Redirection of CD4+ and CD8+ T lymphocytes via an anti-CD3 × anti-CD19 bi-specific antibody combined with cytosine arabinoside and the efficient lysis of patient-derived B-ALL cells.
Redirection of CD4+ and CD8+ T lymphocytes via an anti-CD3 × anti-CD19 bi-specific antibody combined with cytosine arabinoside and the efficient lysis of patient-derived B-ALL cells.
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DOI：
10.1186/s13045-015-0205-6
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发表时间：
2015-10-06
影响因子：
28.5
通讯作者：
Xiong D
中科院分区：
文献类型：
--
作者：
Fan D;Li W;Yang Y;Zhang X;Zhang Q;Yan Y;Yang M;Wang J;Xiong D
B-急性淋巴细胞白血病（B-ALL）来源于B细胞祖细胞。最近，化疗和免疫疗法的适当组合的发展代表了消除癌症的有希望的方法。我们之前构建了双抗体构型的抗CD 3 ×抗CD 19双特异性抗体及其二硫键稳定形式（ds-diabody）。在体外和体内，双抗体或双抗体和Ara-C的组合在增强T细胞针对CD 19+人白血病细胞系Nalm-6的细胞毒性方面是高度有效的。本研究验证了B-ALL患者来源的细胞是否对双抗体或ds-diabody和低剂量Ara-C组合敏感。本研究旨在检测经0.25 μM Ara-C预处理的B-ALL患者源性细胞中表达的B7家族成员B7.1（CD 80）和B7.2（CD 86），并在体外和体内确定双抗体或双抗体与Ara-C联合诱导的T细胞亚型的靶向杀伤能力。我们还测定了治疗期间活化的CD 4+或CD 8 + T细胞释放的细胞因子水平。低剂量Ara-C增强了近50%的B-ALL患者来源细胞样本中的CD 80和CD 86表达。双抗体或双抗体与Ara-C的组合在体外和体内增强T细胞抗B-ALL细胞。CD 8+和CD 4 + T细胞均被有效激活。CD 4+或CD 8 + T细胞同样增强了CD 25和CD 69的表达。然而，CD 8 + T细胞通过在颗粒酶B和穿孔素依赖性机制中重定向靶细胞裂解而做出主要贡献。CD 4 + T细胞通过分泌IL 2发挥重要的免疫调节作用。因此，在双抗体介导的T细胞活化后，CD 4+或CD 8 + T细胞也释放IL 3、IL 6、TNFα和IFNγ。双抗体或双抗体联合低剂量阿糖胞苷诱导的T细胞治疗对肿瘤细胞系和临床试验有效。在体内，由于其增强的稳定性，ds-双抗体比其亲本双抗体更有效。
B-acute lymphoblastic leukemia (B-ALL) is derived from B cell progenitors. Recently, the development of appropriate combinations of chemotherapy and immunotherapy represents a promising approach for eliminating cancer. We previously constructed an anti-CD3 × anti-CD19 bi-specific antibody in a diabody configuration and its disulfide-stabilized format (ds-diabody). The combination of the diabody or ds-diabody and Ara-C was highly effective in enhancing the cytotoxicity of T cells against the CD19+ human leukemia cell-line, Nalm-6, both in vitro and in vivo. This study verified whether B-ALL patient-derived cells were sensitive to the diabody or ds-diabody and low-dosage Ara-C combination. This study aimed to detect the B7 family members B7.1 (CD80) and B7.2 (CD86) that were expressed in B-ALL patient-derived cells pre-treated by Ara-C (0.25 μM) and to determine the targeted killing ability of T cell subtypes induced by the diabody or ds-diabody combination with Ara-C both in vitro and in vivo. We also determined the levels of the cytokines that were released by activated CD4+ or CD8+ T cells during therapy. Low-dose Ara-C enhanced CD80 and CD86 expression in nearly 50 % of specimens of B-ALL patient-derived cells. A combination of diabody or ds-diabody and Ara-C enhanced T cell against B-ALL cells in vitro and in vivo. Both CD8+ and CD4+ T cells were potently activated. Expression of CD25 and CD69 was augmented equally by CD4+ or CD8+ T cells. However, CD8+ T cells made the major contribution by redirecting target cell lysis in a granzyme B and perforin-dependent mechanism. CD4+ T cells played an important immunomodulatory role by secreting IL2. Consequently, IL3, IL6, TNFα, and IFNγ were also released by CD4+ or CD8+ T cells following diabody-mediated T cell activation. T cell therapy induced by diabody or ds-diabody combined with low dose of Ara-C was effective against cancer cell-lines and in clinical trials. In vivo, the ds-diabody was more efficient than its parent diabody due to its enhanced stability.