Abstract：
BACKGROUND: Cytosine-phosphate-guanine oligodeoxynucleotide (CpG ODN) (K3)-a novel synthetic single-stranded DNA immune adjuvant for cancer immunotherapy-induces a potential Th1-type immune response against cancer cells. We conducted a phase I study of CpG ODN (K3) in patients with lung cancer to assess its safety and patients\' immune responses.
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.
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.
摘要：
背景：胞嘧啶-磷酸-鸟嘌呤寡脱氧核苷酸（CpGODN）（K3）-一种用于癌症免疫治疗的新型合成单链DNA免疫佐剂-诱导针对癌细胞的潜在Th1型免疫应答。我们在肺癌患者中进行了CpGODN（K3）的I期研究，以评估其安全性和患者的免疫反应。
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。
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。
