Natural killer (NK) cells are a promising alternative to T cells for cancer immunotherapy. Adoptive therapies with allogeneic, cytokine-activated NK cells are being investigated in clinical trials. However, the optimal cytokine support after adoptive transfer to promote NK cell expansion, and persistence remains unclear. Correlative studies from 2 independent clinical trial cohorts treated with major histocompatibility complex-haploidentical NK cell therapy for relapsed/refractory acute myeloid leukemia revealed that cytokine support by systemic interleukin-15 (IL-15; N-803) resulted in reduced clinical activity, compared with IL-2. We hypothesized that the mechanism responsible was IL-15/N-803 promoting recipient CD8 T-cell activation that in turn accelerated donor NK cell rejection. This idea was supported by increased proliferating CD8+ T-cell numbers in patients treated with IL-15/N-803, compared with IL-2. Moreover, mixed lymphocyte reactions showed that IL-15/N-803 enhanced responder CD8 T-cell activation and proliferation, compared with IL-2 alone. Additionally, IL-15/N-803 accelerated the ability of responding T cells to kill stimulator-derived memory-like NK cells, demonstrating that additional IL-15 can hasten donor NK cell elimination. Thus, systemic IL-15 used to support allogeneic cell therapy may paradoxically limit their therapeutic window of opportunity and clinical activity. This study indicates that stimulating patient CD8 T-cell allo-rejection responses may critically limit allogeneic cellular therapy supported with IL-15. This trial was registered at www.clinicaltrials.gov as #NCT03050216 and #NCT01898793.

中文翻译：

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全身性 IL-15 促进接受自然杀伤细胞过继疗法治疗的患者的同种异体细胞排斥。


自然杀伤 (NK) 细胞是癌症免疫治疗中 T 细胞的一种有前途的替代品。临床试验中正在研究使用同种异体、细胞因子激活的 NK 细胞的过继疗法。然而，过继转移后促进 NK 细胞扩增和持久性的最佳细胞因子支持仍不清楚。来自 2 个独立临床试验队列的相关研究表明，采用主要组织相容性复合物-半相合 NK 细胞疗法治疗复发/难治性急性髓系白血病，全身性白细胞介素 15（IL-15；N-803）的细胞因子支持导致临床活性降低，相比之下与IL-2。我们假设该机制是 IL-15/N-803 促进受体 CD8 T 细胞激活，进而加速供体 NK 细胞排斥。与 IL-2 相比，接受 IL-15/N-803 治疗的患者增殖的 CD8+ T 细胞数量增加支持了这一观点。此外，混合淋巴细胞反应表明，与单独使用 IL-2 相比，IL-15/N-803 增强了应答者 CD8 T 细胞的活化和增殖。此外，IL-15/N-803 加速了响应 T 细胞杀死刺激物衍生的记忆样 NK 细胞的能力，表明额外的 IL-15 可以加速供体 NK 细胞的消除。因此，用于支持同种异体细胞疗法的全身性IL-15可能会矛盾地限制其治疗机会和临床活性。这项研究表明，刺激患者 CD8 T 细胞同种异体排斥反应可能会严重限制 IL-15 支持的同种异体细胞治疗。该试验在 www.clinicaltrials.gov 上注册为#NCT03050216 和#NCT01898793。