Tafasitamab at the blood-brain barrier.
Tafasitamab at the blood-brain barrier.
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他法西他单抗在血脑屏障中的作用。
DOI：
10.1111/bjh.18660
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发表时间：
2023
影响因子：
6.5
通讯作者：
Rubenstein,JamesL
中科院分区：
文献类型：
--
作者：
Rauschecker,AndreasM;Mo,ShirleyS;Randall,Michael;Shen-Sampas,John;Rubenstein,JamesL
众所周知，B 细胞在大多数分化阶段、大多数 B 细胞恶性肿瘤和滤泡树突细胞中都表达 CD19 跨膜糖蛋白。 1, 2 鉴于 CD19 定向嵌合抗原受体 (CAR)-T 细胞和双特异性 T 细胞接合抗体破坏血脑屏障相关的神经毒性发生率很高，3-6 Parker 等人。 7 最近研究了大脑中非 B 细胞表达 CD19 的可能性。利用人脑产生的单细胞 RNA 测序数据，他们鉴定了脑壁细胞或周细胞的 CD19 表达，脑壁细胞或周细胞是调节血脑屏障完整性的神经血管单元的组成部分。 8 壁细胞的 CD19 表达在其他数据集中和免疫组织化学中得到证实，并且在小毛细血管和较大血管中均被发现。 CD19的脑壁细胞表达也表现出区域差异，在海马、岛叶、颞叶、额叶和顶叶中表达较高。最后，研究表明，CD19 的脑壁细胞表达在小鼠中是保守的，并且将靶向小鼠 CD19 的 CAR-T 细胞输注到缺乏 B 细胞的非肥胖糖尿病严重联合免疫缺陷 (NOD/SCID) γ (NSG) 小鼠中，导致血脑屏障通透性增加和壁细胞耗竭。 7 因此，这些结果为 CD19 CAR-T 细胞介导的神经毒性提供了潜在的靶向机制。鉴于这些观察结果以及复发性原发性和继发性中枢神经系统（CNS）淋巴瘤的引人注目的问题，我们在两种情况下评估了tafasitamab（一种抗CD19单克隆抗体）作为免疫功能正常患者的难治性CNS淋巴瘤的新型治疗方法，具有通过干扰壁细胞表达的CD19来调节血脑屏障完整性的潜力，但不会伴随细胞因子释放综合征，因为tafasitamab不会招募细胞毒性物质T 细胞的有效负载。在II期L-MIND研究（ClinicalTrials.gov Identifier：NCT02399085）中，tafasitamab联合来那度胺在复发/难治性侵袭性非霍奇金淋巴瘤中表现出协同疗效，总体缓解率为60%，完全缓解率为43%，与CAR-T相比，毒性特征良好，无神经毒性。值得注意的是，L-MIND 试验排除了先前接受过免疫调节药物以及中枢神经系统淋巴瘤治疗的患者。 9 第一位患者是一名 53 岁男性，出现癫痫发作和右额叶肿块，病理分析显示为大 B 细胞淋巴瘤（活化 B 细胞型）。分期记录了伴随的右肾上腺受累。在外部机构的治疗包括六个周期的高剂量甲氨蝶呤 (HD-MTX) 插入利妥昔单抗、环磷酰胺、阿霉素、长春新碱、泼尼松 (R-CHOP) 加鞘内注射阿糖胞苷，也是六个周期。 7 个月时出现多灶性 CNS 进展，患者被转移到三级护理中心，在那里接受了 8 个周期的 HD-MTX、6 剂替莫唑胺加利妥昔单抗 (MTR)、依托泊苷-ara-C 10、11 巩固治疗，随后进行自体干细胞移植和来那度胺维持治疗。然而，移植后 6 个月，磁共振成像 (MRI) 再次显示多灶性 CNS 进展。第二次复发采用重复 HD-MTX（八个周期）加利妥昔单抗治疗，随后对右侧中央后回难治性病变进行局部照射，随后进行泊马度胺维持治疗，导致中枢神经系统反应持续时间近 2 年。第三个孤立的中枢神经系统……
It is well established that the CD19 transmembrane glycoprotein is expressed by B cells throughout most stages of differentiation, by the majority of B-cell malignancies, and by follicular dendritic cells. 1, 2 Given the high incidence of neurotoxicity associated with blood–brain barrier disruption with CD19-directed chimeric antigen receptor (CAR)-T cells and bispecific T-cell engager antibodies, 3–6 Parker et al. 7 recently investigated the possibility of CD19 expression by non-B cells in the brain. Using single-cell RNA sequencing data generated from human brain, they identified CD19 expression by brain mural cells or pericytes, an integral component of the neurovascular unit that regulates integrity of the blood–brain barrier. 8 CD19 expression by mural cells was confirmed in additional datasets and by immunohistochemistry, and was found along both small capillaries and larger vessels. Brain mural cell expression of CD19 also exhibited regional variation, with higher expression in the hippocampus, insula, temporal, frontal and parietal lobes. Finally, it was demonstrated that brain mural cell expression of CD19 is conserved in mice and that the infusion of CAR-T cells targeting murine CD19 into non-obese diabetic severe combined immunodeficiency (NOD/SCID) gamma (NSG) mice, lacking B cells, resulted in increased blood–brain barrier permeability and mural cell depletion. 7 These results, therefore, provide a potential on-target mechanism for CD19 CAR-T cell mediated neurotoxicity. Given these observations and the compelling problem of relapsed primary and secondary central nervous system (CNS) lymphoma, we evaluated tafasitamab, an anti-CD19 monoclonal antibody, in two cases as a novel therapeutic for refractory CNS lymphomas in immunocompetent patients, with potential to modulate blood–brain barrier integrity by perturbation of CD19 expressed by mural cells, but without concomitant cytokine release syndrome, given that tafasitamab does not recruit the cytotoxic payload of T cells. In the phase II L-MIND study (ClinicalTrials. gov Identifier: NCT02399085), tafasitamab plus lenalidomide exhibited synergistic efficacy in relapsed/refractory aggressive non-Hodgkin lymphoma, with an overall response rate of 60%, complete response rate of 43%, and a favourable toxicity profile compared to CAR-T, without neurotoxicity. Notably, the L-MIND trial excluded patients previously treated with immunomodulatory drugs as well as CNS lymphoma. 9 The first patient is a 53 year-old man who presented with seizure and a right frontal lobe mass that upon pathological analysis revealed large-B cell lymphoma, activated B-cell type. Staging documented concomitant right adrenal involvement. Treatment at an outside institution consisted of six cycles of high-dose methotrexate (HD-MTX) intercalated with rituximab, cyclophosphamide, adriamycin, vincristine, prednisone (R-CHOP) plus intrathecal cytarabine, also six cycles. At 7 months there was multifocal CNS progression and the patient was transferred to a tertiary care centre where he received eight cycles of HD-MTX, six doses of temozolomide plus rituximab (MTR), consolidation with etoposide-ara-C 10, 11 followed by autologous stem cell transplantation and lenalidomide maintenance. However, at 6 months after transplantation, multifocal CNS progression was again evident on magnetic resonance imaging (MRI). This second relapse was treated with repeat HD-MTX (eight cycles) plus rituximab followed by focal irradiation to a refractory lesion in the right postcentral gyrus, followed by pomalidomide maintenance, resulting in a CNS response duration of nearly 2 years. A third isolated CNS …