Toll-like receptor-7 agonist administered subcutaneously in a prolonged dosing schedule in heavily pretreated recurrent breast, ovarian, and cervix cancers.
Toll-like receptor-7 agonist administered subcutaneously in a prolonged dosing schedule in heavily pretreated recurrent breast, ovarian, and cervix cancers.
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Toll 样受体 7 激动剂以延长给药方案皮下注射，用于治疗经过严格预处理的复发性乳腺癌、卵巢癌和宫颈癌。
DOI：
10.1007/s00262-010-0914-1
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发表时间：
2010-12
期刊：
影响因子：
--
通讯作者：
Miller JS
中科院分区：
文献类型：
--
作者：
Geller MA;Cooley S;Argenta PA;Downs LS;Carson LF;Judson PL;Ghebre R;Weigel B;Panoskaltsis-Mortari A;Curtsinger J;Miller JS
研究长期皮下全身给药 852A（一种 Toll 样受体 7 激动剂 (TLR-7)）在复发性乳腺癌、卵巢癌和宫颈癌中的作用，以评估抗肿瘤活性。次要目标包括评估安全性和免疫系统激活。多次治疗失败的复发性乳腺癌、卵巢癌或宫颈癌成人接受 0.6 mg/m2 的 852A 皮下注射，每周两次，持续 12 周。剂量每周增加 0.2 mg/m2 至最大 1.2 mg/m2。收集血清以评估免疫激活。纳入 15 名患者：10 名卵巢患者、2 名宫颈患者和 3 名乳腺癌患者。三人完成了全部 24 次注射。有 2 例 2 级（射血分数降低）、9 例 3 级（1 例心血管、1 例厌食、3 例脱水、2 例感染、2 例肾脏）和 2 例 4 级（肝脏和肌钙蛋白升高）意外毒性。心脏毒性包括三种心肌病（两种无症状）和一种应激相关的非 ST 升高型心肌梗死。五名患者由于可能存在相关副作用而停止治疗。一名患者在注射 24 剂后病情稳定 (SD)，并额外接受了 17 剂。一名宫颈患者在注射 24 剂后出现 SD，3 个月后病情进展，接受化疗并在 18 个月时保持无病状态。观察到免疫激活，如 IP-10 和 IL-1ra 增加所证明的。在使用延长的给药方案皮下递送 TLR-7 激动剂的首次人类经验中，852A 在一些患者中证明了持续的耐受性。临床获益不大，但免疫激活表明有必要进一步研究抗肿瘤应用。由于心脏毒性；对于接受过多次治疗的患者，应谨慎使用 852A 治疗。
To study prolonged subcutaneous dosing of systemic 852A, a Toll-like receptor-7 agonist (TLR-7), in recurrent breast, ovarian and cervix cancer to assess anti-tumor activity. Secondary objectives included assessment of safety and immune system activation. Adults with recurrent breast, ovarian or cervix cancer failing multiple therapies received 0.6 mg/m2 of 852A subcutaneously twice weekly for 12 weeks. Doses increased by 0.2 mg/m2/week to a maximum of 1.2 mg/m2. Serum was collected to assess immune activation. Fifteen patients enrolled: 10 ovarian, 2 cervix and 3 breast. Three completed all 24 injections. There were two grade 2 (decreased ejection fractions), nine grade 3 (1 cardiovascular, 1 anorexia, 3 dehydration, 2 infections, 2 renal) and two grade 4 (hepatic and troponin elevation) unanticipated toxicities. Cardiac toxicities included three cardiomyopathies (two asymptomatic) and one stress-related non-ST elevated myocardial infarction. Five patients discontinued therapy due to possibly associated side effects. One had stable disease (SD) following 24 doses and received 17 additional doses. A cervix patient had SD following 24 doses, progressed 3 months later, received chemotherapy and remains disease free at 18 months. Immune activation, as evidenced by increased IP-10 and IL-1ra, was observed. In this first human experience of a TLR-7 agonist delivered subcutaneously using a prolonged dosing schedule 852A demonstrated sustained tolerability in some patients. Clinical benefit was modest but immune activation was seen suggesting further study of antitumor applications is warranted. Because of cardiac toxicity; treatment with 852A should be used cautiously in heavily pretreated patients.
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影响因子：
6.4
作者：
Bernstein, DI;Harrison, CJ;Miller, RL
通讯作者：
Miller, RL
DOI：
10.1084/jem.20011983
发表时间：
2002-05-20
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Yoneyama H;Narumi S;Zhang Y;Murai M;Baggiolini M;Lanzavecchia A;Ichida T;Asakura H;Matsushima K
通讯作者：
Matsushima K
影响因子：
11.5
作者：
Dudek, Arkadiusz Z.;Yunis, Caria;Miller, Jeffrey S.
通讯作者：
Miller, Jeffrey S.
影响因子：
4.9
作者：
CHEN, M;GRIFFITH, BP;HSIUNG, GD
通讯作者：
HSIUNG, GD
影响因子：
10.3
作者：
Meyer, T;Nindl, I;Stockfleth, E
通讯作者：
Stockfleth, E