METHODS: The primary endpoint was the proportion of dose-limiting toxicities (DLTs) at each dose level. Secondary endpoints included safety profile, an immune response, including dynamic changes in immune cell and cytokine production, and progression-free survival (PFS). In a 3 + 3 dose-escalation design, the dosage levels for CpG ODN (K3) were 5 or 10 mg/body via subcutaneous injection and 0.2 mg/kg via intravenous administration on days 1, 8, 15, and 29.
RESULTS: Nine patients (eight non-small-cell lung cancer; one small-cell lung cancer) were enrolled. We found no DLTs at any dose level and observed no serious treatment-related adverse events. The median observation period after registration was 55 days (range: 46-181 days). Serum IFN-α2 levels, but not inflammatory cytokines, increased in six patients after the third administration of CpG ODN (K3) (mean value: from 2.67 pg/mL to 3.61 pg/mL after 24 hours). Serum IFN-γ (mean value, from 9.07 pg/mL to 12.7 pg/m after 24 hours) and CXCL10 levels (mean value, from 351 pg/mL to 676 pg/mL after 24 hours) also increased in eight patients after the third administration. During the treatment course, the percentage of T-bet-expressing CD8+ T cells gradually increased (mean, 49.8% at baseline and 59.1% at day 29, p = 0.0273). Interestingly, both T-bet-expressing effector memory (mean, 52.7% at baseline and 63.7% at day 29, p = 0.0195) and terminally differentiated effector memory (mean, 82.3% at baseline and 90.0% at day 29, p = 0.0039) CD8+ T cells significantly increased. The median PFS was 398 days.
CONCLUSIONS: This is the first clinical study showing that CpG ODN (K3) activated innate immunity and elicited Th1-type adaptive immune response and cytotoxic activity in cancer patients. CpG ODN (K3) was well tolerated at the dose settings tested, although the maximum tolerated dose was not determined.
BACKGROUND: UMIN-CTR number 000023276. Registered 1 September 2016, https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000026649.
方法:主要终点是每个剂量水平的剂量限制性毒性(DLT)的比例。次要终点包括安全性,免疫反应,包括免疫细胞和细胞因子产生的动态变化,无进展生存期(PFS)。在3+3剂量递增设计中,在第1,8,15和29天,皮下注射CpGODN(K3)的剂量水平为5或10mg/kg,静脉注射为0.2mg/kg.
结果:纳入9例患者(8例非小细胞肺癌;1例小细胞肺癌)。我们没有发现任何剂量水平的DLT,也没有观察到严重的治疗相关不良事件。注册后的中位观察期为55天(范围:46-181天)。血清IFN-α2水平,但不是炎性细胞因子,6名患者在第三次给药CpGODN(K3)后增加(平均值:24小时后从2.67pg/mL到3.61pg/mL)。血清IFN-γ(平均值,24小时后从9.07pg/mL到12.7pg/m)和CXCL10水平(平均值,24小时后从351pg/mL到676pg/mL)在第三次给药后的八名患者中也增加了。在治疗过程中,表达T-bet的CD8+T细胞的百分比逐渐增加(平均值,基线时为49.8%,第29天时为59.1%,p=0.0273)。有趣的是,都是T-bet表达效应记忆(平均,基线时为52.7%,第29天时为63.7%,p=0.0195)和终末分化效应记忆(平均值,基线时为82.3%,第29天时为90.0%,p=0.0039)CD8+T细胞显著增加。中位PFS为398天。
结论:这是第一项临床研究,表明CpGODN(K3)激活了癌症患者的先天免疫并引起Th1型适应性免疫反应和细胞毒性。CpGODN(K3)在测试的剂量设置下耐受性良好,尽管尚未确定最大耐受剂量。
背景:UMIN-CTR编号000023276。2016年9月1日注册,https://upload。乌明。AC.jp/cgi-open-bin/ctr/ctr_view。cgi?recptno=R000026649。