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  P15 - Immuno-biology and Novel Immunotherapeutics (Phase I and Translational) - Novel Immunotherapeutics (Phase I) (ID 154)

  • Event: WCLC 2020
  • Type: Posters
  • Track: Immuno-biology and Novel Immunotherapeutics (Phase I and Translational)
  • Presentations: 1
  • Moderators:
  • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall

  • 35427

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    P15.01 - AMG 757, a Half-Life Extended Bispecific T-Cell Engager (HLE BiTE® Immune Therapy) Targeting DLL3, for the Treatment of Small Cell Lung Cancer (ID 1289)

    00:00 - 00:00  |  Presenting Author(s): Keegan Cooke
    • Abstract
    • Slides

    Introduction
    

    Small cell lung cancer (SCLC) is an aggressive neuroendocrine tumor characterized by initial response to chemotherapy and radiotherapy followed by relapse and rapid progression. Delta-like ligand 3 (DLL3) is an inhibitory Notch ligand that is highly expressed on the surface of most SCLC tumors; DLL3 expression is minimal and mainly cytoplasmic in normal tissues. AMG 757 is an investigational HLE BiTE immune therapy designed to redirect cytotoxic T cells to SCLC cells by binding to DLL3 on tumor cells and CD3 on T cells, resulting in T-cell activation and expansion and T cell–dependent killing of tumor cells.

    Methods
    

    We evaluated the efficacy and pharmacodynamic effects of AMG 757 treatment in three preclinical models of SCLC that express DLL3. The LXFS 1129 patient-derived xenograft (PDX) model develops into subcutaneous tumors in mice. The SHP-77 orthotopic model forms diffuse tumors in the lungs, similar to primary SCLC tumors. The NCI-H82 orthotopic model forms 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 followed by treatment with AMG 757 or a control HLE BiTE molecule.

    Results
    

    In the LXFS 1129 PDX model, treatment with AMG 757 induced complete tumor regression in 8 of 10 mice; treatment with the control HLE BiTE molecule did not inhibit tumor growth. In the orthotopic SHP-77 model, AMG 757 treatment led to significant tumor growth inhibition in the lungs relative to treatment with a control HLE BiTE molecule. In AMG 757–treated mice, increased T-cell trafficking and expansion were observed in tumors, and human CD4+ and CD8+ cell numbers increased significantly in the lungs. In the orthotopic NCI-H82 model, AMG 757 treatment cleared visible lesions from the liver. AMG 757 treatment was associated with increased CD8+ T-cell infiltration and upregulation of the T-cell surface activation markers CD25, CD69, PD-1, and 4-1BB.

    Conclusion
    

    These preclinical data show that AMG 757 can recruit and engage T cells to solid 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. These studies also support the clinical exploration of AMG 757 in patients with extensive disease (ED) SCLC. We are conducting an open-label, ascending, multiple-dose, phase 1 study evaluating AMG 757 as monotherapy and in combination with pembrolizumab in patients with relapsed/refractory ED SCLC who progressed or recurred following at least 1 platinum-based chemotherapy regimen. The study is open and recruiting patients. ClinicalTrials.gov identifier: NCT03319940.

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