Mesenchymal stromal cells as vehicles of tetravalent bispecific Tandab (CD3/CD19) for the treatment of B cell lymphoma combined with IDO pathway inhibitor D-1-methyl-tryptophan.
Mesenchymal stromal cells as vehicles of tetravalent bispecific Tandab (CD3/CD19) for the treatment of B cell lymphoma combined with IDO pathway inhibitor D-1-methyl-tryptophan.
复制标题
间充质基质细胞作为四价双特异性 Tandab (CD3/CD19) 的载体联合 IDO 途径抑制剂 D-1-甲基色氨酸治疗 B 细胞淋巴瘤
DOI：
10.1186/s13045-017-0397-z
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发表时间：
2017-02-23
影响因子：
28.5
通讯作者：
Xiong D
中科院分区：
文献类型：
--
作者：
Zhang X;Yang Y;Zhang L;Lu Y;Zhang Q;Fan D;Zhang Y;Zhang Y;Ye Z;Xiong D
尽管blinatumomab是一种双特异性T细胞结合抗体，在复发或难治性B前体急性淋巴细胞白血病（B-ALL）和B细胞非霍奇金淋巴瘤（B-NHL）患者中表现出较高的临床缓解率，但由于其半衰期短，它仍然存在一些局限性。间充质基质细胞（MSC）由于其对肿瘤的趋向性，成为将治疗药物递送至癌症部位的一种有吸引力的方法，但也应考虑其免疫抑制能力，特别是由吲哚胺 2,3-双加氧酶（IDO）诱导的免疫抑制能力。人脐带源性 MSC (UC-MSC) 经过基因改造，可分泌 Tandab (CD3/CD19)，这是一种四价双特异性串联双抗体，具有两个 CD3 结合位点和两个 CD19 结合位点。通过迁移测定确定体外 MSC 对 Raji 细胞的趋向性，并通过生物发光成像 (BLI) 用萤火虫荧光素酶标记的 MSC (MSC-Luc) 分析体内 MSC 的归巢特性。在体外和体内检测了分泌 MSC 的 Tandab (CD3/CD19) 与 IDO 途径抑制剂 d-1-甲基色氨酸 (D-1MT) 联合诱导的 T 细胞的细胞毒性。纯化的 Tandab (CD3/CD19) 对 CD3 阳性细胞和 CD19 阳性细胞均具有高结合能力，并且能够在 T 细胞存在的情况下诱导 CD19 阳性细胞系（Raji、Daudi 和 BJAB）的特异性裂解。此外，共培养杀伤实验的结果表明，MSC 分泌的 Tandab (CD3/CD19) 也有效。然后，我们证实D-1MT可以通过下调CD98和Jumonji来逆转T细胞无能性并恢复T细胞的增殖能力，从而增强MSC-Tandab引发的T细胞的细胞毒性。此外，在带有Raji细胞的BALB/c裸鼠模型中，MSC-Luc可以选择性地迁移到肿瘤部位。小鼠注射 MSC-Tandab 联合 D-1MT 显着抑制肿瘤生长。这些结果表明，UC-MSC 释放 Tandab (CD3/CD19) 与 D-1MT 联合使用是治疗 B 细胞淋巴瘤的有效治疗工具。本文的在线版本 (doi:10.1186/s13045-017-0397-z) 包含补充材料，可供授权用户使用。
Although blinatumomab, a bispecific T cell engaging antibody, exhibits high clinical response rates in patients with relapsed or refractory B-precursor acute lymphoblastic leukemia (B-ALL) and B cell non-Hodgkin’s lymphoma (B-NHL), it still has some limitations because of its short half-life. Mesenchymal stromal cells (MSCs) represent an attractive approach for delivery of therapeutic agents to cancer sites owing to their tropism towards tumors, but their immunosuppression capabilities, especially induced by indoleamine 2,3-dioxygenase (IDO), should also be taken into consideration. Human umbilical cord-derived MSCs (UC-MSCs) were genetically modified to secrete Tandab (CD3/CD19), a tetravalent bispecific tandem diabody with two binding sites for CD3 and two for CD19. The tropism of MSCs towards Raji cells in vitro was determined by migration assays, and the homing property of MSCs in vivo was analyzed with firefly luciferase-labeled MSCs (MSC-Luc) by bioluminescent imaging (BLI). The cytotoxicity of T cells induced by MSC-secreting Tandab (CD3/CD19) was detected in vitro and in vivo in combination with d-1-methyl-tryptophan (D-1MT), an IDO pathway inhibitor. The purified Tandab (CD3/CD19) was functional with high-binding capability both for CD3-positive cells and CD19-positive cells and was able to induce specific lysis of CD19-positive cell lines (Raji, Daudi, and BJAB) in the presence of T cells. Additionally, results from co-culture killing experiments demonstrated that Tandab (CD3/CD19) secreted from MSCs was also effective. Then, we confirmed that D-1MT could enhance the cytotoxicity of T cells triggered by MSC-Tandab through reversing T cell anergy with down-regulation of CD98 and Jumonji and restoring the proliferation capacity of T cells. Furthermore, MSC-Luc could selectively migrate to tumor site in a BALB/c nude mouse model with Raji cells. And mice injected with MSC-Tandab in combination with D-1MT significantly inhibited the tumor growth. These results suggest that UC-MSCs releasing Tandab (CD3/CD19) is an efficient therapeutic tool for the treatment of B cell lymphoma when combined with D-1MT. The online version of this article (doi:10.1186/s13045-017-0397-z) contains supplementary material, which is available to authorized users.