Tethered IL-15 augments antitumor activity and promotes a stem-cell memory subset in tumor-specific T cells
Tethered IL-15 augments antitumor activity and promotes a stem-cell memory subset in tumor-specific T cells
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DOI：
10.1073/pnas.1610544113
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发表时间：
2016-11-29
影响因子：
11.1
通讯作者：
Cooper, Laurence J. N.
中科院分区：
文献类型：
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作者：
Hurton, Lenka V.;Singh, Harjeet;Cooper, Laurence J. N.
过继免疫治疗通过嵌合抗原受体(CAR)将T细胞重定向至CD19，是一种能够在输血细胞持续存活的情况下诱导B细胞恶性肿瘤完全肿瘤消退的研究治疗方法。T记忆干细胞(T-SCM)保持了长期存活的优越潜力，但在制造这个T细胞亚群方面存在挑战，因为它们在循环中的淋巴细胞中很少见。我们报告了一种临床相关的方法，利用睡美人平台生成具有保留T-SCM潜力的CAR+T细胞。由于IL-15是T细胞记忆的基础，我们通过将CAR与膜结合的嵌合IL-15(MbIL15)共表达来整合其共刺激特性。MBIL15-CAR T细胞通过信号转导和转录激活因子5产生不依赖CAR信号的增强的T细胞持久性，没有明显的自主生长或转化，实现了对CD19(+)白血病的有效排斥。长寿T细胞是CD45RO(Neg)CCR7(+)CD95(+)，表型与T-SCM最相似，具有记忆样转录特征。总体而言，这些结果表明，CAR(+)T细胞可以发展成长期持续存在的记忆干细胞表型，通过MBIL15信号来维持。这一观察结果值得在临床试验中进行评估。
Adoptive immunotherapy retargeting T cells to CD19 via a chimeric antigen receptor (CAR) is an investigational treatment capable of inducing complete tumor regression of B-cell malignancies when there is sustained survival of infused cells. T-memory stem cells (T-SCM) retain superior potential for long-lived persistence, but challenges exist in manufacturing this T-cell subset because they are rare among circulating lymphocytes. We report a clinically relevant approach to generating CAR+ T cells with preserved T-SCM potential using the Sleeping Beauty platform. Because IL-15 is fundamental to T-cell memory, we incorporated its costimulatory properties by coexpressing CAR with a membrane-bound chimeric IL-15 (mbIL15). The mbIL15-CAR T cells signaled through signal transducer and activator of transcription 5 to yield improved T-cell persistence independent of CAR signaling, without apparent autonomous growth or transformation, and achieved potent rejection of CD19(+) leukemia. Long-lived T cells were CD45RO(neg)CCR7(+) CD95(+), phenotypically most similar to T-SCM, and possessed a memory-like transcriptional profile. Overall, these results demonstrate that CAR(+) T cells can develop long-term persistence with a memory stem-cell phenotype sustained by signaling through mbIL15. This observation warrants evaluation in clinical trials.