College of Life Science and Technology, Huazhong Agricultural University, Wuhan, Hubei, China.
Department of Thoracic Surgery, Jilin University Second Hospital, Changchun, Jilin, China.
J Immunother Cancer. 2020 Jun;8(1). doi: 10.1136/jitc-2020-000785.
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.
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.
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.
Our results demonstrated that DLL3-targeted bispecific antibody plus PD-1 inhibition was effective in controlling SCLC growth.
小细胞肺癌（SCLC）占肺癌的 15%，这种恶性肿瘤的主要治疗方法是化疗和放疗。Delta-like 3（DLL3）是 SCLC 免疫治疗的一个有吸引力的靶点，因为它的表达高度局限于 SCLC，在正常成人组织中几乎没有出现。在本研究中，我们旨在通过 T 细胞的参与来探索 DLL3 靶向 SCLC 免疫治疗的疗效。
作为概念验证，我们构建了 DLL3 靶向的双特异性抗体和嵌合抗原受体（CAR）修饰的 T 细胞。单独或与程序性死亡受体-1（PD-1）抑制性抗体联合使用，评估这些治疗方法在体外和体内的肿瘤抑制活性。
体外研究表明，DLL3 双特异性抗体和 CAR-T 均能有效地杀伤 DLL3 阳性癌细胞，包括天然的 SCLC 细胞系 H446、H196、H82 和强制过表达 DLL3 的人工 A431 细胞。在异种移植小鼠模型的体内研究中，双特异性抗体和 CAR-T 均能抑制肿瘤生长，而与 PD-1 抑制性抗体联合治疗可显著提高 DLL3 双特异性抗体的疗效，但对 CAR-T 细胞无效。
我们的结果表明，DLL3 靶向的双特异性抗体加 PD-1 抑制可有效控制 SCLC 的生长。
