CAR-T（CAR-T）细胞疗法在非肿瘤性疾病中的应用
Chimeric antigen receptor T (CAR-T) cell therapy in non-oncological diseases.
CAR-T（CAR-T）细胞在血液系统恶性肿瘤中的应用推动了这种免疫治疗形式的显著进展。
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
来那度胺难治性多发性骨髓瘤中的 Cilta-cel 或标准治疗
英文原题：Cilta-cel or Standard Care in Lenalidomide-Refractory Multiple Myeloma.
查看英文原题
Cilta-cel or Standard Care in Lenalidomide-Refractory Multiple Myeloma.
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研究概要
在既往接受过一至三线治疗且对来那度胺耐药的骨髓瘤患者中，单次输注 cilta-cel 较标准治疗可降低疾病进展或死亡风险。（由 Janssen 和 Legend Biotech 资助；CARTITUDE-4 ClinicalTrials.gov 注册号，NCT04181827。）
研究思路结论见上方概要
背景
西达基奥仑赛（cilta-cel）是一种靶向B细胞成熟抗原（BCMA）的CAR-T 细胞疗法，对既往接受过多线治疗的复发/难治性多发性骨髓瘤患者有效。我们在来那度胺难治性疾病的患者中，于更早的治疗线次下研究了西达基奥仑赛。
方法
在这项3期、随机、开放标签试验中，我们将来那度胺难治性多发性骨髓瘤患者分配至接受cilta-cel或由医生选择的有效标准治疗。所有患者既往均接受过一至三线治疗。主要结局为无进展生存期。
结果
共有419例患者接受了随机分组（208例接受cilta-cel治疗，211例接受标准治疗）。中位随访时间为15.9个月（范围0.1至27.3），cilta-cel组的中位无进展生存期未达到，标准治疗组为11.8个月（风险比0.26；95%置信区间[CI]0.18至0.38；P<0.001）。12个月时的无进展生存率在cilta-cel组为75.9%（95%CI 69.4至81.1），在标准治疗组为48.6%（95%CI 41.5至55.3）。cilta-cel组较标准治疗组有更多患者达到总体缓解（84.6% vs. 67.3%）、完全缓解或更好（73.1% vs. 21.8%）以及微小残留病阴性（60.6% vs. 15.6%）。任何原因死亡分别报告于39例和46例患者（风险比0.78；95%CI 0.5至1.2）。大多数患者在治疗期间报告了3级或4级不良事件。在接受治疗人群中接受cilta-cel治疗的176例患者中，134例（76.1%）发生细胞因子释放综合征（3级或4级，1.1%；无5级），8例（4.5%）发生免疫效应细胞相关神经毒性综合征（均为1级或2级），1例出现运动和神经认知症状（1级），16例（9.1%）出现颅神经麻痹（2级，8.0%；3级，1.1%），5例（2.8%）出现CAR-T 相关周围神经病变（1级或2级，2.3%；3级，0.6%）。
展开英文摘要原文
BACKGROUND
Ciltacabtagene autoleucel (cilta-cel), a B-cell maturation antigen (BCMA)-directed CAR T-cell therapy, is effective in heavily pretreated patients with relapsed or refractory multiple myeloma. We investigated cilta-cel in earlier treatment lines in patients with lenalidomide-refractory disease.
METHODS
In this phase 3, randomized, open-label trial, we assigned patients with lenalidomide-refractory multiple myeloma to receive cilta-cel or the physician's choice of effective standard care. All the patients had received one to three previous lines of treatment. The primary outcome was progression-free survival.
RESULTS
A total of 419 patients underwent randomization (208 to receive cilta-cel and 211 to receive standard care). At a median follow-up of 15.9 months (range, 0.1 to 27.3), the median progression-free survival was not reached in the cilta-cel group and was 11.8 months in the standard-care group (hazard ratio, 0.26; 95% confidence interval [CI], 0.18 to 0.38; P<0.001). Progression-free survival at 12 months was 75.9% (95% CI, 69.4 to 81.1) in the cilta-cel group and 48.6% (95% CI, 41.5 to 55.3) in the standard-care group. More patients in the cilta-cel group than in the standard-care group had an overall response (84.6% vs. 67.3%), a complete response or better (73.1% vs. 21.8%), and an absence of minimal residual disease (60.6% vs. 15.6%). Death from any cause was reported in 39 patients and 46 patients, respectively (hazard ratio, 0.78; 95% CI, 0.5 to 1.2). Most patients reported grade 3 or 4 adverse events during treatment. Among the 176 patients who received cilta-cel in the as-treated population, 134 (76.1%) had cytokine release syndrome (grade 3 or 4, 1.1%; no grade 5), 8 (4.5%) had immune effector cell-associated neurotoxicity syndrome (all grade 1 or 2), 1 had movement and neurocognitive symptoms (grade 1), 16 (9.1%) had cranial nerve palsy (grade 2, 8.0%; grade 3, 1.1%), and 5 (2.8%) had CAR-T-related peripheral neuropathy (grade 1 or 2, 2.3%; grade 3, 0.6%).
CONCLUSIONS
A single cilta-cel infusion resulted in a lower risk of disease progression or death than standard care in lenalidomide-refractory patients with multiple myeloma who had received one to three previous therapies. (Funded by Janssen and Legend Biotech; CARTITUDE-4 ClinicalTrials.gov number, NCT04181827.).
论文信息
- 作者
- San-Miguel J、Dhakal B、Yong K、Spencer A、Anguille S、Mateos MV、Fernández de Larrea C、Martínez-López J
- 单位
- From the Cancer Center Clínica Universidad de Navarra, Centro Investigación Medica Aplicada, Instituto de Investigación de Navarra, Centro Investigación Biomédica en Red Cáncer (CIBERONC), Pamplona (J.S.-M.), the University Hospital of Salamanca, Instituto de Investigación Biomédica de Salamanca, Centro Investigación del Cáncer, CIBERONC, Salamanca (M.-V.M.), the Amyloidosis and Myeloma Unit, Department of Hematology, Hospital Clínic of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Barcelona (C.F.L.), the Hematological Malignancies Clinical Research Unit, Hospital 12 de Octubre Universidad Complutense, Centro Nacional de Investigaciones Oncológicas, CIBERONC, Madrid (J.M.-L.), and the Institut Català d'Oncologia and Institut Josep Carreras, Hospital Germans Trias i Pujol, Badalona (A.O.) - all in Spain; the Medical College of Wisconsin, Milwaukee (B.D.); the University College London Cancer Institute (K.Y.) and University College London Hospitals, NHS Foundation Trust (R.P.), London, University Hospitals Bristol and Weston NHS Foundation Trust, Bristol (J. Griffin), and Janssen Research and Development, High Wycombe (J. Gilbert) - all in the United Kingdom; Monash University (A. Spencer) and the Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Sir Peter MacCallum Department of Oncology, University of Melbourne (S.J.H.), Melbourne, VIC, and Royal Prince Alfred Hospital and the University of Sydney, Sydney (P.J.H.) - all in Australia; the Vaccine and Infectious Disease Institute, University of Antwerp, Antwerp, and the Division of Hematology and Center for Cell Therapy and Regenerative Medicine, Antwerp University Hospital, Edegem - both in Belgium (S.A.); the Department of Hematology, University Hospital Hôtel-Dieu, Nantes (P.M., C.T.), and Service d'Hématologie et Thérapie Cellulaire, Hôpital La Milétrie, and Centre d'investigation Clinique INSERM 1402, Poitiers University Hospital, Poitiers (X.L.) - both in France; Tel Aviv Sourasky Medical Center (I.A., Y.C.C.) and the Sackler Faculty of Medicine, Tel Aviv University (Y.C.C.) - both in Tel Aviv, Israel; IRCCS Azienda Ospedaliero-Universitaria di Bologna, Seràgnoli Institute of Hematology, and the Department of Medical and Surgical Sciences, Bologna University School of Medicine, Bologna, Italy (M.C.); the Department of Hematology, Japanese Red Cross Medical Center, Tokyo (T.I.); the Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea (S.J.K.); the Department of Hematology, University Medical Center Groningen, Groningen (W.R.), and Amsterdam University Medical Center, Vrije Universiteit Amsterdam, Amsterdam (N.W.C.J.D.) - both in the Netherlands; Poznan University of Medical Sciences, Poznan, Poland (D.D.); Stanford University School of Medicine, Stanford, CA (S.S.); the University of Alabama at Birmingham, Birmingham (L.J.C.); Ohio State University Comprehensive Cancer Center, Columbus (A.M.K.); Janssen Research and Development, Raritan (N.L., J.M.S., C.C.J., K.C., T.Y., S.N.), and Legend Biotech, Somerset (E.F., L.P., N.P.) - both in New Jersey; Janssen, Buenos Aires (C.L.); Cilag International, Zug, Switzerland (A. Slaughter); Janssen Research and Development, Spring House, PA (K.L., E.Z.); Janssen China Research and Development, Shanghai (D.C.); and Universitätsklinikum Würzburg, Medizinische Klinik und Poliklinik II, Würzburg, Germany (H.E.).Spain
- 文献类型
- III 期临床试验 · 对照研究 · 随机对照试验 · 非美国政府资助研究
- 期刊
- The New England journal of medicine2023 Jul 27
- 原文标识
- PubMed 37272512 · DOI 10.1056/NEJMoa2303379