Shi Wenyin, Siemann Dietmar W
Department of Radiation Oncology, Shands Cancer Center, University of Florida, Gainesville, FL 32610, USA.
Anticancer Res. 2006 Sep-Oct;26(5A):3445-53.
4-1BB (CD137) is a member of the tumor necrosis factor receptor superfamily. It interacts with 4-1BB ligand (4-1BBL) and delivers a costimulatory signal for T cell activation. The immune response induced by 4-1BB monoclonal antibodies (mAbs) has been shown to have a marked augmentation of tumor-selective cytolytic T cell activity.
The antitumor efficacy of agonistic 4-1BB mAbs (BMS-469492, Bristol-Meyer Squibb), used alone or in combination with radiation therapy, was evaluated in murine lung (M109) and breast (EMT6) carcinoma models.
Treatment with BMS-469492 led to only a modest growth retardation in M109 tumors (3 days, p > 0.05), but a significant growth delay in EMT6 tumors (12.5 days, p < 0.05). When BMS-469492 was administered in conjunction with single dose radiation therapy (5, 10 or 15 Gy), enhanced tumor responses were noted only at the highest evaluated radiation dose (15 Gy). In contrast, in the EMT6 model, BMS-469492 treatment resulted in enhanced antitumor effects at all radiation doses. In addition, the response of EMT6 tumors to fractionated radiotherapy also was significantly increased when BMS-469492 was included in the treatment protocol.
These results suggest that monoclonal antibodies against 4-1BB may not only be efficacious in cancer immunotherapy, but may also have utility when applied in combination with conventional anticancer treatments, such as radiation therapy.
4-1BB（CD137）是肿瘤坏死因子受体超家族的成员。它与4-1BB配体（4-1BBL）相互作用，并为T细胞活化传递共刺激信号。已证明4-1BB单克隆抗体（mAb）诱导的免疫反应可显著增强肿瘤选择性细胞毒性T细胞活性。
在小鼠肺癌（M109）和乳腺癌（EMT6）模型中评估了激动性4-1BB mAb（BMS-469492，百时美施贵宝公司）单独使用或与放射治疗联合使用的抗肿瘤疗效。
用BMS-469492治疗仅导致M109肿瘤的生长有适度延迟（3天，p>0.05），但EMT6肿瘤有显著的生长延迟（12.5天，p<0.05）。当BMS-469492与单剂量放射治疗（5、10或15 Gy）联合使用时，仅在评估的最高放射剂量（15 Gy）下观察到肿瘤反应增强。相比之下，在EMT6模型中，BMS-469492治疗在所有放射剂量下均导致抗肿瘤作用增强。此外，当治疗方案中包含BMS-469492时，EMT6肿瘤对分割放射治疗的反应也显著增加。
这些结果表明，抗4-1BB单克隆抗体不仅在癌症免疫治疗中可能有效，而且与传统抗癌治疗（如放射治疗）联合应用时也可能有用。
