Georgia Cancer Center, Augusta University, Augusta, Georgia.
Adaptive Biotechnologies, Seattle, Washington.
Cancer Immunol Res. 2017 Sep;5(9):755-766. doi: 10.1158/2326-6066.CIR-17-0292.
Combination therapies that depend on checkpoint inhibitor antibodies (Abs) such as for PD-1 or its ligand (PD-L1) together with immune stimulatory agonist Abs like anti-OX40 are being tested in the clinic to achieve improved antitumor effects. Here, we studied the potential therapeutic and immune effects of one such combination: Ab to PD-1 with agonist Ab to OX40/vaccine. We tested the antitumor effects of different treatment sequencing of this combination. We report that simultaneous addition of anti-PD-1 to anti-OX40 negated the antitumor effects of OX40 Ab. Antigen-specific CD8 T-cell infiltration into the tumor was diminished, the resultant antitumor response weakened, and survival reduced. Although we observed an increase in IFNγ-producing E7-specifc CD8 T cells in the spleens of mice treated with the combination of PD-1 blockade with anti-OX40/vaccine, these cells underwent apoptosis both in the periphery and the tumor. These results indicate that anti-PD-1 added at the initiation of therapy exhibits a detrimental effect on the positive outcome of anti-OX40 agonist Ab. These findings have important implications on the design of combination immunotherapy for cancer, demonstrating the need to test treatment combination and sequencing before moving to the clinic. .
联合治疗依赖于检查点抑制剂抗体（如 PD-1 或其配体 PD-L1）与免疫刺激激动剂抗体（如抗 OX40），目前正在临床中进行测试，以实现更好的抗肿瘤效果。在这里，我们研究了一种这样的组合的潜在治疗和免疫效果：PD-1 抗体与 OX40/疫苗的激动剂抗体。我们测试了这种组合的不同治疗顺序的抗肿瘤效果。我们报告说，同时添加抗 PD-1 和抗 OX40 会抵消 OX40 抗体的抗肿瘤作用。抗原特异性 CD8 T 细胞浸润肿瘤减少，抗肿瘤反应减弱，生存时间缩短。尽管我们观察到在接受 PD-1 阻断联合 OX40 激动剂抗体/疫苗治疗的小鼠脾脏中，E7 特异性 CD8 T 细胞产生 IFNγ增加，但这些细胞在外周和肿瘤中均发生凋亡。这些结果表明，在治疗开始时添加抗 PD-1 对抗 OX40 激动剂抗体的积极结果产生不利影响。这些发现对癌症联合免疫治疗的设计具有重要意义，表明在进入临床之前需要测试治疗组合和顺序。
