Clinical and Immune Effects of Lenalidomide in Combination with Gemcitabine in Patients with Advanced Pancreatic Cancer

Purpose
To assess the immunomodulatory and clinical effects of lenalidomide with standard treatment of gemcitabine in patients with advanced pancreatic cancer.
Patients and Methods
Patients with advanced pancreatic cancer were treated in first line with lenalidomide orally for 21 days of a 28 days cycle and the standard regimen for gemcitabine. In Part I, which we previously have reported, the dose of lenalidomide was defined (n = 12). In Part II, every other consecutive patient was treated with either lenalidomide (Group A, n = 11) or gemcitabine (Group B, n = 10) during cycle 1. From cycle 2 on, all Part II patients received the combination.
Results
A significant decrease in the proliferative response of peripheral blood mononuclear cells and the frequency of DCs were noted in patients at baseline compared to healthy control donors while the frequencies of CD4+ and CD8+ T cells, NK-cells and MDSCs were significantly higher in patients compared to controls. In Group A, a significant increase in the absolute numbers of activated (HLA-DR+) CD4 and CD8 T cells and CD8 effector memory T cells (p<0.01) was noted during treatment. A statistical increment in the absolute numbers of Tregs were seen after cycle 1 (p<0.05). The addition of gemcitabine, reduced most lymphocyte subsets (p<0.05). In Group B, the proportion of lymphocytes remained unchanged during the study period. There was no difference in overall survival, progression free survival and survival rate at one year comparing the two groups.
Discussion
Patients with advanced pancreatic carcinoma had impaired immune functions. Lenalidomide augmented T cell reactivities, which were abrogated by gemcitabine. However, addition of lenalidomide to gemcitabine seemed to have no therapeutic impact compared to gemcitabine alone in this non-randomized study.
Trial Registration
ClinicalTrials.gov NCT01547260

研究目的
本研究旨在评估来那度胺（lenalidomide）联合吉西他滨（gemcitabine）标准疗法对晚期胰腺癌患者的免疫调节作用与临床疗效。

受试者与研究方法
晚期胰腺癌一线治疗患者以28天为一个治疗周期，其中来那度胺口服给药持续21天，同时联合吉西他滨标准给药方案。本研究分为两个部分：第一部分（既往已发表，样本量n=12）已确定来那度胺的给药剂量；第二部分中，连续入组的患者在第1周期分别接受来那度胺（A组，n=11）或吉西他滨（B组，n=10）单药治疗；自第2周期起，第二部分所有患者均接受联合治疗方案。

研究结果
基线状态下，与健康对照者相比，晚期胰腺癌患者的外周血单个核细胞（peripheral blood mononuclear cells）增殖反应及树突状细胞（dendritic cells, DCs）频率显著降低，而CD4+ T细胞（CD4+ T cells）、CD8+ T细胞（CD8+ T cells）、自然杀伤细胞（natural killer cells, NK-cells）及髓系来源抑制细胞（myeloid-derived suppressor cells, MDSCs）的频率则显著高于对照者。
A组患者治疗期间，活化的（人类白细胞抗原-DR+，human leukocyte antigen-DR+）CD4、CD8 T细胞及CD8效应记忆T细胞（effector memory T cells）的绝对计数显著升高（p<0.01）；第1周期结束后，调节性T细胞（regulatory T cells, Tregs）的绝对计数出现统计学意义上的升高（p<0.05）。联合吉西他滨治疗后，多数淋巴细胞亚群的绝对计数显著降低（p<0.05）。B组患者在整个研究期间的淋巴细胞比例无明显变化。两组患者的总生存期（overall survival）、无进展生存期（progression free survival）及1年生存率均无显著差异。

讨论
晚期胰腺癌患者存在免疫功能受损的情况。来那度胺可增强T细胞反应性，但该效应可被吉西他滨抵消。本项非随机研究显示，在吉西他滨基础上加用来那度胺，与单用吉西他滨相比未带来额外的治疗获益。

试验注册
ClinicalTrials.gov NCT01547260