短程白细胞介素-15 连续输注导致有效自然杀伤细胞的大量扩增：与抗肿瘤抗体联合治疗的意义。
Short-course IL-15 given as a continuous infusion led to a massive expansion of effective NK cells: implications for combination therapy with antitumor antibodies.
机构信息
Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA.
Department of Laboratory Medicine, NIH Clinical Center, Bethesda, Maryland, USA.
出版信息
J Immunother Cancer. 2021 Apr;9(4). doi: 10.1136/jitc-2020-002193.
BACKGROUND
Full application of cytokines as oncoimmunotherapeutics requires identification of optimal regimens. Our initial effort with intravenous bolus recombinant human interleukin-15 (rhIL-15) was limited by postinfusional reactions. Subcutaneous injection and continuous intravenous infusion for 10 days (CIV-10) provided rhIL-15 with less toxicity with CIV-10 giving the best increases in CD8 lymphocytes and natural killer (NK) cells. To ease rhIL-15 administration, we shortened time of infusion. Treatment with rhIL-15 at a dose of 3-5 µg/kg as a 5-day continuous intravenous infusion (CIV-5) had no dose-limiting toxicities while effector cell stimulation was comparable to the CIV-10 regimen.
METHODS
Eleven patients with metastatic cancers were treated with rhIL-15 CIV-5, 3 µg (n=4), 4 µg (n=3), and 5 µg/kg/day (n=4) in a phase I dose-escalation study (April 6, 2012).
RESULTS
Impressive expansions of NK cells were seen at all dose levels (mean 34-fold), including CD56 NK cells (mean 144-fold for 4 µg/kg), as well as an increase in CD8 T cells (mean 3.38-fold). At 5 µg/kg/day, there were no dose-limiting toxicities but pulmonary capillary leak and slower patient recovery. This led to our choice of the 4 µg/kg as CIV-5 dose for further testing. Cytolytic capacity of CD56 and CD56 NK cells was increased by interleukin-15 assayed by antibody-dependent cellular cytotoxicity (ADCC), natural cytotoxicity and natural killer group 2D-mediated cytotoxicity. The best response was stable disease.
CONCLUSIONS
IL-15 administered as CIV-5 substantially expanded NK cells with increased cytotoxic functions. Tumor-targeting monoclonal antibodies dependent on ADCC as their mechanism of action including alemtuzumab, obinutuzumab, avelumab, and mogamulizumab could benefit from those NK cell expansions and provide a promising therapeutic strategy.
TRIAL REGISTRATION NUMBERS
NCT01572493, NCT03759184, NCT03905135, NCT04185220 and NCT02689453.
背景
充分应用细胞因子作为肿瘤免疫治疗需要确定最佳方案。我们最初使用静脉推注重组人白细胞介素-15（rhIL-15）的尝试受到输注后反应的限制。皮下注射和连续静脉输注 10 天（CIV-10）使 rhIL-15 的毒性降低，而 CIV-10 使 CD8 淋巴细胞和自然杀伤（NK）细胞的增加最佳。为了便于 rhIL-15 的给药，我们缩短了输注时间。rhIL-15 以 3-5 µg/kg 的剂量连续静脉输注 5 天（CIV-5），没有剂量限制毒性，而效应细胞刺激与 CIV-10 方案相当。
方法
11 名转移性癌症患者参加了一项 I 期剂量递增研究（2012 年 4 月 6 日），分别接受 rhIL-15 CIV-5 治疗，剂量为 3µg（n=4）、4µg（n=3）和 5µg/kg/天（n=4）。
结果
在所有剂量水平上均观察到 NK 细胞的显著扩增（平均 34 倍），包括 CD56 NK 细胞（4µg/kg 时平均 144 倍），以及 CD8 T 细胞的增加（平均 3.38 倍）。5µg/kg/天时，无剂量限制毒性，但有肺毛细血管渗漏和患者恢复较慢。这导致我们选择 4µg/kg 作为 CIV-5 的剂量进行进一步测试。通过抗体依赖性细胞毒性（ADCC）测定的白细胞介素-15 扩增的 CD56 和 CD56 NK 细胞的细胞溶解能力增加，自然细胞毒性和自然杀伤组 2D 介导的细胞毒性。最佳反应是疾病稳定。
结论
静脉滴注 5 天的 IL-15 可显著扩增 NK 细胞，并增强其细胞毒性功能。依赖 ADCC 作为其作用机制的肿瘤靶向单克隆抗体，包括阿仑单抗、奥滨尤妥珠单抗、avelumab 和 mogamulizumab，可能受益于这些 NK 细胞扩增，并提供一种有前途的治疗策略。
临床试验注册号
NCT01572493、NCT03759184、NCT03905135、NCT04185220 和 NCT02689453。
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