CELL INTELLIGENCE · 肿瘤细胞治疗研究

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TIL（肿瘤浸润淋巴细胞）疗法或伊匹木单抗治疗晚期黑色素瘤

英文原题：Tumor-Infiltrating Lymphocyte Therapy or Ipilimumab in Advanced Melanoma.

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Tumor-Infiltrating Lymphocyte Therapy or Ipilimumab in Advanced Melanoma.

PubMed 2022/12/08（内容时间） N Engl J Med Q1 · IF 84.5（JCR 2025）

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技术：TIL黑色素瘤地区：欧洲
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研究概要

在晚期黑色素瘤患者中，接受 TIL 治疗者的无进展生存期显著长于接受 ipilimumab 者。

中文摘要

背景

免疫检查点抑制剂和靶向治疗显著改善了晚期黑色素瘤患者的结局，但约半数患者无法获得持久获益。TIL（肿瘤浸润淋巴细胞）过继细胞治疗的I–II期试验显示出有希望的应答，但缺乏III期试验数据来确定TIL治疗晚期黑色素瘤的作用。

方法

这项III期、多中心、开放标签试验以1:1比例将不可切除的IIIC或IV期黑色素瘤患者随机分配接受TIL治疗，或抗细胞毒性T淋巴细胞相关抗原4治疗（伊匹木单抗，3 mg/kg）。输注至少5×10^9个TIL前，先给予非清髓性淋巴细胞清除化疗（环磷酰胺加氟达拉滨），之后给予大剂量白细胞介素2。主要终点为无进展生存期。

结果

共168例患者（86%的疾病对抗程序性死亡受体1治疗难治）被分配至TIL组或伊匹木单抗组，各84例。在意向治疗人群中，TIL组中位无进展生存期为7.2个月（95%置信区间[CI]：4.2–13.1），伊匹木单抗组为3.1个月（95% CI：3.0–4.3）；疾病进展或死亡风险比为0.50（95% CI：0.35–0.72；P<0.001）。两组客观缓解率分别为49%（95% CI：38%–60%）和21%（95% CI：13%–32%）。中位总生存期分别为25.8个月（95% CI：18.2个月至未达到）和18.9个月（95% CI：13.8–32.6）。所有接受TIL治疗的患者均发生3级或以上治疗相关不良事件，伊匹木单抗组为57%；TIL组事件主要为化疗相关骨髓抑制。

结论

晚期黑色素瘤患者接受TIL治疗的无进展生存期显著长于接受伊匹木单抗者。（资助方：荷兰癌症协会等；ClinicalTrials.gov编号：NCT02278887。）

展开英文摘要原文
BACKGROUND

Immune checkpoint inhibitors and targeted therapies have dramatically improved outcomes in patients with advanced melanoma, but approximately half these patients will not have a durable benefit. Phase 1-2 trials of adoptive cell therapy with tumor-infiltrating lymphocytes (TILs) have shown promising responses, but data from phase 3 trials are lacking to determine the role of TILs in treating advanced melanoma.

METHODS

In this phase 3, multicenter, open-label trial, we randomly assigned patients with unresectable stage IIIC or IV melanoma in a 1:1 ratio to receive TIL or anti-cytotoxic T-lymphocyte antigen 4 therapy (ipilimumab at 3 mg per kilogram of body weight). Infusion of at least 5 10 9 TILs was preceded by nonmyeloablative, lymphodepleting chemotherapy (cyclophosphamide plus fludarabine) and followed by high-dose interleukin-2. The primary end point was progression-free survival.

RESULTS

A total of 168 patients (86% with disease refractory to anti-programmed death 1 treatment) were assigned to receive TILs (84 patients) or ipilimumab (84 patients). In the intention-to-treat population, median progression-free survival was 7.2 months (95% confidence interval [CI], 4.2 to 13.1) in the TIL group and 3.1 months (95% CI, 3.0 to 4.3) in the ipilimumab group (hazard ratio for progression or death, 0.50; 95% CI, 0.35 to 0.72; P<0.001); 49% (95% CI, 38 to 60) and 21% (95% CI, 13 to 32) of the patients, respectively, had an objective response. Median overall survival was 25.8 months (95% CI, 18.2 to not reached) in the TIL group and 18.9 months (95% CI, 13.8 to 32.6) in the ipilimumab group. Treatment-related adverse events of grade 3 or higher occurred in all patients who received TILs and in 57% of those who received ipilimumab; in the TIL group, these events were mainly chemotherapy-related myelosuppression.

CONCLUSIONS

In patients with advanced melanoma, progression-free survival was significantly longer among those who received TIL therapy than among those who received ipilimumab. (Funded by the Dutch Cancer Society and others; ClinicalTrials.gov number, NCT02278887.).

论文信息

作者
Rohaan MW、Borch TH、van den Berg JH、Met Ö、Kessels R、Geukes Foppen MH、Stoltenborg Granhøj J、Nuijen B
单位
From the Division of Medical Oncology (M.W.R., M.H.G.F., M.K., J.S.W.B., J.V.T., C.U.B., A.M.-E., S.K., S.W., J.B.A.G.H.), the BioTherapeutics Unit, Hospital Pharmacy (J.H. van den Berg, C.N., M.Z., S.S.), the Divisions of Pharmacy and Pharmacology (B.N., J.H. Beijnen), Molecular Oncology and Immunology (I.J., T.N.S., J.B.A.G.H.), Biometrics (R.K., L.D.V.W., M. van Dijk, L.G.G.-O., L.H.M.V., A.T.A., H.T.), Psychosocial Research and Epidemiology (R.M.T.H., V.P.R., W.H.H.), Radiology (F.L.), and Surgical Oncology (A.C.J.A., W.J.H., M.W.J.M.W.), Netherlands Cancer Institute, the Department of Hematopoiesis, Sanquin Research and Landsteiner Laboratory (M.H., C.V.), and the Department of Medical Oncology, Amsterdam University Medical Center, Vrije Universiteit Amsterdam (A.J.M.E.), Amsterdam, the Department of Healthcare Innovation and Evaluation, Julius Center for Health Sciences and Primary Care (R.M.T.H.),&#xa0;the Department of Medical Oncology, University Medical Center Utrecht, Utrecht University (K.P.M.S.), Trial and Data Center, Princess Maxima Center for Pediatric Oncology (H.T.), and Oncode Institute (T.N.S.), Utrecht, the Department of Health Technology and Services Research, University of Twente (V.P.R.), and the Department of Medical Oncology, Medical Spectrum Twente (D.P.), Enschede, the Department of Medical Oncology, Erasmus Medical Center, Rotterdam (A.A.M.V.), the Department of Medical Oncology, University Medical Center Groningen, Groningen (G.A.P.H.), the Department of Medical Oncology, Amphia Hospital, Breda (M.A.M.S.-B.), the Department of Medical Oncology, Maastricht University Medical Center, Maastricht (M.J.B.A.), the Department of Medical Oncology, Isala, Zwolle (J.-W.B.G.), the Department of Medical Oncology, M&#xe1;xima Medical Center, Eindhoven (G.V.), the Departments of Medical Oncology (E.K.), Biomedical Data Sciences (M.W.J.M.W.), Hematology (T.N.S.), and Clinical Oncology (J.B.A.G.H.), Leiden University Medical Center, Leiden, the Department of Medical Oncology, Radboud University Medical Center, Nijmegen (M.J.B.-S.), the Department of Medical Oncology, Medical Center Leeuwarden, Leeuwarden (W.E.F.), and the Department of Medical Oncology, Zuyderland Medical Center, Sittard-Geleen (F.W.P.J.B.) - all in the Netherlands; the Department of Oncology, National Center for Cancer Immune Therapy (T.H.B., &#xd6;.M., J.S.G., I.M.N., T.J.M., R.B.H., E.E., M. Donia, I.M.S.), and the Department of Plastic Surgery (L.R.H.),&#xa0;Copenhagen University Hospital, Herlev, Denmark; and Melanoma Institute Australia, the Faculty of Medicine and Health, University of Sydney, and Royal Prince Alfred Hospital - all in Sydney (A.C.J.A.).Netherlands
文献类型
多中心研究 · 随机对照试验 · 非美国政府资助研究
期刊
The New England journal of medicine2022 Dec 8
原文标识
PubMed 36477031　·　DOI 10.1056/NEJMoa2210233

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