肿瘤细胞治疗研究
英文原题：Allogeneic CAR T Cells Targeting DLL3 Are Efficacious and Safe in Preclinical Models of Small Cell Lung Cancer.
本文展示的临床前疗效和安全性数据支持将 DLL3 CAR T 细胞作为治疗小细胞肺癌（SCLC）的潜在临床候选进一步评估。
目的：小细胞肺癌（SCLC）具有侵袭性，治疗选择有限。Delta样配体3（DLL3）在SCLC及其他若干神经内分泌肿瘤中高表达，而正常组织中的表达仅限于脑垂体和睾丸等组织且RNA表达水平有限，因此是治疗SCLC及其他实体瘤的有前景CAR T细胞靶点。实验设计：研究者对大量基于抗DLL3单链可变片段（scFv）的CAR进行体内外活性表征。为了解其对脑垂体和脑组织产生毒性的可能性，研究者在小鼠体内接种皮下或颅内DLL3表达肿瘤，并使用可与小鼠DLL3交叉反应的CAR T细胞治疗。结果：部分CAR能够高敏感识别DLL3密度较低的靶细胞，并在体外长期杀伤。在SCLC皮下和全身性体内模型中，输注DLL3 CAR T细胞产生强效抗肿瘤作用，包括完全缓解。检测到CAR T细胞浸润垂体中间叶和后叶，但未观察到脑或垂体组织损伤，垂体激素分泌功能也未丧失。结论：本文提供的临床前疗效和安全性数据支持进一步评估DLL3 CAR T细胞作为SCLC潜在临床候选疗法。
PURPOSE: Small cell lung cancer (SCLC) is an aggressive disease with limited treatment options. Delta-like ligand 3 (DLL3) is highly expressed on SCLC and several other types of neuroendocrine cancers, with limited normal tissue RNA expression in brain, pituitary, and testis, making it a promising CAR T-cell target for SCLC and other solid tumor indications. EXPERIMENTAL DESIGN: A large panel of anti-DLL3 scFv-based CARs were characterized for both in vitro and in vivo activity. To understand the potential for pituitary and brain toxicity, subcutaneous or intracranial tumors expressing DLL3 were implanted in mice and treated with mouse cross-reactive DLL3 CAR T cells. RESULTS: A subset of CARs demonstrated high sensitivity for targets with low DLL3 density and long-term killing potential in vitro. Infusion of DLL3 CAR T cells led to robust antitumor efficacy, including complete responses, in subcutaneous and systemic SCLC in vivo models. CAR T-cell infiltration into intermediate and posterior pituitary was detected, but no tissue damage in brain or pituitary was observed, and the hormone-secretion function of the pituitary was not ablated. CONCLUSIONS: In summary, the preclinical efficacy and safety data presented here support further evaluation of DLL3 CAR T cells as potential clinical candidates for the treatment of SCLC.
MEMBER ACCOUNT
登录成功会直接打开下一页。
