Felix Joana, Lambert Jérome, Roelens Marie, Maubec Eve, Guermouche Hélène, Pages Cécile, Sidina Irina, Cordeiro Debora J, Maki Guitta, Chasset François, Porcher Raphaël, Bagot Martine, Caignard Anne, Toubert Antoine, Lebbé Céleste, Moins-Teisserenc Hélène
INSERM, UMR-1160, Institut Universitaire d'Hématologie, Paris, France; Université Paris Diderot, Sorbonne Paris Cité, Paris, France.
Université Paris Diderot, Sorbonne Paris Cité, Paris, France; AP-HP, Hôpital Saint-Louis, Service de Biostatistique et Informatique Médicale, Paris, France; INSERM, UMR 1153, Center de Recherche Epidémiologie et Statistique (CRESS), Paris, France.
Oncoimmunology. 2016 Feb 18;5(7):1136045. doi: 10.1080/2162402X.2015.1136045. eCollection 2016 Jul.
Therapy targeting CTLA-4 immune checkpoint provides increased survival in patients with advanced melanoma. However, immunotherapy is frequently associated with delayed and heterogeneous clinical responses and it is important to identify prognostic immunological correlates of clinical endpoints.
77 patients with stage III/IV melanoma were treated with ipilimumab alone every 3 weeks, during 9 weeks. Blood samples were collected at the baseline and before each dose for in depth immune monitoring.
The median follow-up was 28 mo with a median survival of 7 mo. Survival and clinical benefit were significantly improved when absolute lymphocyte count at the baseline was above 1 × 10(9)/L. Notably, ipilimumab had a global effect on memory T cells, with an early increase of central and effector subsets in patients with disease control. By contrast, percentages of stem cell memory T cells (TSCM) gradually decreased despite stable absolute counts and sustained proliferation, suggesting a process of differentiation. Higher proportions of eomes(+) and Ki-67(+) T cells were observed, with enhanced skin homing potential and induction of cytotoxic markers.
These results suggest that CTLA-4 blockade is able to reshape the memory subset with the potential involvement of Eomes and memory subsets including TSCM.
靶向CTLA-4免疫检查点的治疗可提高晚期黑色素瘤患者的生存率。然而，免疫疗法常常与延迟且异质性的临床反应相关，识别临床终点的预后免疫相关性很重要。
77例III/IV期黑色素瘤患者每3周接受一次伊匹单抗单药治疗，为期9周。在基线期及每次给药前采集血样以进行深入的免疫监测。
中位随访时间为28个月，中位生存期为7个月。当基线时的绝对淋巴细胞计数高于1×10⁹/L时，生存期和临床获益显著改善。值得注意的是，伊匹单抗对记忆T细胞有整体影响，疾病得到控制的患者中，中枢和效应亚群早期增加。相比之下，干细胞记忆T细胞（TSCM）的百分比逐渐下降，尽管绝对计数稳定且持续增殖，提示存在分化过程。观察到Eomes⁺和Ki-67⁺ T细胞比例更高，皮肤归巢潜能增强且细胞毒性标志物诱导增加。
这些结果表明，CTLA-4阻断能够重塑记忆亚群，Eomes及包括TSCM在内的记忆亚群可能参与其中。
