Combined DLL3-targeted bispecific antibody with PD-1 inhibition is efficient to suppress small cell lung cancer growth
Combined DLL3-targeted bispecific antibody with PD-1 inhibition is efficient to suppress small cell lung cancer growth
复制标题
DLL3靶向双特异性抗体与PD-1抑制相结合可有效抑制小细胞肺癌生长
DOI：
10.1136/jitc-2020-000785
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发表时间：
2020-01-01
影响因子：
10.9
通讯作者：
Feng, Mingqian
中科院分区：
文献类型：
--
作者：
Chen, Xin;Amar, Norhan;Feng, Mingqian
背景小细胞肺癌（small cell lung cancer，SCLC）占肺癌的15%，其主要治疗方法是化疗和放疗。δ样3（DLL 3）是SCLC免疫治疗的有吸引力的靶标，因为其表达高度限于SCLC，在正常成人组织上的外观可忽略。在本研究中，我们的目的是探索DLL 3靶向SCLC免疫治疗通过T细胞的参与的疗效。方法作为概念验证，我们构建了DLL 3靶向的双特异性抗体和嵌合抗原受体（CAR）修饰的T细胞。评价这些治疗单独或与程序性死亡-1（PD-1）抑制性抗体组合的体外和体内肿瘤抑制活性。结果体外研究表明，DLL 3双特异性抗体和CAR-T均能有效杀伤DLL 3阳性癌细胞，包括天然SCLC细胞系H446、H196、H82和强过表达DLL 3的人工A431细胞。在异种移植小鼠模型中的体内研究表明，双特异性抗体和CAR-T都抑制了肿瘤生长，并且与PD-1抑制性抗体的联合治疗显著改善了DLL 3双特异性抗体的功效，但没有改善CAR-T细胞的功效。结论我们的结果表明DLL 3靶向双特异性抗体加PD-1抑制剂在控制SCLC生长中是有效的。
Background Small cell lung cancer (SCLC) accounts for 15% of lung cancers, and the primary treatment of this malignancy is chemotherapy and radiotherapy. Delta-like 3 (DLL3) is an attractive target for SCLC immunotherapy since its expression is highly restricted to SCLC with a neglectable appearance on normal adult tissues. In the current study, we aimed to explore the efficacy of DLL3-targeted SCLC immunotherapy via the engagement of T cell. Methods As a proof of concept, we constructed DLL3-targeted bispecific antibody and chimeric antigen receptor (CAR)-modified T cells. In vitro and in vivo tumor-suppression activity of these treatments alone or in combination with a Program Death-1 (PD-1) inhibitory antibody was evaluated. Results In vitro studies showed that both DLL3 bispecific antibody and CAR-T efficiently killed DLL3-positive cancer cells, including the native SCLC cell lines H446, H196, H82, and the artificial A431 cells that were forcefully overexpressing DLL3. In vivo studies in xenograft mouse models demonstrated that both bispecific antibody and CAR-T suppressed the tumor growth, and combination therapy with PD-1 inhibitory antibody dramatically improved the efficacy of the DLL3 bispecific antibody, but not the CAR-T cells. Conclusions Our results demonstrated that DLL3-targeted bispecific antibody plus PD-1 inhibition was effective in controlling SCLC growth.