Vo Dang-Nghiem, Alexia Catherine, Allende-Vega Nerea, Morschhauser Franck, Houot Roch, Menard Cedric, Tarte Karin, Cartron Guillaume, Villalba Martin
INSERM U1183, Université de Montpellier 1, UFR Médecine, Montpellier, France.
Institute for Regenerative Medicine and Biotherapy (IRMB), CHU Montpellier, Montpellier, France.
Oncoimmunology. 2017 Dec 20;7(4):e1409322. doi: 10.1080/2162402X.2017.1409322. eCollection 2018.
Obinutuzumab (OBZ) shows stronger antibody-dependent cell cytotoxicity (ADCC) compared to rituximab and improved clinical activity for treating certain CD20 neoplasia. However, the efficacy of monoclonal antibody (mAb) as a monotherapy is limited. Natural Killer (NK) cells are mediators of ADCC. Hematological cancer patients possess antitumor NK cells that are unable to control disease, possibly because they are dysfunctional. The immunomodulatory drug lenalidomide (LEN) could be a treatment to restore exhausted NK cell cytotoxic functions. The clinical trial GALEN is a Phase Ib/II study of OBZ combined with LEN for the treatment of relapsed/refractory follicular and aggressive (DLBCL and MCL) B-cell Lymphoma. During treatment, we analyzed specific aspects of NK cell biology. Treatment reversed the immature NK phenotype of patients and increased expression of NK activating receptors. Inhibitory receptors were either unchanged or decreased. There was a strong NK response at the end of the 1st cycle: NK number and intracellular granzyme B (GrzB) expression decreased, degranulation increased and NK responded better to allogeneic target challenge. Moreover, the interaction of NK cells with B cell targets, measured by trogocytosis, decreased during treatment. At the end of treatment, when target cells had been wiped out, the proportion of reactive NK cells (CD69, CD45RARO, CD107a, CD19) strongly decreased. Because all patients received LEN and OBZ, it was uncertain which drug was responsible of our observations, or even if a combination of both products was necessary for the described effects on this lymphocyte lineage.
与利妥昔单抗相比，奥滨尤妥珠单抗（OBZ）表现出更强的抗体依赖性细胞毒性（ADCC），并且在治疗某些CD20肿瘤方面具有更好的临床活性。然而，单克隆抗体（mAb）作为单一疗法的疗效有限。自然杀伤（NK）细胞是ADCC的介质。血液系统癌症患者拥有抗肿瘤NK细胞，但这些细胞无法控制疾病，可能是因为它们功能失调。免疫调节药物来那度胺（LEN）可能是一种恢复耗竭的NK细胞细胞毒性功能的治疗方法。GALEN临床试验是一项Ib/II期研究，旨在评估OBZ联合LEN治疗复发/难治性滤泡性和侵袭性（弥漫性大B细胞淋巴瘤和套细胞淋巴瘤）B细胞淋巴瘤的疗效。在治疗过程中，我们分析了NK细胞生物学的特定方面。治疗逆转了患者不成熟的NK表型，并增加了NK激活受体的表达。抑制性受体要么未改变，要么减少。在第1周期结束时出现了强烈的NK反应：NK细胞数量和细胞内颗粒酶B（GrzB）表达减少，脱颗粒增加，NK细胞对异基因靶标攻击的反应更好。此外，通过噬细胞作用测量的NK细胞与B细胞靶标的相互作用在治疗期间减少。在治疗结束时，当靶细胞被清除后，反应性NK细胞（CD69、CD45RARO、CD107a、CD19）的比例大幅下降。由于所有患者都接受了LEN和OBZ治疗，因此不确定是哪种药物导致了我们观察到的结果，甚至不确定两种产品的组合对于所述的对该淋巴细胞谱系的影响是否必要。
