Abstract 4558: Antitumor activity of AMG757, a half-life extended (HLE) bispecific T-cell engager (BiTE®) immune therapy targeting DLL3, in human PDX and orthotopic mouse models of small cell lung cancer (SCLC)
Authors: Cooke Keegan , Estrada Juan , Zhan Jinghui , Werner Jonathan , Caenepeel Sean , Giffin Mike , Bailis Julie M. , Coxon Angela , Hughes Paul E. , Canon Jude 
Published: September 2020

SCLC is a highly aggressive neuroendocrine tumor with poor prognosis and limited therapeutic options. Delta-like ligand 3 (DLL3) is a tumor-associated antigen that is highly specific for SCLC; expression is elevated in tumors but minimal and mainly cytoplasmic in normal tissues. AMG 757 is an HLE BiTE® immune therapy that is designed to redirect T-cell cytotoxicity to cancer cells by binding to DLL3 on the surface of cancer cells and CD3 on T cells. AMG 757 is being evaluated in a phase 1 clinical trial in patients with relapsed/refractory SCLC (NCT03319940). We evaluated the efficacy and pharmacodynamic (PD) effects of AMG 757 in three preclinical models of SCLC that express DLL3. We used the LXFS 1129 patient-derived xenograft (PDX) model to assess AMG 757 efficacy in established, subcutaneously implanted tumors similar to human SCLC tumors with their associated stroma. We also developed two orthotopic models of SCLC (SHP-77 and H82) to assess AMG 757 efficacy and PD at biologically relevant sites. In the SHP-77 orthotopic model, cells injected intravenously trafficked to the lungs where they formed diffuse tumors similar to primary SCLC tumors. In the H82 orthotopic model, cells injected intravenously formed discrete metastatic lesions in the liver, mimicking a major site for SCLC metastasis. In each model, mice bearing established tumors received a single infusion of human T cells and were then dosed with AMG 757 or a control HLE BiTE molecule. In the LXFS 1129 PDX model, treatment with AMG 757 induced complete tumor regression in 8 out of 10 mice, whereas treatment with the control HLE BiTE molecule showed no tumor growth inhibition. In the orthotopic SHP-77 model, treatment with AMG 757 led to significant tumor growth inhibition in the lungs relative to treatment with a control HLE BiTE molecule; the bioluminescence (BLI) signal decreased to near the limit of detection 22 days after start of treatment. AMG 757 antitumor activity was associated with increased T-cell trafficking and expansion in tumors; a single dose of AMG 757 significantly increased the number of human CD4+ and CD8+ cells in lungs as assessed by flow cytometry. In the orthotopic H82 model, AMG 757 treatment completely cleared visible lesions from the liver, as assessed by a decrease in BLI to near-background levels and macroscopic analysis of the liver tissue. AMG 757 antitumor activity was associated with increased CD8+ T-cell infiltration as assessed by flow cytometry and IHC and upregulation of the T cell surface activation markers CD25, CD69, PD-1, and 4-1BB as assessed by flow cytometry. Together, these preclinical data demonstrate that AMG 757 can recruit and engage T cells to tumors, consistent with the BiTE® mechanism of action, and that AMG 757-mediated redirected T-cell lysis can drive significant antitumor activity in established SCLC tumor models.

Citation Format: Keegan Cooke, Juan Estrada, Jinghui Zhan, Jonathan Werner, Sean Caenepeel, Mike Giffin, Julie M. Bailis, Angela Coxon, Paul E. Hughes, Jude Canon. Antitumor activity of AMG757, a half-life extended (HLE) bispecific T-cell engager (BiTE®) immune therapy targeting DLL3, in human PDX and orthotopic mouse models of small cell lung cancer (SCLC) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4558.