肿瘤细胞治疗研究
英文原题：Targeting FcγRIIB by antagonistic antibody BI-1206 improves the efficacy of rituximab-based therapies in aggressive mantle cell lymphoma.
这些数据支持靶向这一新型免疫检查点阻断可增强利妥昔单抗为基础方案在具有多重耐药性的侵袭性MCL模型中的治疗活性。
尽管FDA已批准多种靶向治疗和免疫治疗，但不可避免的复发仍是套细胞淋巴瘤（MCL）患者面临的主要治疗挑战。Fcγ受体（FcγRs）在调节抗体介导的免疫中发挥重要作用。FcγRIIB是FcγR家族中唯一的免疫检查点抑制性成员，已被认为与免疫细胞脱敏及肿瘤细胞对抗CD20抗体利妥昔单抗和其他抗体介导免疫治疗的耐药有关；然而，关于其在侵袭性MCL患者，尤其是多重耐药患者中的表达及其免疫调节功能，目前知之甚少。在本研究中，我们发现FcγRIIB在MCL细胞系和原发患者样本中普遍表达。与ibrutinib/rituximab初治、敏感或耐药样本相比，CAR T治疗后复发患者样本中FcγRIIB表达显著更高（p < 0.0001）。在JeKo-1细胞中，利妥昔单抗诱导的CD20内化可被BI-1206完全阻断，BI-1206是一种靶向FcγRIIB的重组人单克隆抗体。利妥昔单抗-ibrutinib、利妥昔单抗-venetoclax和利妥昔单抗-CHOP联合治疗也可诱导CD20内化，而BI-1206同样可有效阻断这一过程。在JeKo-1细胞系来源的异种移植模型中，BI-1206显著增强了利妥昔单抗-ibrutinib（p = 0.05）和利妥昔单抗-venetoclax（p = 0.02）的体内抗MCL疗效，但未增强利妥昔单抗-CHOP联合方案的疗效。在患者来源异种移植（PDX）模型中，BI-1206作为单药显示出高效力（p < 0.0001，在一个对ibrutinib和venetoclax均耐药但对rituximab和lenalidomide联合方案（R2治疗的临床前模拟）敏感的侵袭性PDX模型中，与载体对照相比）。BI-1206在对rituximab、ibrutinib和CAR T治疗三重耐药的PDX模型中使rituximab单药治疗的疗效增敏（p = 0.030）。此外，BI-1206显著增强了rituximab-venetoclax联合方案的疗效（p < 0.05），使25%的小鼠获得长期肿瘤缓解。总之，这些数据支持靶向这一新的免疫检查点阻断可增强基于rituximab的方案在具有多重耐药的侵袭性MCL模型中的治疗活性。
Inevitable relapses remain as the major therapeutic challenge in patients with mantle cell lymphoma (MCL) despite FDA approval of multiple targeted therapies and immunotherapies. Fc gamma receptors (Fc Rs) play important roles in regulating antibody-mediated immunity. Fc RIIB, the unique immune-checkpoint inhibitory member of the Fc R family, has been implicated in immune cell desensitization and tumor cell resistance to the anti-CD20 antibody rituximab and other antibody-mediated immunotherapies; however, little is known about its expression and its immune-modulatory function in patients with aggressive MCL, especially those with multi-resistance. In this study, we found that Fc RIIB was ubiquitously expressed in both MCL cell lines and primary patient samples. Fc RIIB expression is significantly higher in CAR T-relapsed patient samples (p < 0.0001) compared to ibrutinib/rituximab-na ve, sensitive or resistant samples. Rituximab-induced CD20 internalization in JeKo-1 cells was completely blocked by concurrent treatment with BI-1206, a recombinant human monoclonal antibody targeting Fc RIIB. Combinational therapies with rituximab-ibrutinib, rituximab-venetoclax and rituximab-CHOP also induced CD20 internalization which was again effectively blocked by BI-1206. BI-1206 significantly enhanced the in vivo anti-MCL efficacy of rituximab-ibrutinib (p = 0.05) and rituximab-venetoclax (p = 0.02), but not the rituximab-CHOP combination in JeKo-1 cell line-derived xenograft models. In patient-derived xenograft (PDX) models, BI-1206, as a single agent, showed high potency (p < 0.0001, compared to vehicle control) in one aggressive PDX model that is resistant to both ibrutinib and venetoclax but sensitive to the combination of rituximab and lenalidomide (the preclinical mimetic of R 2 therapy). BI-1206 sensitized the efficacy of rituximab monotherapy in a PDX model with triple resistance to rituximab, ibrutinib and CAR T-therapies (p = 0.030). Moreover, BI-1206 significantly enhanced the efficacy of the rituximab-venetoclax combination (p < 0.05), which led to long-term tumor remission in 25% of mice. Altogether, these data support that targeting this new immune-checkpoint blockade enhances the therapeutic activity of rituximab-based regimens in aggressive MCL models with multi-resistance.
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