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

Abstract Small 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.