Combining PD-1 blockade with DLL3-targeted T cell engager potentiates antitumor efficacy in small cell lung cancer

Small cell lung cancer (SCLC) is an aggressive neuroendocrine malignancy characterized by rapid proliferation, early metastasis, and poor prognosis. Despite initial sensitivity to chemotherapy and immune checkpoint blockade, most patients experience disease relapse, highlighting the urgent need for novel therapeutic strategies. Delta-like ligand 3 (DLL3) is highly expressed on the surface of SCLC cells but minimally on normal tissues, making it an ideal target for T-cell-engaging therapies. However, limited immune infiltration and the immunosuppressive tumor microenvironment often restrict the efficacy of TCEs in SCLC. Given the complementary mechanism of TCE (T cell engager) mediated cytotoxicity and PD-1 blockade-induced T-cell activation, our research found that combining a DLL3-targeted TCE with PD-1 inhibition could enhance antitumor immune responses significantly and improve therapeutic outcomes in SCLC. In PBMC-humanized mouse models bearing SHP77 (DLL3-high expression) or NCI-H69 (DLL3-low expression) xenografts, DLL3 TCE combined with pembrolizumab achieved significant antitumor efficacy than DLL3 TCE monotherapy. To elucidate the underlying mechanisms, we found a marked increase infiltration of human CD45 + immune cells in tumors after combination treatment. In tumors treated with DLL3 TCE alone, PD-1 expression on tumor-infiltrated T cells was upregulated, suggesting T-cell activation accompanied by the inhibitory immune regulation. Notably, PD-1 expression decreased upon co-administration with pembrolizumab, indicating that PD-1 blockade effectively reversed immunosuppressive microenvironment and enhanced immune-mediated tumor clearance. Furthermore, the combination treatment not only promoted T-cell priming and activation but also enhanced recognition between cancer cells and T cells within the tumor microenvironment, indicating a more inflamed immunologically active phenotype. This strategy provides a strong preclinical rationale for clinical evaluation of DLL3-targeted TCEs in combination with immune checkpoint inhibitors for the treatment of SCLC.