Klaver Yarne, van Steenbergen Sabine C L, Sleijfer Stefan, Debets Reno, Lamers Cor H J
Laboratory of Tumor Immunology, Department of Medical Oncology, Erasmus MC-Cancer Institute , Rotterdam , Netherlands.
Department of Medical Oncology, Erasmus MC-Cancer Institute , Rotterdam , Netherlands.
Front Immunol. 2016 Dec 26;7:648. doi: 10.3389/fimmu.2016.00648. eCollection 2016.
Autologous T cells were genetically modified to express a chimeric antigen receptor (CAR) directed toward carboxy-anhydrase-IX (CAIX) and used to treat patients with CAIX-positive metastatic renal cell carcinoma. In this study, we questioned whether the T cell maturation stage in the pre-infusion product affected CAIX CAR expression and function as well as CAR T cell numbers and expansion. During the 14 days expansion of CAR T cells prior to administration, we observed shifts from a predominant CD4 to a CD8 T cell phenotype and from a significant fraction of naïve to central effector T cells. Surface expression of the CAR was equally distributed among different T cell subsets and T cell maturation stages. During T cell culture days 14-18 (which covered patient treatment days 1-5), T cells demonstrated a decline in CAR expression level per cell irrespective of T cell maturation stage, although the proportion of CAR-positive T cells and CAR-mediated T cell effector functions remained similar for both CD4 and CD8 T cell populations. Notably, patients with a higher fraction of naïve CD8 T cells at baseline (prior to genetic modification) or central effector CD8 T cells at 2 weeks of CAR T cell culture demonstrated a higher fold expansion and absolute numbers of circulating CAR T cells at 1 month after start of therapy. We conclude that the T cell maturation stage prior to and during CAR T cell expansion culture is related to CAR T cell expansion.
将自体T细胞进行基因改造，使其表达靶向碳酸酐酶IX（CAIX）的嵌合抗原受体（CAR），并用于治疗CAIX阳性转移性肾细胞癌患者。在本研究中，我们探讨了输注前产品中的T细胞成熟阶段是否会影响CAIX CAR的表达和功能以及CAR T细胞数量和扩增情况。在给药前CAR T细胞的14天扩增过程中，我们观察到从主要的CD4 T细胞表型向CD8 T细胞表型的转变，以及从相当一部分幼稚T细胞向中央效应T细胞的转变。CAR的表面表达在不同的T细胞亚群和T细胞成熟阶段中均匀分布。在T细胞培养的第14 - 18天（涵盖患者治疗的第1 - 5天），无论T细胞成熟阶段如何，每个细胞的CAR表达水平均呈下降趋势，尽管CD4和CD8 T细胞群体中CAR阳性T细胞的比例和CAR介导的T细胞效应功能保持相似。值得注意的是，在基线时（基因改造前）幼稚CD8 T细胞比例较高或在CAR T细胞培养2周时中央效应CD8 T细胞比例较高的患者，在治疗开始后1个月时循环CAR T细胞的扩增倍数和绝对数量更高。我们得出结论，CAR T细胞扩增培养之前和期间的T细胞成熟阶段与CAR T细胞扩增有关。
