Krämer Isabelle, Engelhardt Melanie, Fichtner Sabrina, Neuber Brigitte, Medenhoff Sergej, Bertsch Uta, Hillengass Jens, Raab Marc-Steffen, Hose Dirk, Ho Anthony D, Goldschmidt Hartmut, Hundemer Michael
Department of Internal Medicine V, University of Heidelberg , Heidelberg, Germany.
Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany; National Center for Tumor Diseases, University of Heidelberg, Heidelberg, Germany.
Oncoimmunology. 2016 Feb 18;5(5):e1139662. doi: 10.1080/2162402X.2016.1139662. eCollection 2016 May.
Immunomodulation is an important part of lenalidomide's mode of action. We analyzed the impact of lenalidomide on T cells from patients with multiple myeloma during lenalidomide therapy in vivo and in patients with lenalidomide-refractory disease in vitro Patients enrolled in the German Speaking Myeloma Multicenter Group (GMMG) MM5 trial received a consolidation therapy with two cycles of lenalidomide after autologous stem cell transplantation (ASCT). Half of the study population continued treatment with lenalidomide maintenance therapy for 2 y, while the other patients received lenalidomide maintenance therapy until complete remission. We analyzed 58 patients with (n = 30) or without (n = 28) lenalidomide therapy and 12 patients refractory to lenalidomide with regards to their anti-myeloma-specific T-cell responses displayed by IFNγ, Granzyme B, and Perforin secretion. The immunophenotype of T-cells was investigated by flow cytometry. Significantly, more myeloma-specific T-cell responses were observed in patients during lenalidomide therapy, compared to patients without treatment. Furthermore, we found on T-cells from patients treated with lenalidomide a decreased CD45RA expression, indicating a maturated immunophenotype and a decreased expression of CD57, indicating functional T cells. An improved myeloma-specific T-cell response was observed in 6 out of 12 heavily pretreated patients (refractory to lenalidomide) after in vitro incubation with lenalidomide. Complementary to the results in vivo, lenalidomide decreased CD45RA expression on T cells in vitro.
免疫调节是来那度胺作用机制的重要组成部分。我们分析了来那度胺在体内治疗期间对多发性骨髓瘤患者T细胞的影响，以及在体外对来那度胺难治性疾病患者T细胞的影响。参加德语骨髓瘤多中心组（GMMG）MM5试验的患者在自体干细胞移植（ASCT）后接受了两个周期来那度胺的巩固治疗。一半的研究人群继续接受来那度胺维持治疗2年，而其他患者接受来那度胺维持治疗直至完全缓解。我们分析了58例接受（n = 30）或未接受（n = 28）来那度胺治疗的患者，以及12例对来那度胺难治的患者，观察其通过IFNγ、颗粒酶B和穿孔素分泌所显示的抗骨髓瘤特异性T细胞反应。通过流式细胞术研究T细胞的免疫表型。值得注意的是，与未接受治疗的患者相比，接受来那度胺治疗的患者中观察到更多的骨髓瘤特异性T细胞反应。此外，我们发现接受来那度胺治疗患者的T细胞上CD45RA表达降低，表明免疫表型成熟，CD57表达降低，表明T细胞功能正常。在12例经过大量预处理（对来那度胺难治）的患者中，有6例在体外与来那度胺孵育后观察到骨髓瘤特异性T细胞反应有所改善。与体内结果互补，来那度胺在体外可降低T细胞上的CD45RA表达。
