The University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia.
Cancer Immunol Res. 2017 Mar;5(3):191-197. doi: 10.1158/2326-6066.CIR-16-0249. Epub 2017 Jan 23.
Combinations of mAbs that target various components of T-cell activation/inhibition may work synergistically to improve antitumor immunity against cancer. In this study, we investigated the therapeutic potential of combining an anticancer vaccination strategy with antibodies targeting an immune stimulatory (4-1BB) and immune inhibitory (PD-1) receptor, in a preclinical model of spontaneously arising c-Myc-driven B-cell lymphoma. In Eμ-myc transgenic mice, we reveal that 4-1BB agonistic mAb treatment alone was sufficient to drive antitumor immunity and prevent disease progression in 70% of mice. When combined with an α-GalCer-loaded, irradiated tumor cell vaccine, 4-1BB mAb treatment led to increased expansion of effector CD8 T-cell populations and protection of long-term surviving mice against tumor rechallenge. Unexpectedly, PD-1 blockade did not provide therapeutic benefit. The T-cell-promoting effects and antitumor activity of 4-1BB mAb were diminished when used simultaneously with a PD-1-blocking mAb. This was associated with a rapid and dramatic reduction in effector CD8 T-cell subsets in the presence of PD-1 blockade. These findings reveal that supporting T-cell activation therapeutically is effective for controlling B-cell lymphomas; however, caution is required when combining antibody-mediated modulation of both costimulatory and coinhibitory T-cell receptors. .
针对 T 细胞激活/抑制的各种成分的 mAb 组合可能会协同作用，以提高针对癌症的抗肿瘤免疫。在这项研究中，我们研究了在自发发生的 c-Myc 驱动的 B 细胞淋巴瘤的临床前模型中，将抗癌疫苗接种策略与针对免疫刺激（4-1BB）和免疫抑制（PD-1）受体的抗体相结合的治疗潜力。在 Eμ-myc 转基因小鼠中，我们发现单独使用 4-1BB 激动性 mAb 治疗足以在 70％的小鼠中驱动抗肿瘤免疫并防止疾病进展。当与负载α-GalCer 的辐照肿瘤细胞疫苗联合使用时，4-1BB mAb 治疗导致效应 CD8 T 细胞群体的扩增增加，并保护长期存活的小鼠免受肿瘤再挑战。出乎意料的是，PD-1 阻断没有提供治疗益处。当与 PD-1 阻断 mAb 同时使用时，4-1BB mAb 的 T 细胞促进作用和抗肿瘤活性会降低。这与 PD-1 阻断存在时效应性 CD8 T 细胞亚群的迅速而明显减少有关。这些发现表明，在治疗上支持 T 细胞激活对于控制 B 细胞淋巴瘤是有效的；然而，在联合使用抗体调节共刺激和共抑制 T 细胞受体时需要谨慎。
