Hagner Patrick R, Chiu Hsiling, Ortiz Maria, Apollonio Benedetta, Wang Maria, Couto Suzana, Waldman Michelle F, Flynt Erin, Ramsay Alan G, Trotter Matthew, Gandhi Anita K, Chopra Rajesh, Thakurta Anjan
Celgene Corporation, Summit, NJ, USA.
Celgene Corporation, Sevilla, Spain.
Br J Haematol. 2017 Nov;179(3):399-409. doi: 10.1111/bjh.14866. Epub 2017 Aug 2.
Lenalidomide is an immunomodulatory agent that has demonstrated clinical benefit for patients with relapsed or refractory mantle cell lymphoma (MCL); however, despite this observed clinical activity, the mechanism of action (MOA) of lenalidomide has not been characterized in this setting. We investigated the MOA of lenalidomide in clinical samples from patients enrolled in the CC-5013-MCL-002 trial (NCT00875667) comparing single-agent lenalidomide versus investigator's choice single-agent therapy and validated our findings in pre-clinical models of MCL. Our results revealed a significant increase in natural killer (NK) cells relative to total lymphocytes in lenalidomide responders compared to non-responders that was associated with a trend towards prolonged progression-free survival and overall survival. Clinical response to lenalidomide was independent of baseline tumour microenvironment expression of its molecular target, cereblon, as well as genetic mutations reported to impact clinical response to the Bruton tyrosine kinase inhibitor ibrutinib. Preclinical experiments revealed lenalidomide enhanced NK cell-mediated cytotoxicity against MCL cells via increased lytic immunological synapse formation and secretion of granzyme B. In contrast, lenalidomide exhibited minimal direct cytotoxic effects against MCL cells. Taken together, these data provide the first insight into the clinical activity of lenalidomide against MCL, revealing a predominately immune-mediated MOA.
来那度胺是一种免疫调节剂，已证明对复发或难治性套细胞淋巴瘤（MCL）患者具有临床益处；然而，尽管观察到这种临床活性，但来那度胺在这种情况下的作用机制（MOA）尚未明确。我们在参加CC - 5013 - MCL - 002试验（NCT00875667）的患者临床样本中研究了来那度胺的作用机制，该试验比较了来那度胺单药治疗与研究者选择的单药治疗，并在MCL的临床前模型中验证了我们的发现。我们的结果显示，与无反应者相比，来那度胺反应者中自然杀伤（NK）细胞相对于总淋巴细胞显著增加，这与无进展生存期和总生存期延长的趋势相关。来那度胺的临床反应独立于其分子靶点脑啡肽的基线肿瘤微环境表达，以及据报道影响对布鲁顿酪氨酸激酶抑制剂伊布替尼临床反应的基因突变。临床前实验表明，来那度胺通过增加溶解性免疫突触形成和颗粒酶B的分泌，增强了NK细胞对MCL细胞的细胞毒性。相比之下，来那度胺对MCL细胞的直接细胞毒性作用极小。综上所述，这些数据首次揭示了来那度胺对MCL的临床活性，揭示了一种主要由免疫介导的作用机制。
