Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates.
Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates.
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DOI：
10.1200/jco.2009.26.7609
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发表时间：
2010-07-01
期刊：
影响因子：
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通讯作者：
Topalian SL
中科院分区：
文献类型：
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作者：
Brahmer JR;Drake CG;Wollner I;Powderly JD;Picus J;Sharfman WH;Stankevich E;Pons A;Salay TM;McMiller TL;Gilson MM;Wang C;Selby M;Taube JM;Anders R;Chen L;Korman AJ;Pardoll DM;Lowy I;Topalian SL
程序性死亡-1（PD-1）是一种表达于活化T细胞上的抑制性受体，可抑制抗肿瘤免疫。这项I期研究旨在确定抗PD-1阻断剂在治疗难治性实体瘤患者中的安全性和耐受性，并初步评估抗肿瘤活性、药效学和免疫学相关性。39例晚期转移性黑色素瘤、结直肠癌（CRC）、去势抵抗性前列腺癌、非小细胞肺癌（NSCLC）或肾细胞癌（RCC）患者在剂量递增的6例患者队列中接受抗PD-1（MDX-1106）单次静脉输注，剂量为0.3、1、3或10 mg/kg，随后在15例患者扩展队列中接受10 mg/kg。3个月时有临床获益证据的患者有资格接受重复治疗。抗PD-1耐受性良好：在1例接受5次1 mg/kg剂量的黑色素瘤患者中观察到1起严重不良事件，即炎性结肠炎。观察到1例持久完全缓解（CRC）和2例部分缓解（PR;黑色素瘤，RCC）。另外2例患者（黑色素瘤、NSCLC）出现显著的病灶肿瘤消退，不符合PR标准。抗PD-1的血清半衰期为12至20天。然而，药效学表明，无论剂量如何，输注后≥ 2个月，循环T细胞上PD-1分子的持续平均占用率> 70%。在9例患者中，肿瘤细胞表面B7-H1表达似乎与治疗反应的可能性相关。用间歇性抗体给药阻断PD-1免疫检查点耐受性良好，并且与抗肿瘤活性的证据相关。有必要探索替代给药方案和与疫苗、靶向治疗和/或其他检查点抑制剂的联合治疗。
Programmed death-1 (PD-1), an inhibitory receptor expressed on activated T cells, may suppress antitumor immunity. This phase I study sought to determine the safety and tolerability of anti–PD-1 blockade in patients with treatment-refractory solid tumors and to preliminarily assess antitumor activity, pharmacodynamics, and immunologic correlates. Thirty-nine patients with advanced metastatic melanoma, colorectal cancer (CRC), castrate-resistant prostate cancer, non–small-cell lung cancer (NSCLC), or renal cell carcinoma (RCC) received a single intravenous infusion of anti–PD-1 (MDX-1106) in dose-escalating six-patient cohorts at 0.3, 1, 3, or 10 mg/kg, followed by a 15-patient expansion cohort at 10 mg/kg. Patients with evidence of clinical benefit at 3 months were eligible for repeated therapy. Anti–PD-1 was well tolerated: one serious adverse event, inflammatory colitis, was observed in a patient with melanoma who received five doses at 1 mg/kg. One durable complete response (CRC) and two partial responses (PRs; melanoma, RCC) were seen. Two additional patients (melanoma, NSCLC) had significant lesional tumor regressions not meeting PR criteria. The serum half-life of anti–PD-1 was 12 to 20 days. However, pharmacodynamics indicated a sustained mean occupancy of > 70% of PD-1 molecules on circulating T cells ≥ 2 months following infusion, regardless of dose. In nine patients examined, tumor cell surface B7-H1 expression appeared to correlate with the likelihood of response to treatment. Blocking the PD-1 immune checkpoint with intermittent antibody dosing is well tolerated and associated with evidence of antitumor activity. Exploration of alternative dosing regimens and combinatorial therapies with vaccines, targeted therapies, and/or other checkpoint inhibitors is warranted.