Susanne Hipp 1 , Vladimir Voynov 2 , Barbara Drobits-Handl 3 , Craig Giragossian 2 , Francesca Trapani 4 , Andrew E Nixon 2 , Justin M Scheer 2 , Paul J Adam 5 Show Affiliations »
Abstract
PURPOSE: Small cell lung cancer (SCLC) is the most lethal and aggressive subtype of lung carcinoma characterized by highly chemotherapy-resistant recurrence in the majority of patients. To effectively treat SCLC, we have developed a unique and novel IgG-like T-cell engaging bispecific antibody (ITE) that potently redirects T-cells to specifically lyse SCLC cells expressing Delta-like ligand 3 (DLL3), an antigen that is frequently expressed on the cell surface of SCLC cells, with no to very little detectable expression in normal tissues. EXPERIMENTAL DESIGN: The antitumor activity and mode of action of DLL3/CD3 ITE was evaluated in vitro using SCLC cell lines and primary human effector cells and in vivo in an SCLC xenograft model reconstituted with human CD3+ T-cells. RESULTS: Selective binding of DLL3/CD3 ITE to DLL3-positive tumor cells and T-cells induces formation of an immunological synapse resulting in tumor cell lysis and activation of T-cells. In a human T-cell engrafted xenograft model, the DLL3/CD3 ITE leads to an increase in infiltration of T-cells into the tumor tissue resulting in apoptosis of the tumor cells and tumor regression. Consistent with the mode of action, the DLL3/CD3 ITE treatment led to upregulation of PD-1, PD-L1, and LAG-3. CONCLUSIONS: This study highlights the ability of the DLL3/CD3 ITE to induce strictly DLL3-dependent T-cell redirected lysis of tumor cells and recruitment of T-cells into noninflamed tumor tissues leading to tumor regression in a preclinical in vivo model. These data support clinical testing of the DLL3/CD3 ITE in patients with SCLC. ©2020 American Association for Cancer Research.
PURPOSE: Small cell lung cancer (SCLC ) is the most lethal and aggressive subtype of lung carcinoma characterized by highly chemotherapy-resistant recurrence in the majority of patients . To effectively treat SCLC , we have developed a unique and novel IgG-like T-cell engaging bispecific antibody (ITE) that potently redirects T-cells to specifically lyse SCLC cells expressing Delta-like ligand 3 (DLL3 ), an antigen that is frequently expressed on the cell surface of SCLC cells, with no to very little detectable expression in normal tissues. EXPERIMENTAL DESIGN: The antitumor activity and mode of action of DLL3 /CD3 ITE was evaluated in vitro using SCLC cell lines and primary human effector cells and in vivo in an SCLC xenograft model reconstituted with human CD3+ T-cells. RESULTS: Selective binding of DLL3 /CD3 ITE to DLL3 -positive tumor cells and T-cells induces formation of an immunological synapse resulting in tumor cell lysis and activation of T-cells. In a human T-cell engrafted xenograft model, the DLL3 /CD3 ITE leads to an increase in infiltration of T-cells into the tumor tissue resulting in apoptosis of the tumor cells and tumor regression. Consistent with the mode of action, the DLL3 /CD3 ITE treatment led to upregulation of PD-1 , PD-L1 , and LAG-3 . CONCLUSIONS: This study highlights the ability of the DLL3 /CD3 ITE to induce strictly DLL3 -dependent T-cell redirected lysis of tumor cells and recruitment of T-cells into noninflamed tumor tissues leading to tumor regression in a preclinical in vivo model. These data support clinical testing of the DLL3 /CD3 ITE in patients with SCLC . ©2020 American Association for Cancer Research.
Entities: Disease
Gene
Species
Year: 2020
PMID： 32554516 DOI： 10.1158/1078-0432.CCR-20-0926
Source DB: PubMed Journal: Clin Cancer Res ISSN： 1078-0432 Impact factor: 12.531