Murillo Oihana, Arina Ainhoa, Hervas-Stubbs Sandra, Gupta Anjana, McCluskey Brandon, Dubrot Juan, Palazón Asís, Azpilikueta Arantza, Ochoa Maria C, Alfaro Carlos, Solano Sarai, Pérez-Gracia José L, Oyajobi Babatunde O, Melero Ignacio
Gene Therapy Unit, Centro de Investigación Médica Aplicada, Pamplona, Spain.
Clin Cancer Res. 2008 Nov 1;14(21):6895-906. doi: 10.1158/1078-0432.CCR-08-0285.
Eradication of post-treatment residual myeloma cells is needed to prevent relapses, and immunostimulatory monoclonal antibodies (mAb) such as anti-CD137, CTLA-4, CD40, etc., which enhance the immune response against malignancies, represent a means of achieving this purpose. This study explores anti-CD137 mAbs for multiple myeloma treatment in preclinical models of the disease because they safely augment tumor immunity and are in clinical trials for other cancers.
The antitumor effect of anti-CD137 mAb on mouse plasmacytomas derived from HOPC and NS0 cell lines was studied and compared with that of anti-CTLA-4, anti-CD40, and anti-ICAM-2 mAbs. The antitumor effect of anti-CD137 mAb was also examined in a mouse syngeneic disseminated myeloma (5TGM1) model, which more closely resembles human multiple myeloma. Depletions of specific cell populations and gene-targeted mice were used to unravel the requirements for tumor rejection.
Agonistic mAb against CD137 and blocking anti-CTLA-4 mAb showed activity against i.p. HOPC tumors, resulting in extended survival of mice that also became immune to rechallenge. Anti-CD137 mAbs induced complete eradications of established s.c. NS0-derived tumors that were dependent on IFN-gamma, natural killer cells, and CD8(+) T lymphocytes. Natural killer cells accumulated in tumor draining lymph nodes and showed increased IFN-gamma production. Antitumor efficacy of anti-CD137 mAb was preserved in CD28-deficient mice despite the fact that CD28 signaling increases the expression of CD137 on CD8(+) T cells. Importantly, anti-CD137 mAb treatment significantly decreased systemic tumor burden in the disseminated 5TGM1 model.
The immune-mediated antitumor activity of anti-CD137 mAb in mouse models holds promise for myeloma treatment in humans.
为预防复发，需要清除治疗后残留的骨髓瘤细胞，而免疫刺激单克隆抗体（mAb），如抗CD137、CTLA-4、CD40等，可增强针对恶性肿瘤的免疫反应，是实现这一目的的一种手段。本研究在该疾病的临床前模型中探索抗CD137单克隆抗体用于多发性骨髓瘤治疗，因为它们能安全增强肿瘤免疫，且正在进行针对其他癌症的临床试验。
研究了抗CD137单克隆抗体对源自HOPC和NS0细胞系的小鼠浆细胞瘤的抗肿瘤作用，并与抗CTLA-4、抗CD40和抗ICAM-2单克隆抗体进行比较。还在更接近人类多发性骨髓瘤的小鼠同基因播散性骨髓瘤（5TGM1）模型中检测了抗CD137单克隆抗体的抗肿瘤作用。使用特定细胞群的耗竭和基因靶向小鼠来阐明肿瘤排斥的要求。
抗CD137激动性单克隆抗体和抗CTLA-4阻断性单克隆抗体对腹腔内HOPC肿瘤显示出活性，延长了小鼠的生存期，且小鼠对再次攻击产生免疫。抗CD137单克隆抗体诱导已建立的皮下NS0来源肿瘤完全清除，这依赖于干扰素-γ、自然杀伤细胞和CD8(+) T淋巴细胞。自然杀伤细胞在肿瘤引流淋巴结中积聚，并显示干扰素-γ产生增加。尽管CD28信号增加CD8(+) T细胞上CD137的表达，但抗CD137单克隆抗体的抗肿瘤功效在CD28缺陷小鼠中得以保留。重要的是，抗CD137单克隆抗体治疗显著降低了播散性5TGM1模型中的全身肿瘤负荷。
抗CD137单克隆抗体在小鼠模型中的免疫介导抗肿瘤活性为人类骨髓瘤治疗带来了希望。
