Specific lymphocyte subsets predict response to adoptive cell therapy using expanded autologous tumor-infiltrating lymphocytes in metastatic melanoma patients.
Specific lymphocyte subsets predict response to adoptive cell therapy using expanded autologous tumor-infiltrating lymphocytes in metastatic melanoma patients.
复制标题
DOI：
10.1158/1078-0432.ccr-12-1177
复制
发表时间：
2012-12-15
期刊：
影响因子：
--
通讯作者：
Hwu P
中科院分区：
文献类型：
--
作者：
Radvanyi LG;Bernatchez C;Zhang M;Fox PS;Miller P;Chacon J;Wu R;Lizee G;Mahoney S;Alvarado G;Glass M;Johnson VE;McMannis JD;Shpall E;Prieto V;Papadopoulos N;Kim K;Homsi J;Bedikian A;Hwu WJ;Patel S;Ross MI;Lee JE;Gershenwald JE;Lucci A;Royal R;Cormier JN;Davies MA;Mansaray R;Fulbright OJ;Toth C;Ramachandran R;Wardell S;Gonzalez A;Hwu P
使用自体肿瘤浸润淋巴细胞 (TIL) 的过继细胞疗法 (ACT) 是治疗对传统疗法无反应的转移性黑色素瘤的一种有前途的治疗方法。我们在此报告一项正在进行的 II 期临床试验的结果，该试验测试使用 TIL 进行 ACT 对转移性黑色素瘤患者的疗效，以及特定患者临床特征和输注 TIL 的表型属性与临床反应的关联。总共有 31 名暂时性淋巴细胞清除患者接受了扩大的 TIL 治疗，随后接受了两个周期的高剂量 (HD) IL-2 治疗。确定了患者临床特征和输注 T 细胞表型对临床反应的影响。总体而言，使用免疫相关反应标准 (irRC)，15/31 (48.4%) 患者获得客观临床反应，其中 2 名患者 (6.5%) 获得完全反应。 9/15 (60%) 的有反应患者观察到无进展生存期 >12 个月。与客观肿瘤消退显着相关的因素包括输注的 TIL 数量较多、输注产品中 CD8+ T 细胞比例较高、CD8+ 群体分化程度更高的效应表型以及共表达负性共刺激分子“B 和 T 淋巴细胞衰减剂”(BTLA) 的 CD8+ T 细胞频率较高。未发现有反应者和无反应者之间 TIL 端粒长度存在显着差异。这些结果表明，使用扩增的自体 TIL 进行免疫治疗能够在转移性黑色素瘤患者中实现持久的临床反应，并且输注 TIL 中的 CD8+ T 细胞，特别是分化的效应细胞和表达 BTLA 的细胞，与肿瘤消退相关。
Adoptive cell therapy (ACT) using autologous tumor-infiltrating lymphocytes (TIL) is a promising treatment for metastatic melanoma unresponsive to conventional therapies. We report here on the results of an ongoing Phase II clinical trial testing the efficacy of ACT using TIL in metastatic melanoma patients and the association of specific patient clinical characteristics and the phenotypic attributes of the infused TIL with clinical response. Altogether, 31 transiently lymphodepleted patients were treated with their expanded TIL followed by two cycles of high-dose (HD) IL-2 therapy. The effects of patient clinical features and the phenotypes of the T-cells infused on clinical response were determined. Overall, 15/31 (48.4%) patients had an objective clinical response using immune-related response criteria (irRC), with two patients (6.5%) having a complete response. Progression-free survival of >12 months was observed for 9/15 (60%) of the responding patients. Factors significantly associated with objective tumor regression included a higher number of TIL infused, a higher proportion of CD8+ T-cells in the infusion product, a more differentiated effector phenotype of the CD8+ population and a higher frequency of CD8+ T-cells co-expressing the negative costimulation molecule “B- and T-lymphocyte attenuator” (BTLA). No significant difference in telomere lengths of TIL between responders and non-responders was identified. These results indicate that immunotherapy with expanded autologous TIL is capable of achieving durable clinical responses in metastatic melanoma patients and that CD8+ T-cells in the infused TIL, particularly differentiated effectors cells and cells expressing BTLA, are associated with tumor regression.