Brahmer Julie R, Drake Charles G, Wollner Ira, Powderly John D, Picus Joel, Sharfman William H, Stankevich Elizabeth, Pons Alice, Salay Theresa M, McMiller Tracee L, Gilson Marta M, Wang Changyu, Selby Mark, Taube Janis M, Anders Robert, Chen Lieping, Korman Alan J, Pardoll Drew M, Lowy Israel, Topalian Suzanne L
From the Johns Hopkins University School of Medicine and the Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD; Henry Ford Health Systems, Detroit, MI; Carolina BioOncology Institute, Huntersville, NC; Washington University School of Medicine Siteman Cancer Center, St Louis, MO; and Medarex, Bloomsbury, NJ, and Milpitas, CA.
J Clin Oncol. 2023 Feb 1;41(4):715-723. doi: 10.1200/JCO.22.02270.
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.
程序性死亡因子1（PD-1）是一种在活化T细胞上表达的抑制性受体，可能会抑制抗肿瘤免疫。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，并初步评估其抗肿瘤活性、药效学及免疫相关性。
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例患者队列中接受单次静脉输注抗PD-1（MDX-1106），剂量分别为0.3、1、3或10mg/kg，随后是15例患者的10mg/kg扩展队列。有3个月临床获益证据的患者 eligible for重复治疗。
抗PD-1耐受性良好：1例接受1mg/kg剂量5次的黑色素瘤患者出现1例严重不良事件，即炎症性结肠炎。观察到1例持久完全缓解（CRC）和2例部分缓解（PRs；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，但未达到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分子的平均占有率持续>70%。在9例接受检查的患者中，肿瘤细胞表面B7-H1表达似乎与治疗反应的可能性相关。
间歇性抗体给药阻断PD-1免疫检查点耐受性良好，并有抗肿瘤活性证据。有必要探索替代给药方案以及与疫苗、靶向治疗和/或其他检查点抑制剂的联合治疗。
