Schwartzentruber D J, Hom S S, Dadmarz R, White D E, Yannelli J R, Steinberg S M, Rosenberg S A, Topalian S L
Surgery Branch and Biostatistics and Data Management Section, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
J Clin Oncol. 1994 Jul;12(7):1475-83. doi: 10.1200/JCO.1994.12.7.1475.
To correlate in vitro characteristics of tumor-infiltrating lymphocytes (TIL) with clinical response to TIL immunotherapy in patients with metastatic melanoma.
Forty-one melanoma patients undergoing 43 separate treatment courses with TIL and interleukin-2 (IL-2) from December 1990 through November 1992 were studied prospectively. Multiple patient and treatment characteristics were evaluated for response correlates. In addition, TIL were assayed within 7 days of infusion for characteristics such as doubling time, cell-surface phenotype, autologous tumor lysis in 4-hour chromium-51 release assays, and cytokine secretion following autologous tumor stimulation.
Nine patients experienced complete or partial tumor regressions. Clinical parameters such as age, sex, sites of disease, performance status, and prior therapies were similar in responders and nonresponders. Treatment variables such as the cumulative IL-2 dose and concomitant administration of cyclophosphamide or interferon (IFN)-alpha were not predictive of response, although responders received 33% more TIL. However, statistically significant differences in favor of clinical response were noted for extranodal source of TIL (v lymph node), shorter culture duration (mean, 38 v 47 days), shorter TIL doubling time (2.6 v 3.7 days), greater autologous tumor lysis by TIL (30% v 15%; effector-to-target [E:T], 40:1), and secretion of granulocyte-macrophage colony-stimulating factor (GM-CSF) by TIL following autologous tumor stimulation (six of nine responders v eight of 32 nonresponders).
The associations of TIL lysis of autologous tumor and younger TIL age with clinical response observed in this study are supportive of previous reports, and these findings will be useful in designing future clinical trials. The new observation correlating GM-CSF secretion by TIL with clinical response is interesting and needs further substantiation.
将肿瘤浸润淋巴细胞（TIL）的体外特性与转移性黑色素瘤患者TIL免疫治疗的临床反应相关联。
对1990年12月至1992年11月期间接受43个单独疗程TIL和白细胞介素-2（IL-2）治疗的41例黑色素瘤患者进行前瞻性研究。评估了多个患者和治疗特征以寻找反应相关因素。此外，在输注TIL的7天内对其进行检测，评估其倍增时间、细胞表面表型、4小时51铬释放试验中的自体肿瘤溶解情况以及自体肿瘤刺激后的细胞因子分泌等特征。
9例患者出现肿瘤完全或部分消退。反应者和无反应者在年龄、性别、疾病部位、体能状态和既往治疗等临床参数方面相似。治疗变量如累积IL-2剂量以及环磷酰胺或α干扰素（IFN）的联合使用并不能预测反应，尽管反应者接受的TIL多33%。然而，在TIL的结外来源（相对于淋巴结）、较短的培养时间（平均38天对47天）、较短的TIL倍增时间（2.6天对3.7天）、TIL更高的自体肿瘤溶解率（30%对15%；效应细胞与靶细胞比例[E:T]为40:1）以及自体肿瘤刺激后TIL分泌粒细胞-巨噬细胞集落刺激因子（GM-CSF）方面（9例反应者中有6例，32例无反应者中有8例），观察到有利于临床反应的统计学显著差异。
本研究中观察到的TIL对自体肿瘤的溶解以及TIL较年轻与临床反应的关联支持了先前的报道，这些发现将有助于设计未来的临床试验。TIL分泌GM-CSF与临床反应相关的新观察结果很有趣，需要进一步证实。
