单细胞追踪揭示黑色素瘤 TIL 治疗过程中肿瘤反应性 T 细胞的可塑性
Single-cell tracking reveals tumor-reactive T cell plasticity during melanoma TIL therapy.
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CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
无 IL-2 的 TIL（肿瘤浸润淋巴细胞）治疗联合 PD-1 阻断在晚期妇科肿瘤中展现强效疗效
英文原题：IL-2-free tumor-infiltrating lymphocyte therapy with PD-1 blockade demonstrates potent efficacy in advanced gynecologic cancer.
查看英文原题
IL-2-free tumor-infiltrating lymphocyte therapy with PD-1 blockade demonstrates potent efficacy in advanced gynecologic cancer.
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研究概要
我们改良的 TIL 治疗方案显示出可控的安全性，且 TIL 在不经静脉给予 IL-2 的情况下仍可存活并增殖，在晚期妇科肿瘤患者中显示出强效疗效。
中文摘要
背景
TIL（肿瘤浸润淋巴细胞）疗法受到强效淋巴清除和大剂量静脉注射白细胞介素 2（IL-2）的限制。为解决这些局限，我们开展临床前和临床研究，评估一种创新改良方案在晚期妇科癌症患者中的安全性、抗肿瘤活性和药代动力学。
方法
采用局部复发宫颈癌患者样本建立患者来源异种移植（PDX）模型。在改良 TIL 疗法方案中，将肿瘤组织切碎后于体外扩增 TIL，不使用饲养细胞。患者接受低剂量环磷酰胺淋巴清除，随后输注 TIL，不给予静脉注射 IL-2。主要终点为安全性；次要终点包括客观缓解率、缓解持续时间和 T 细胞持久性。
结果
在配对 PDX 模型中，同源 TIL 可有效缩小肿瘤（p < 0.0001），并在体内无需 IL-2 存在而发挥作用。临床部分所有入组患者均成功接受改良方案 TIL 输注，安全性可控。在 14 例可评估患者中，5 例（36%；95% CI 16.3–61.2）出现客观缓解，其中 3 例完全缓解分别持续至 19.5、15.4 和 5.2 个月。缓解者总生存期（OS）长于未缓解者（p = 0.036）。所有患者输注的 TIL 均持续增殖并长期存留；缓解者的增殖更强，这由第 14 天（p = 0.004）和第 30 天（p = 0.004）输注 TIL 与外周 T 细胞间 TCR 克隆型的 Morisita 重叠指数（MOI）所反映。第 14 天 CD8+/CD4+ 比值改变幅度较大与更长 OS 相关（p = 0.010）。
结论
改良 TIL 治疗方案的安全性可控；无需静脉给予 IL-2，TIL 仍可存活和增殖，并在晚期妇科癌症患者中显示出显著疗效。试验注册：NCT04766320，2021 年 1 月 4 日。
展开英文摘要原文
BACKGROUND
Tumor-infiltrating lymphocyte (TIL) therapy has been restricted by intensive lymphodepletion and high-dose intravenous interleukin-2 (IL-2) administration. To address these limitations, we conducted preclinical and clinical studies to evaluate the safety, antitumor activity, and pharmacokinetics of an innovative modified regimen in patients with advanced gynecologic cancer.
METHODS
Patient-derived xenografts (PDX) were established from a local recurrent cervical cancer patient. TILs were expanded ex vivo from minced tumors without feeder cells in the modified TIL therapy regimen. Patients underwent low-dose cyclophosphamide lymphodepletion followed by TIL infusion without intravenous IL-2. The primary endpoint was safety; the secondary endpoints included objective response rate, duration of response, and T cell persistence.
RESULTS
In matched patient-derived xenografts (PDX) models, homologous TILs efficiently reduced tumor size (p < 0.0001) and underwent IL-2 absence in vivo. In the clinical section, all enrolled patients received TIL infusion using a modified TIL therapy regimen successfully with a manageable safety profile. Five (36%, 95% CI 16.3-61.2) out of 14 evaluable patients experienced objective responses, and three complete responses were ongoing at 19.5, 15.4, and 5.2 months, respectively. Responders had longer overall survival (OS) than non-responders (p = 0.036). Infused TILs showed continuous proliferation and long-term persistence in all patients and showed greater proliferation in responders which was indicated by the Morisita overlap index (MOI) of TCR clonotypes between infused TILs and peripheral T cells on day 14 (p = 0.004) and day 30 (p = 0.004). Higher alteration of the CD8 + /CD4 + ratio on day 14 indicated a longer OS (p = 0.010).
CONCLUSIONS
Our modified TIL therapy regimen demonstrated manageable safety, and TILs could survive and proliferate without IL-2 intravenous administration, showing potent efficacy in patients with advanced gynecologic cancer. TRIAL REGISTRATION: NCT04766320, Jan 04, 2021.
论文信息
- 作者
- Guo J、Wang C、Luo N、Wu Y、Huang W、Zhu J、Shi W、Ding J
- 第一作者单位
- Department of Obstetrics and Gynecology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.China
- 通讯作者单位
- Department of Obstetrics and Gynecology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China. mdcheng18@tongji.edu.cn.China
- 文献类型
- 非美国政府资助研究
- 期刊
- BMC medicine2024 May 20
- 原文标识
- PubMed 38769543 · DOI 10.1186/s12916-024-03420-0