Daniel Pollyea, Tessa Kerre, Dries Deeren, Yves Beguin, Tara L. Lin, David A. Sallman, Sebastien Anguille, William G. Blum, Anne Flament, Eytan Breman, Caroline Lonez
{"title":"MICA/MICB下调可改善复发或难治性急性髓性白血病或骨髓增生异常瘤患者NKG2DL CAR - t细胞的细胞持久性和临床活性","authors":"Daniel Pollyea, Tessa Kerre, Dries Deeren, Yves Beguin, Tara L. Lin, David A. Sallman, Sebastien Anguille, William G. Blum, Anne Flament, Eytan Breman, Caroline Lonez","doi":"10.1038/s41375-025-02767-4","DOIUrl":null,"url":null,"abstract":"<p>The NKG2D receptor binds eight ligands (NKG2DL) overexpressed in a wide range of malignancies, but largely absent on non-neoplastic cells. Initial clinical evaluation of NKG2DL chimeric antigen receptor (CAR) T-cells (CYAD-01) in patients with relapsed or refractory (r/r) acute myeloid leukemia (AML) or myelodysplastic neoplasia (MDS) demonstrated low durability of responses and short cell persistence. Two Phase I trials were initiated to evaluate the effect of lymphodepletion prior to a single CAR T-cell infusion in a similar r/r AML/MDS patient population. The DEPLETHINK trial (NCT03466320) evaluated CYAD-01 while the CYCLE-1 trial (NCT04167696) evaluated a next-generation NKG2DL CAR, CYAD-02, where the two main NKG2D ligands MICA and B are downregulated, to increase CAR T-cell persistence. Seventeen and twelve patients were treated in the DEPLETHINK and CYCLE-1 trials, and confirmed the good tolerability of both products with cytokine release syndrome (CRS) grade 3 or 4 reported in 25% and 33.3% of patients, respectively. CYAD-02 presented an higher engraftment and an improved clinical activity (17% objective response rate) compared to CYAD-01 (no objective response). Altogether, our data provide proof of principle that knock-down of MICA/B can enhance CAR T-cell persistence and efficacy while maintaining a good safety profile.</p><figure></figure>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"35 1","pages":""},"PeriodicalIF":13.4000,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Downregulation of MICA/MICB improves cell persistence and clinical activity of NKG2DL CAR T-cells in patients with relapsed or refractory acute myeloid leukemia or myelodysplastic neoplasia\",\"authors\":\"Daniel Pollyea, Tessa Kerre, Dries Deeren, Yves Beguin, Tara L. Lin, David A. Sallman, Sebastien Anguille, William G. Blum, Anne Flament, Eytan Breman, Caroline Lonez\",\"doi\":\"10.1038/s41375-025-02767-4\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p>The NKG2D receptor binds eight ligands (NKG2DL) overexpressed in a wide range of malignancies, but largely absent on non-neoplastic cells. Initial clinical evaluation of NKG2DL chimeric antigen receptor (CAR) T-cells (CYAD-01) in patients with relapsed or refractory (r/r) acute myeloid leukemia (AML) or myelodysplastic neoplasia (MDS) demonstrated low durability of responses and short cell persistence. Two Phase I trials were initiated to evaluate the effect of lymphodepletion prior to a single CAR T-cell infusion in a similar r/r AML/MDS patient population. The DEPLETHINK trial (NCT03466320) evaluated CYAD-01 while the CYCLE-1 trial (NCT04167696) evaluated a next-generation NKG2DL CAR, CYAD-02, where the two main NKG2D ligands MICA and B are downregulated, to increase CAR T-cell persistence. Seventeen and twelve patients were treated in the DEPLETHINK and CYCLE-1 trials, and confirmed the good tolerability of both products with cytokine release syndrome (CRS) grade 3 or 4 reported in 25% and 33.3% of patients, respectively. CYAD-02 presented an higher engraftment and an improved clinical activity (17% objective response rate) compared to CYAD-01 (no objective response). Altogether, our data provide proof of principle that knock-down of MICA/B can enhance CAR T-cell persistence and efficacy while maintaining a good safety profile.</p><figure></figure>\",\"PeriodicalId\":18109,\"journal\":{\"name\":\"Leukemia\",\"volume\":\"35 1\",\"pages\":\"\"},\"PeriodicalIF\":13.4000,\"publicationDate\":\"2025-09-15\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Leukemia\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1038/s41375-025-02767-4\",\"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":"Leukemia","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1038/s41375-025-02767-4","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"HEMATOLOGY","Score":null,"Total":0}
Downregulation of MICA/MICB improves cell persistence and clinical activity of NKG2DL CAR T-cells in patients with relapsed or refractory acute myeloid leukemia or myelodysplastic neoplasia
The NKG2D receptor binds eight ligands (NKG2DL) overexpressed in a wide range of malignancies, but largely absent on non-neoplastic cells. Initial clinical evaluation of NKG2DL chimeric antigen receptor (CAR) T-cells (CYAD-01) in patients with relapsed or refractory (r/r) acute myeloid leukemia (AML) or myelodysplastic neoplasia (MDS) demonstrated low durability of responses and short cell persistence. Two Phase I trials were initiated to evaluate the effect of lymphodepletion prior to a single CAR T-cell infusion in a similar r/r AML/MDS patient population. The DEPLETHINK trial (NCT03466320) evaluated CYAD-01 while the CYCLE-1 trial (NCT04167696) evaluated a next-generation NKG2DL CAR, CYAD-02, where the two main NKG2D ligands MICA and B are downregulated, to increase CAR T-cell persistence. Seventeen and twelve patients were treated in the DEPLETHINK and CYCLE-1 trials, and confirmed the good tolerability of both products with cytokine release syndrome (CRS) grade 3 or 4 reported in 25% and 33.3% of patients, respectively. CYAD-02 presented an higher engraftment and an improved clinical activity (17% objective response rate) compared to CYAD-01 (no objective response). Altogether, our data provide proof of principle that knock-down of MICA/B can enhance CAR T-cell persistence and efficacy while maintaining a good safety profile.
期刊介绍:
Title: Leukemia
Journal Overview:
Publishes high-quality, peer-reviewed research
Covers all aspects of research and treatment of leukemia and allied diseases
Includes studies of normal hemopoiesis due to comparative relevance
Topics of Interest:
Oncogenes
Growth factors
Stem cells
Leukemia genomics
Cell cycle
Signal transduction
Molecular targets for therapy
And more
Content Types:
Original research articles
Reviews
Letters
Correspondence
Comments elaborating on significant advances and covering topical issues