背景:肿瘤浸润性淋巴细胞(TIL)治疗一直受到密集的淋巴清除和大剂量静脉内白介素2(IL-2)给药的限制。为了解决这些限制,我们进行了临床前和临床研究,以评估安全性,抗肿瘤活性,和创新的改良方案在晚期妇科癌症患者中的药代动力学。
方法:从局部复发的宫颈癌患者中建立患者源性异种移植物(PDX)。在改良的TIL治疗方案中,从没有饲养细胞的切碎的肿瘤离体扩增TIL。患者接受低剂量环磷酰胺淋巴吸收,然后输注TIL而不静脉注射IL-2。主要终点是安全性;次要终点包括客观缓解率,响应的持续时间,和T细胞持久性。
结果:在匹配的患者源性异种移植物(PDX)模型中,同源TIL可有效减小肿瘤大小(p<0.0001),体内IL-2缺失.在临床部分,所有入组患者均采用改良TIL治疗方案成功接受TIL输注,安全性可控.五个(36%,95%CI16.3-61.2)14名可评估患者经历了客观反应,在19.5、15.4和5.2个月,三个完整的答复正在进行中,分别。反应者的总生存期(OS)长于非反应者(p=0.036)。在第14天(p=0.004)和第30天(p=0.004),输注的TIL和外周T细胞之间的TCR克隆型的Morisita重叠指数(MOI)表明,在所有患者中输注的TIL显示连续增殖和长期持续,并且在应答者中显示更大的增殖。第14天CD8+/CD4+比率的更高改变表明OS更长(p=0.010)。
结论:我们改良的TIL治疗方案显示出可控的安全性,和TIL可以存活和增殖没有IL-2静脉给药,在晚期妇科癌症患者中显示出有效的疗效。
背景:NCT04766320,2021年1月4日。
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.
BACKGROUND: NCT04766320, Jan 04, 2021.