Ménard Cédric, Ghiringhelli François, Roux Stephan, Chaput Nathalie, Mateus Christine, Grohmann Ursula, Caillat-Zucman Sophie, Zitvogel Laurence, Robert Caroline
Center of Clinical Investigations, CBT507, Institut Gustave Roussy, Villejuif, France.
Clin Cancer Res. 2008 Aug 15;14(16):5242-9. doi: 10.1158/1078-0432.CCR-07-4797.
Anti-CTL antigen-4 (CTLA-4) monoclonal antibody (mAb) has led to encouraging antitumor activity associated with immune-related adverse events in patients with heavily pretreated melanoma. However, mechanisms of action and surrogate immunologic markers of efficacy have not been reported thus far.
We monitored the immune responses of 10 melanoma patients included in a phase II clinical trial, which evaluated the efficacy of a second line of therapy of tremelimumab anti-CTLA-4 mAb in patients with metastatic melanoma. The frequency of blood leukocyte populations in association with T cell and regulatory T cell (Treg) functions were evaluated.
Prior to therapy, patients with advanced melanoma presented with a severe CD4+ and CD8+ T cell lymphopenia associated with blunted T-cell proliferative capacities that could be assigned to Treg. Tremelimumab rapidly restored the effector and memory CD4+ and CD8+ T-cell pool and TCR-dependent T-cell proliferation that became entirely resistant to Treg-mediated suppression. Progression-free survival and overall survival was directly correlated with the acquisition of a biological response defined as the resistance of peripheral lymphocytes to Treg-inhibitory effects (obtained in 7 of 10 patients).
CTLA-4 blockade seems to be a valuable strategy to revive reactive memory T cells anergized in the context of stage IV melanoma, and our work suggests that memory T-cell resistance to Treg resulting from anti-CTLA-4 treatment might be a biological activity marker for tremelimumab in patients with melanoma.
抗细胞毒性T淋巴细胞相关抗原4（CTLA-4）单克隆抗体（mAb）已在预处理严重的黑色素瘤患者中展现出令人鼓舞的抗肿瘤活性，并伴有免疫相关不良事件。然而，迄今为止尚未报道其作用机制和疗效的替代免疫标志物。
我们监测了10例黑色素瘤患者的免疫反应，这些患者纳入了一项II期临床试验，该试验评估了曲美木单抗抗CTLA-4 mAb作为转移性黑色素瘤患者二线治疗的疗效。评估了与T细胞和调节性T细胞（Treg）功能相关的血液白细胞群体频率。
治疗前，晚期黑色素瘤患者存在严重的CD4+和CD8+ T细胞淋巴细胞减少，伴有T细胞增殖能力减弱，这可能归因于Treg。曲美木单抗迅速恢复了效应和记忆CD4+和CD8+ T细胞库以及TCR依赖性T细胞增殖，使其完全抵抗Treg介导的抑制。无进展生存期和总生存期与获得一种生物学反应直接相关，该生物学反应定义为外周淋巴细胞对Treg抑制作用的抵抗（10例患者中有7例获得）。
CTLA-4阻断似乎是恢复在IV期黑色素瘤背景下失能的反应性记忆T细胞的一种有价值策略，并且我们的研究表明，抗CTLA-4治疗导致的记忆T细胞对Treg的抵抗可能是黑色素瘤患者曲美木单抗的生物学活性标志物。
