Reddy Nishitha, Hernandez-Ilizaliturri Francisco J, Deeb George, Roth Mark, Vaughn Mary, Knight Joy, Wallace Paul, Czuczman Myron S
Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
Br J Haematol. 2008 Jan;140(1):36-45. doi: 10.1111/j.1365-2141.2007.06841.x. Epub 2007 Nov 9.
The immunomodulatory drugs (IMiDs) lenalidomide and actimid (also known as CC-4047) are thalidomide analogues which are more potent than their parental compound. In combination with rituximab, we have previously demonstrated that IMiDs have synergistic in vivo anti-tumour activity in preclinical studies in a human lymphoma severe combined immunodeficiency mouse model. This report further explored the mechanisms by which IMiDs exert their anti-lymphoma effects. Following exposure of subcutaneous lymphoma tumours in murine models to IMiDs, there was a significant increase in the recruitment of natural killer (NK) cells to tumour sites. This increase in NK cells was mediated via stimulation of dendritic cells and modification of the cytokine microenvironment associated with an increase in monocyte chemotactic protein-1, tumour necrosis factor-alpha and interferon-gamma and probably augmented rituximab-associated antibody-dependent cellular cytotoxicity. IMiDs also had significant anti-angiogenic effects in our B-cell lymphoma models. Thus, by modulation of the immune system mediated via dendritic cells and NK cells, changing the cytokine milieu, as well as by their anti-angiogenic effects, IMiDs in combination with rituximab resulted in augmented in vivo anti-tumour effects against B-cell lymphoma. Our positive preclinical data adds additional support for the evaluation of IMiDs plus rituximab in patients with relapsed/refractory B-cell lymphoma.
免疫调节药物(IMiDs)来那度胺和阿地米德(也称为CC - 4047)是沙利度胺类似物,其效力比母体化合物更强。在与利妥昔单抗联合使用时,我们之前已经证明,在人淋巴瘤严重联合免疫缺陷小鼠模型的临床前研究中,IMiDs具有体内协同抗肿瘤活性。本报告进一步探讨了IMiDs发挥抗淋巴瘤作用的机制。在小鼠模型中,皮下淋巴瘤肿瘤暴露于IMiDs后,自然杀伤(NK)细胞向肿瘤部位的募集显著增加。NK细胞的这种增加是通过刺激树突状细胞和改变细胞因子微环境介导的,这与单核细胞趋化蛋白-1、肿瘤坏死因子-α和干扰素-γ的增加相关,并且可能增强了利妥昔单抗相关的抗体依赖性细胞毒性。IMiDs在我们的B细胞淋巴瘤模型中也具有显著的抗血管生成作用。因此,通过经由树突状细胞和NK细胞介导的免疫系统调节、改变细胞因子环境以及它们的抗血管生成作用,IMiDs与利妥昔单抗联合使用对B细胞淋巴瘤产生了增强的体内抗肿瘤作用。我们阳性的临床前数据为评估IMiDs加用利妥昔单抗治疗复发/难治性B细胞淋巴瘤患者提供了更多支持。