A Multicenter Phase I Trial on the Safety and Preliminary Efficacy of DLL3-CAR-NK Cells in the Treatment of Relapsed / Refractory Extensive Stage Small Cell Lung Cancer

This is a multicenter, open-label, phase I clinical trial aimed to evaluate the safety and efficacy of DLL3-CAR-NK cells treatment for relapsed and refractory extensive small cell lung cancer (ES-SCLC).

开始日期2022-09-01

申办/合作机构

天津市肿瘤医院

100 项与 DLL3-CAR-NK Cells(Tianjin Medical University Cancer Institute and Hospital) 相关的临床结果

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100 项与 DLL3-CAR-NK Cells(Tianjin Medical University Cancer Institute and Hospital) 相关的转化医学

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100 项与 DLL3-CAR-NK Cells(Tianjin Medical University Cancer Institute and Hospital) 相关的专利（医药）

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项与 DLL3-CAR-NK Cells(Tianjin Medical University Cancer Institute and Hospital) 相关的文献（医药）

2024-07-01·Immunology

TREM1/DAP12 based novel multiple chain CAR‐T cells targeting DLL3 show robust anti‐tumour efficacy for small cell lung cancer

Article

作者: Qiu, Mantang ; Huang, Peng ; Shi, Xuefei ; Wang, Enxiu ; Chen, Yuli ; Hu, Yanming ; Lu, Kaihua ; Nie, Fengqi ; Cai, Jingsheng ; Sun, Ming

AbstractSmall cell lung cancer (SCLC), recognized as the most aggressive subtype of lung cancer, presents an extremely poor prognosis. Currently, patients with small cell lung cancer face a significant dearth of effective alternative treatment options once they experience recurrence and progression after first‐line therapy. Despite the promising efficacy of immunotherapy, particularly immune checkpoint inhibitors in non‐small cell lung cancer (NSCLC) and various other tumours, its impact on significantly enhancing the prognosis of SCLC patients remains elusive. DLL3 has emerged as a compelling target for targeted therapy in SCLC due to its high expression on the membranes of SCLC and other neuroendocrine carcinoma cells, with minimal to no expression in normal cells. Our previous work led to the development of a novel multiple chain chimeric antigen receptor (CAR) leveraging the TREM1 receptor and DAP12, which efficiently activated T cells and conferred potent cell cytotoxicity. In this study, we have developed a DLL3‐TREM1/DAP12 CAR‐T (DLL3‐DT CAR‐T) therapy, demonstrating comparable anti‐tumour efficacy against SCLC cells in vitro. In murine xenograft and patient‐derived xenograft models, DLL3‐DT CAR‐T cells exhibited a more robust tumour eradication efficiency than second‐generation DLL3‐BBZ CAR‐T cells. Furthermore, we observed elevated memory phenotypes, induced durable responses, and activation under antigen‐presenting cells in DLL3‐DT CAR‐T cells. Collectively, these findings suggest that DLL3‐DT CAR‐T cells may offer a novel and potentially effective therapeutic strategy for treating DLL3‐expressing SCLC and other solid tumours.

2023-05-01·The Journal of clinical investigation

IL-18-secreting CAR T cells targeting DLL3 are highly effective in small cell lung cancer models.

Article

作者: Jaspers, Janneke E ; Ciampricotti, Metamia ; Rudin, Charles M ; Khan, Jonathan F ; Godfrey, William D ; Lopez, Andrea V ; Brentjens, Renier J

Patients with small cell lung cancer (SCLC) generally have a poor prognosis and a median overall survival of only about 13 months, indicating the urgent need for novel therapies. Delta-like protein 3 (DLL3) has been identified as a tumor-specific cell surface marker on neuroendocrine cancers, including SCLC. In this study, we developed a chimeric antigen receptor (CAR) against DLL3 that displays antitumor efficacy in xenograft and murine SCLC models. CAR T cell expression of the proinflammatory cytokine IL-18 greatly enhanced the potency of DLL3-targeting CAR T cell therapy. In a murine metastatic SCLC model, IL-18 production increased the activation of both CAR T cells and endogenous tumor-infiltrating lymphocytes. We also observed an increased infiltration, repolarization, and activation of antigen-presenting cells. Additionally, human IL-18-secreting anti-DLL3 CAR T cells showed an increased memory phenotype, less exhaustion, and induced durable responses in multiple SCLC models, an effect that could be further enhanced with anti-PD-1 blockade. All together, these results define DLL3-targeting CAR T cells that produce IL-18 as a potentially promising novel strategy against DLL3-expressing solid tumors.

2023-03-01·Clinical Cancer Research

Allogeneic CAR T Cells Targeting DLL3 Are Efficacious and Safe in Preclinical Models of Small Cell Lung Cancer

Article

作者: Mak, Yvonne S.L. ; Zhang, Yi ; Sasu, Barbra J. ; Sai, Tao ; Lay, Cecilia ; Sutton, Janette ; Melton, Zea ; Van Blarcom, Thomas ; Panowski, Siler H. ; Smith, Bryan A. ; Tacheva-Grigorova, Silvia K.

AbstractPurpose: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.

100 项与 DLL3-CAR-NK Cells(Tianjin Medical University Cancer Institute and Hospital) 相关的药物交易

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研发状态

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适应症	最高研发状态	国家/地区	公司	日期
广泛期小细胞肺癌	临床1期	中国	天津市肿瘤医院	2022-09-01
广泛期小细胞肺癌	临床1期	中国	天津市肿瘤研究所	2022-09-01
小细胞肺癌复发	临床1期	中国	天津市肿瘤医院	2022-09-01