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Expanded natural killer cells potentiate the antimyeloma activity of daratumumab, lenalidomide, and dexamethasone in a myeloma xenograft model
The development of new treatment agents in recent decades has significantly improved the survival of patients with multiple myeloma (MM). Nonetheless, MM remains an incurable disease; therefore, novel combination therapies are required. Natural killer (NK) cells are one of the safest immunotherapeut...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer Berlin Heidelberg
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10110729/ https://www.ncbi.nlm.nih.gov/pubmed/36385211 http://dx.doi.org/10.1007/s00262-022-03322-1 |
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author | Thangaraj, Jaya Lakshmi Jung, Sung-Hoon Vo, Manh-Cuong Chu, Tan-Huy Phan, Minh-Trang Thi Lee, Kyung-Hwa Ahn, Seo-Yeon Kim, Mihee Song, Ga-Young Ahn, Jae-Sook Yang, Deok-Hwan Kim, Hyeoung-Joon Cho, Duck Lee, Je-Jung |
author_facet | Thangaraj, Jaya Lakshmi Jung, Sung-Hoon Vo, Manh-Cuong Chu, Tan-Huy Phan, Minh-Trang Thi Lee, Kyung-Hwa Ahn, Seo-Yeon Kim, Mihee Song, Ga-Young Ahn, Jae-Sook Yang, Deok-Hwan Kim, Hyeoung-Joon Cho, Duck Lee, Je-Jung |
author_sort | Thangaraj, Jaya Lakshmi |
collection | PubMed |
description | The development of new treatment agents in recent decades has significantly improved the survival of patients with multiple myeloma (MM). Nonetheless, MM remains an incurable disease; therefore, novel combination therapies are required. Natural killer (NK) cells are one of the safest immunotherapeutic options. In this study, we found that the anti-myeloma activity of expanded NK cells (eNKs) was improved by daratumumab, lenalidomide, and dexamethasone (DRd) in an MM xenograft mouse model. NK cells expanded from peripheral blood mononuclear cells collected from MM patients were highly cytotoxic against DRd pretreated tumor cells in vitro. To mimic the clinical protocol, a human MM xenograft model was developed using human RPMI8226-RFP-FLuc cells in NOD/SCID IL-2Rγ(null) (NSG) mice. MM bearing mice were randomly divided into six groups: no treatment, eNK, Rd, Rd + eNKs, DRd, and DRd + eNKs. DRd significantly enhanced the cytotoxicity of eNKs by upregulating NK cell activation ligands and effector function. DRd in combination with eNKs significantly reduced the serum M-protein level and prolonged mouse survival. In addition, DRd significantly increased the persistence of eNK and homing to MM sites. These results show that the anti-myeloma activity of ex vivo-expanded and activated NK cells is augmented by the immunomodulatory effect of DRd in MM-bearing mice, suggesting the therapeutic potential of this combination for MM patients. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00262-022-03322-1. |
format | Online Article Text |
id | pubmed-10110729 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Springer Berlin Heidelberg |
record_format | MEDLINE/PubMed |
spelling | pubmed-101107292023-04-19 Expanded natural killer cells potentiate the antimyeloma activity of daratumumab, lenalidomide, and dexamethasone in a myeloma xenograft model Thangaraj, Jaya Lakshmi Jung, Sung-Hoon Vo, Manh-Cuong Chu, Tan-Huy Phan, Minh-Trang Thi Lee, Kyung-Hwa Ahn, Seo-Yeon Kim, Mihee Song, Ga-Young Ahn, Jae-Sook Yang, Deok-Hwan Kim, Hyeoung-Joon Cho, Duck Lee, Je-Jung Cancer Immunol Immunother Research The development of new treatment agents in recent decades has significantly improved the survival of patients with multiple myeloma (MM). Nonetheless, MM remains an incurable disease; therefore, novel combination therapies are required. Natural killer (NK) cells are one of the safest immunotherapeutic options. In this study, we found that the anti-myeloma activity of expanded NK cells (eNKs) was improved by daratumumab, lenalidomide, and dexamethasone (DRd) in an MM xenograft mouse model. NK cells expanded from peripheral blood mononuclear cells collected from MM patients were highly cytotoxic against DRd pretreated tumor cells in vitro. To mimic the clinical protocol, a human MM xenograft model was developed using human RPMI8226-RFP-FLuc cells in NOD/SCID IL-2Rγ(null) (NSG) mice. MM bearing mice were randomly divided into six groups: no treatment, eNK, Rd, Rd + eNKs, DRd, and DRd + eNKs. DRd significantly enhanced the cytotoxicity of eNKs by upregulating NK cell activation ligands and effector function. DRd in combination with eNKs significantly reduced the serum M-protein level and prolonged mouse survival. In addition, DRd significantly increased the persistence of eNK and homing to MM sites. These results show that the anti-myeloma activity of ex vivo-expanded and activated NK cells is augmented by the immunomodulatory effect of DRd in MM-bearing mice, suggesting the therapeutic potential of this combination for MM patients. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00262-022-03322-1. Springer Berlin Heidelberg 2022-11-16 2023 /pmc/articles/PMC10110729/ /pubmed/36385211 http://dx.doi.org/10.1007/s00262-022-03322-1 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Research Thangaraj, Jaya Lakshmi Jung, Sung-Hoon Vo, Manh-Cuong Chu, Tan-Huy Phan, Minh-Trang Thi Lee, Kyung-Hwa Ahn, Seo-Yeon Kim, Mihee Song, Ga-Young Ahn, Jae-Sook Yang, Deok-Hwan Kim, Hyeoung-Joon Cho, Duck Lee, Je-Jung Expanded natural killer cells potentiate the antimyeloma activity of daratumumab, lenalidomide, and dexamethasone in a myeloma xenograft model |
title | Expanded natural killer cells potentiate the antimyeloma activity of daratumumab, lenalidomide, and dexamethasone in a myeloma xenograft model |
title_full | Expanded natural killer cells potentiate the antimyeloma activity of daratumumab, lenalidomide, and dexamethasone in a myeloma xenograft model |
title_fullStr | Expanded natural killer cells potentiate the antimyeloma activity of daratumumab, lenalidomide, and dexamethasone in a myeloma xenograft model |
title_full_unstemmed | Expanded natural killer cells potentiate the antimyeloma activity of daratumumab, lenalidomide, and dexamethasone in a myeloma xenograft model |
title_short | Expanded natural killer cells potentiate the antimyeloma activity of daratumumab, lenalidomide, and dexamethasone in a myeloma xenograft model |
title_sort | expanded natural killer cells potentiate the antimyeloma activity of daratumumab, lenalidomide, and dexamethasone in a myeloma xenograft model |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10110729/ https://www.ncbi.nlm.nih.gov/pubmed/36385211 http://dx.doi.org/10.1007/s00262-022-03322-1 |
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