selected as the appropriate myeloablative method because it provided a higher success rate of humanization (approximately 80%) and longer survival time (45 weeks). We proved the development of functional T cells by demonstrating the anticancer effect of the programmed cell death-1 (PD-1) inhibitor in our humanized mice but not in non-humanized NSG mice. After confirming the long-lasting humanization state (45 weeks), we further investigated the response durability of the PD-1 inhibitor and biomarkers in our humanized mice. Early increase in serum tumor necrosis factor α levels, late increase in serum interleukin 6 levels and increase in tumor-infiltrating CD8+ T lymphocytes correlated more with a durable response over 60 days than with a non-durable response.Conclusions Our CD34+ humanized mouse model is the first in vivo platform for testing the long-term efficacy of anticancer immunotherapies and biomarkers, given that none of the preclinical models has ever been evaluated for such a long duration.https://jitc.bmj.com/content/8/2/e001513.full |
| spellingShingle | Yong Wha Moon Nahee Park Kamal Pandey Sei Kyung Chang Ah-Young Kwon Young Bin Cho Jin Hur Nar Bahadur Katwal Seung Ki Kim Seung Ah Lee Gun Woo Son Jong Min Jo Hee Jung Ahn Preclinical platform for long-term evaluation of immuno-oncology drugs using hCD34+ humanized mouse model Journal for ImmunoTherapy of Cancer |
| title | Preclinical platform for long-term evaluation of immuno-oncology drugs using hCD34+ humanized mouse model |
| title_full | Preclinical platform for long-term evaluation of immuno-oncology drugs using hCD34+ humanized mouse model |
| title_fullStr | Preclinical platform for long-term evaluation of immuno-oncology drugs using hCD34+ humanized mouse model |
| title_full_unstemmed | Preclinical platform for long-term evaluation of immuno-oncology drugs using hCD34+ humanized mouse model |
| title_short | Preclinical platform for long-term evaluation of immuno-oncology drugs using hCD34+ humanized mouse model |
| title_sort | preclinical platform for long term evaluation of immuno oncology drugs using hcd34 humanized mouse model |
| url | https://jitc.bmj.com/content/8/2/e001513.full |
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