State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, P.R. China.
Hum Gene Ther. 2013 Aug;24(8):751-60. doi: 10.1089/hum.2013.051.
Chemotherapeutic drugs can enhance an immune response of the host against the tumor in addition to killing cancer cells by direct cytotoxicity. Therefore, the combination of chemotherapy and immunotherapy is a promising approach for eliminating tumors, particularly in advanced stages. A strategic medication is to use a bispecific antibody format that is capable of recruiting polyclonal T cells around antibody-target-expressing tumor cells. Recently, we have constructed a bispecific antibody, anti-CD3×anti-CD19, in a diabody configuration. In this study, we measured B7 family members B7.1 (CD80) and B7.2 (CD86) expressed on a CD19(+) human leukemia cell line, Nalm-6, stimulated by cytosine arabinoside (Ara-C). We found that a low concentration of Ara-C could upregulate CD80 expressed on CD19(+) Nalm-6 cells. The cytotoxicity of T lymphocytes against Nalm-6 cells in vitro and in vivo mediated by the anti-CD3×anti-CD19 diabody with or without a low dose of Ara-C was compared. The combination of the anti-CD3×anti-CD19 diabody and Ara-C showed the greatest effectiveness in enhancing the cytotoxicity of T cells against the tumor cells in vitro and in vivo. Activated T cells expressed higher levels of CD25 and CD69 and released more interleukin 2. Both perforin/granzyme B system and Fas/FasL pathway were involved in the diabody-induced T-cell cytotoxicity. Moreover, the activated T cells could upregulate ICAM-3 expression on Nalm-6 cells, and inhibition of LFA-1-ICAM-3 interaction impaired cytotoxicity of T cells. It was noted that Ara-C could upregulate CD80 expressed on two of five specimens of acute B lymphoblastic leukemia patient-derived cells. Cytotoxicity of T cells against these two patient-derived cells was enhanced in the presence of the anti-CD3×anti-CD19 diabody. These findings indicate that treatment strategy using both cytotoxic lymphocyte-based immunotherapy and chemotherapy may have synergistic effects.
化疗药物除了通过直接细胞毒性杀伤癌细胞外，还可以增强宿主对肿瘤的免疫反应。因此，化疗和免疫疗法的联合是消除肿瘤的一种很有前途的方法，尤其是在晚期。一种策略是使用能够募集围绕表达抗体靶标的肿瘤细胞的多克隆 T 细胞的双特异性抗体格式。最近，我们构建了一种双特异性抗体，抗 CD3×抗 CD19，采用二价抗体构型。在这项研究中，我们测量了细胞因子阿拉伯糖苷（Ara-C）刺激的 CD19(+)人白血病细胞系 Nalm-6 上表达的 B7 家族成员 B7.1（CD80）和 B7.2（CD86）。我们发现低浓度的 Ara-C 可以上调 CD19(+)Nalm-6 细胞上表达的 CD80。比较了含有或不含有低剂量 Ara-C 的抗 CD3×抗 CD19 二价抗体在体外和体内对 T 淋巴细胞对 Nalm-6 细胞的细胞毒性。抗 CD3×抗 CD19 二价抗体与 Ara-C 的组合在增强 T 细胞对肿瘤细胞的体外和体内细胞毒性方面显示出最大的效果。激活的 T 细胞表达更高水平的 CD25 和 CD69，并释放更多的白细胞介素 2。穿孔素/颗粒酶 B 系统和 Fas/FasL 途径均参与了二价抗体诱导的 T 细胞细胞毒性。此外，激活的 T 细胞可以上调 Nalm-6 细胞上的 ICAM-3 表达，而抑制 LFA-1-ICAM-3 相互作用会损害 T 细胞的细胞毒性。值得注意的是，Ara-C 可以上调五份急性 B 淋巴细胞白血病患者来源细胞中的两份细胞上表达的 CD80。在存在抗 CD3×抗 CD19 二价抗体的情况下，T 细胞对这两种患者来源细胞的细胞毒性增强。这些发现表明，基于细胞毒性淋巴细胞的免疫疗法和化学疗法联合治疗策略可能具有协同作用。
