A First-in-Human Phase I Study of Subcutaneous Outpatient Recombinant Human IL15 (rhIL15) in Adults with Advanced Solid Tumors.
A First-in-Human Phase I Study of Subcutaneous Outpatient Recombinant Human IL15 (rhIL15) in Adults with Advanced Solid Tumors.
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DOI：
10.1158/1078-0432.ccr-17-2451
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发表时间：
2018-04-01
期刊：
影响因子：
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通讯作者：
Conlon KC
中科院分区：
文献类型：
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作者：
Miller JS;Morishima C;McNeel DG;Patel MR;Kohrt HEK;Thompson JA;Sondel PM;Wakelee HA;Disis ML;Kaiser JC;Cheever MA;Streicher H;Creekmore SP;Waldmann TA;Conlon KC
临床前数据确定了白细胞介素-15作为一种稳态因子和NK和CD 8 + T细胞功能的强大刺激剂，这是临床测试的基础。在难治性实体瘤癌症患者中进行了皮下（SC）rhIL-15的首次人体门诊I期剂量递增试验。治疗包括连续两周每天（星期一-星期五）皮下注射rhIL-15（10次总剂量/周期）。通过RECIST评估临床应答。评价rhIL-15和免疫生物标志物的药代动力学。19例患者接受rhIL-15治疗，剂量水平为0.25、0.5、1、2和3 mcg/kg/天。14例患者完成了≥ 2个周期的治疗，耐受性良好。1起严重不良事件（SAE），2级胰腺炎，需要住院过夜。在接受3 mcg/kg/天治疗的患者发生与低血压和肌钙蛋白升高相关的3级心源性胸痛剂量限制性SAE后，停止入组。未观察到客观缓解;然而，几例患者病情稳定，包括1例肾细胞癌患者，该患者继续方案治疗2年。治疗诱导了循环NK细胞的显著扩增，尤其是在CD 56 bright亚群中。在循环CD 8 + T细胞中发现了成比例但不太显著的增加，2和3 mcg/kg患者的最大扩增为3倍。SC rhIL-15治疗耐受性良好，使循环NK和CD 8 + T细胞显著增加。该方案确立了一种安全的门诊患者皮下注射rhIL-15方案，剂量为2 mcg/kg/天，适合自我注射，并有可能作为联合免疫抑制剂。临床前实验表明，白细胞介素-15（IL-15）可以控制稳态并刺激自然杀伤（NK）和抗原特异性CD 8 + T细胞活性，而不引起活化诱导的细胞死亡（AICD）或促进调节性T细胞（Treg）功能。对这些特性的认识导致2007年NCI免疫治疗研讨会将IL-15指定为具有最高临床开发潜力的免疫抑制剂。在重组人（rh）IL-15每日30分钟静脉推注（IVB）的首次人体临床试验中遇到的意外毒性严重限制了剂量的增加。临床前和非人灵长类动物毒理学实验表明，皮下（SC）给药应降低峰浓度并改善临床耐受性。这是首次使用门诊患者皮下注射rhIL-15进行人体试验，其药物递送量是IVB的6倍，并诱导了强大的免疫激活水平。这些结果将允许将IL-15免疫疗法出口到门诊患者，并测试组合策略以改善癌症治疗。
Preclinical data established Interleukin-15 as a homeostatic factor and powerful stimulator of NK and CD8+ T cell function, the basis for clinical testing. A first-in-human outpatient phase I dose escalation trial of subcutaneous (SC) rhIL-15 was conducted in refractory solid tumor cancer patients. Therapy consisted of daily (Monday - Friday) SC injections of rhIL-15 for two consecutive weeks (10 total doses/cycle). Clinical response was assessed by RECIST. Pharmacokinetics of rhIL-15 and immune biomarkers were evaluated. Nineteen patients were treated with rhIL-15 at dose levels of 0.25, 0.5, 1, 2 and 3 mcg/kg/day. Fourteen patients completed ≥ 2 cycles of therapy that was well tolerated. One serious adverse event (SAE), grade 2 pancreatitis, required overnight hospitalization. Enrollment was halted after a patient receiving 3 mcg/kg/day developed a dose limiting SAE of grade 3 cardiac chest pain associated with hypotension and increased troponin. No objective responses were observed; however, several patients had disease stabilization including a renal cell carcinoma patient who continued protocol treatment for 2 years. The treatment induced profound expansion of circulating NK cells, especially among the CD56bright subset. A proportional but less dramatic increase was found among circulating CD8+ T cells with maximal 3-fold expansion for the 2 and 3 mcg/kg patients. SC rhIL-15 treatment was well tolerated, producing substantial increases in circulating NK and CD8+ T cells. This protocol establishes a safe outpatient SC rhIL-15 regimen of 2 mcg/kg/day dosing amenable to self-injection and with potential as a combination immunotherapeutic agent. Preclinical experiments demonstrated that Interleukin-15 (IL-15) can control homeostasis and stimulate natural killer (NK) and antigen-specific CD8+ T cell activity without causing activation induced cell death (AICD) or promoting T regulatory (Treg) cell function. Recognition of these properties led to the designation of IL-15 as the immunotherapeutic with highest potential for clinical development by the 2007 NCI Immunotherapy Workshop. Unexpected toxicities encountered in the first-in-human clinical trial of recombinant human (rh)IL-15 given as daily 30-minute intravenous bolus (IVB) infusions severely limited dose escalation. Preclinical and non-human primate toxicology experiments suggested that subcutaneous (SC) administration should lower peak concentrations and improve clinical tolerance. This is a first-in-human experience with outpatient subcutaneous rhIL-15, allowing 6-fold more drug delivery than IVB, and inducing robust levels of immune activation. These results will allow the export of IL-15 immunotherapy to an outpatient setting and testing of combinatorial strategies to improve cancer treatment.