Department of Immunotherapeutics (Medinet), The University of Tokyo Hospital, Tokyo, Japan.
J Immunother. 2012 Jul;35(6):460-72. doi: 10.1097/CJI.0b013e31826092db.
CD137 (4-1BB) is an important costimulatory ligand and a potent stimulator of T-cell responses. It has been used therapeutically to stimulate immunity against several solid malignancies as well as to modulate susceptibility to autoimmune disease and infection. However, clinical trials of anti-CD137 agonistic antibody have been suspended because of deleterious side effects. To overcome this problem, we fine-tuned the combination of adoptive transfer of tumor-specific cytotoxic T lymphocytes (CTL) and anti-CD137 monoclonal antibody (mAb) treatment. B16 melanoma cells (1 × 10(6)) were implanted subcutaneously in C57BL/6 mice. On day 9, CTLs (1 × 10(7)) were intravenously injected into tumor-bearing mice. Transferred CTL distributed throughout the body and infiltrated into the tumor. CD137 expression was upregulated on tumor-infiltrating CTL, but not in other tissues or other cell types. Therefore, mice received anti-CD137 mAb (100 μg) 3 days after CTL transfer. interferon-γ was produced in the tumor only by transferred CTL, not recipient-derived cells. The functional CTLs in the tumor were increased and interferon-γ production per cell was augmented by anti-CD137 treatment. It was not detected in CTL found in other tissues. Consistent with this, no organ damage was observed on anti-CD137 treatment. On the basis of the spatiotemporal expression of CD137 on tumor-infiltrating CTLs, anti-CD137 mAb selectively activated these tumor-infiltrating cells, augmented their antitumor activity and greatly decreased tumor growth. Tumor-specific CTL can guide agonistic anti-CD137 mAb to the tumor and in turn, become functionally augmented. Thus, CD137 mAb therapy may become feasible again in combination with tumor-specific CTL therapy.
CD137（4-1BB）是一种重要的共刺激配体，也是 T 细胞反应的有效刺激物。它已被用于治疗多种实体恶性肿瘤，以刺激免疫反应，以及调节自身免疫性疾病和感染的易感性。然而，由于有害的副作用，抗 CD137 激动性抗体的临床试验已经暂停。为了克服这个问题，我们对过继转移肿瘤特异性细胞毒性 T 淋巴细胞（CTL）和抗 CD137 单克隆抗体（mAb）治疗进行了微调。将 1×10（6）个 B16 黑色素瘤细胞皮下植入 C57BL/6 小鼠。在第 9 天，将 CTL（1×10（7））静脉注射到荷瘤小鼠体内。转移的 CTL 分布于全身并浸润肿瘤。肿瘤浸润 CTL 上调 CD137 表达，但在其他组织或其他细胞类型中没有表达。因此，在 CTL 转移后 3 天，小鼠接受抗 CD137 mAb（100μg）治疗。只有转移的 CTL 在肿瘤中产生干扰素-γ，而不是受者来源的细胞。肿瘤中功能性 CTL 增加，抗 CD137 治疗增加了每个细胞产生干扰素-γ的能力。在其他组织中未检测到 CTL。与此一致的是，在抗 CD137 治疗时未观察到器官损伤。基于肿瘤浸润 CTL 上 CD137 的时空表达，抗 CD137 mAb 选择性地激活这些肿瘤浸润细胞，增强其抗肿瘤活性，并大大减少肿瘤生长。肿瘤特异性 CTL 可以引导激动性抗 CD137 mAb 进入肿瘤，反过来，使 CTL 功能增强。因此，CD137 mAb 疗法可能再次与肿瘤特异性 CTL 疗法相结合成为可行的治疗方法。
