Juheon Lee, Eunjeong Choi, Bohwa Han, Jeong-A Kim, Dana Jung, Kyeong-Hee Kim, Sung Yong Oh, Sung-Hyun Kim, Kyung-Soo Ha, Ji-Hoon Kim, Ji Hyun Lee, Duck Cho, Junsang Doh, Seok-Ho Kim
{"title":"肿瘤启动CD8+自然杀伤t样细胞作为复发/难治性多发性骨髓瘤的有效新细胞疗法","authors":"Juheon Lee, Eunjeong Choi, Bohwa Han, Jeong-A Kim, Dana Jung, Kyeong-Hee Kim, Sung Yong Oh, Sung-Hyun Kim, Kyung-Soo Ha, Ji-Hoon Kim, Ji Hyun Lee, Duck Cho, Junsang Doh, Seok-Ho Kim","doi":"10.1186/s40164-025-00707-7","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Relapsed and refractory multiple myeloma (RRMM) remains a major clinical challenge, as most patients eventually relapse following standard treatments and are left with limited therapeutic options. Although b-cell maturation antigen (BCMA) CAR-T cell therapy has recently shown remarkable efficacy in select patients, broader implementation is hindered by its reliance on autologous cells, prolonged manufacturing timelines, high costs, and severe immune-related toxicities. These challenges have prompted an urgent demand for safer, more accessible, and rapidly applicable immunotherapeutic alternatives.</p><p><strong>Methods: </strong>CBMC (cord blood mononuclear cells) were cultured with irradiated BMMC (bone marrow mononuclear cells) from RRMM patients in the presence of defined cytokines, aiming to develop a new therapeutic immune cell product for RRMM. Their phenotypic and functional characteristics, including non-MHC-restricted and MHC-restricted cytotoxicity mechanisms, were analyzed using surface marker profiling, cytokine secretion assays, in vitro cytotoxicity assays, functional and blocking assays. Antitumor activity was evaluated in xenograft mouse models using MM.1 S and RPMI-8226 cells.</p><p><strong>Results: </strong>We successfully generated CD8<sup>+</sup> NKT-like cells through tumor priming, which exhibited potent cytotoxicity and elevated cytokine production against multiple myeloma cell lines and primary RRMM samples. Mechanistically, tumor-priming CD8<sup>+</sup> NKT-like cells (TPNC) cytotoxicity was mediated by both non-MHC-restricted pathways involving LFA-1 and DNAM-1, and MHC-restricted, TCR-mediated recognition. TPNC efficiently formed immune synapses, rapidly polarized cytotoxic granules, and engaged in serial killing. In xenograft models, TPNC significantly suppressed tumor progression, prolonged survival, and persisted in circulation without observable toxicity. Based on these findings, we extended the tumor-priming strategy to acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL), successfully generating TPNC with robust cytotoxic activity. In ALL samples, TPNC exhibited cytotoxicity comparable to anti-CD19 CAR-NK cells.</p><p><strong>Conclusions: </strong>TPNC represents a novel cytotoxic lymphocyte product generated through tumor-driven priming. Their dual recognition capacity, functional versatility, and favorable safety profile highlight their potential as a scalable and personalized immunotherapy platform for hematologic malignancies.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"116"},"PeriodicalIF":13.5000,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12482268/pdf/","citationCount":"0","resultStr":"{\"title\":\"Tumor-priming CD8<sup>+</sup> natural killer T-like cells as an efficient novel cell therapy for relapsed/refractory multiple myeloma.\",\"authors\":\"Juheon Lee, Eunjeong Choi, Bohwa Han, Jeong-A Kim, Dana Jung, Kyeong-Hee Kim, Sung Yong Oh, Sung-Hyun Kim, Kyung-Soo Ha, Ji-Hoon Kim, Ji Hyun Lee, Duck Cho, Junsang Doh, Seok-Ho Kim\",\"doi\":\"10.1186/s40164-025-00707-7\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Relapsed and refractory multiple myeloma (RRMM) remains a major clinical challenge, as most patients eventually relapse following standard treatments and are left with limited therapeutic options. Although b-cell maturation antigen (BCMA) CAR-T cell therapy has recently shown remarkable efficacy in select patients, broader implementation is hindered by its reliance on autologous cells, prolonged manufacturing timelines, high costs, and severe immune-related toxicities. These challenges have prompted an urgent demand for safer, more accessible, and rapidly applicable immunotherapeutic alternatives.</p><p><strong>Methods: </strong>CBMC (cord blood mononuclear cells) were cultured with irradiated BMMC (bone marrow mononuclear cells) from RRMM patients in the presence of defined cytokines, aiming to develop a new therapeutic immune cell product for RRMM. Their phenotypic and functional characteristics, including non-MHC-restricted and MHC-restricted cytotoxicity mechanisms, were analyzed using surface marker profiling, cytokine secretion assays, in vitro cytotoxicity assays, functional and blocking assays. Antitumor activity was evaluated in xenograft mouse models using MM.1 S and RPMI-8226 cells.</p><p><strong>Results: </strong>We successfully generated CD8<sup>+</sup> NKT-like cells through tumor priming, which exhibited potent cytotoxicity and elevated cytokine production against multiple myeloma cell lines and primary RRMM samples. Mechanistically, tumor-priming CD8<sup>+</sup> NKT-like cells (TPNC) cytotoxicity was mediated by both non-MHC-restricted pathways involving LFA-1 and DNAM-1, and MHC-restricted, TCR-mediated recognition. TPNC efficiently formed immune synapses, rapidly polarized cytotoxic granules, and engaged in serial killing. In xenograft models, TPNC significantly suppressed tumor progression, prolonged survival, and persisted in circulation without observable toxicity. Based on these findings, we extended the tumor-priming strategy to acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL), successfully generating TPNC with robust cytotoxic activity. In ALL samples, TPNC exhibited cytotoxicity comparable to anti-CD19 CAR-NK cells.</p><p><strong>Conclusions: </strong>TPNC represents a novel cytotoxic lymphocyte product generated through tumor-driven priming. Their dual recognition capacity, functional versatility, and favorable safety profile highlight their potential as a scalable and personalized immunotherapy platform for hematologic malignancies.</p>\",\"PeriodicalId\":12180,\"journal\":{\"name\":\"Experimental Hematology & Oncology\",\"volume\":\"14 1\",\"pages\":\"116\"},\"PeriodicalIF\":13.5000,\"publicationDate\":\"2025-09-29\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12482268/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Experimental Hematology & Oncology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1186/s40164-025-00707-7\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"HEMATOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Experimental Hematology & Oncology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1186/s40164-025-00707-7","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"HEMATOLOGY","Score":null,"Total":0}
Tumor-priming CD8+ natural killer T-like cells as an efficient novel cell therapy for relapsed/refractory multiple myeloma.
Background: Relapsed and refractory multiple myeloma (RRMM) remains a major clinical challenge, as most patients eventually relapse following standard treatments and are left with limited therapeutic options. Although b-cell maturation antigen (BCMA) CAR-T cell therapy has recently shown remarkable efficacy in select patients, broader implementation is hindered by its reliance on autologous cells, prolonged manufacturing timelines, high costs, and severe immune-related toxicities. These challenges have prompted an urgent demand for safer, more accessible, and rapidly applicable immunotherapeutic alternatives.
Methods: CBMC (cord blood mononuclear cells) were cultured with irradiated BMMC (bone marrow mononuclear cells) from RRMM patients in the presence of defined cytokines, aiming to develop a new therapeutic immune cell product for RRMM. Their phenotypic and functional characteristics, including non-MHC-restricted and MHC-restricted cytotoxicity mechanisms, were analyzed using surface marker profiling, cytokine secretion assays, in vitro cytotoxicity assays, functional and blocking assays. Antitumor activity was evaluated in xenograft mouse models using MM.1 S and RPMI-8226 cells.
Results: We successfully generated CD8+ NKT-like cells through tumor priming, which exhibited potent cytotoxicity and elevated cytokine production against multiple myeloma cell lines and primary RRMM samples. Mechanistically, tumor-priming CD8+ NKT-like cells (TPNC) cytotoxicity was mediated by both non-MHC-restricted pathways involving LFA-1 and DNAM-1, and MHC-restricted, TCR-mediated recognition. TPNC efficiently formed immune synapses, rapidly polarized cytotoxic granules, and engaged in serial killing. In xenograft models, TPNC significantly suppressed tumor progression, prolonged survival, and persisted in circulation without observable toxicity. Based on these findings, we extended the tumor-priming strategy to acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL), successfully generating TPNC with robust cytotoxic activity. In ALL samples, TPNC exhibited cytotoxicity comparable to anti-CD19 CAR-NK cells.
Conclusions: TPNC represents a novel cytotoxic lymphocyte product generated through tumor-driven priming. Their dual recognition capacity, functional versatility, and favorable safety profile highlight their potential as a scalable and personalized immunotherapy platform for hematologic malignancies.
期刊介绍:
Experimental Hematology & Oncology is an open access journal that encompasses all aspects of hematology and oncology with an emphasis on preclinical, basic, patient-oriented and translational research. The journal acts as an international platform for sharing laboratory findings in these areas and makes a deliberate effort to publish clinical trials with 'negative' results and basic science studies with provocative findings.
Experimental Hematology & Oncology publishes original work, hypothesis, commentaries and timely reviews. With open access and rapid turnaround time from submission to publication, the journal strives to be a hub for disseminating new knowledge and discussing controversial topics for both basic scientists and busy clinicians in the closely related fields of hematology and oncology.