Lenvatinib Plus Anti-PD-1 Combination Therapy for Advanced Cancers: Defining Mechanisms of Resistance in an Inducible Transgenic Model of Thyroid Cancer

• DOI: 10.1089/thy.2021.0371
• Publication Date: 2021-10-13T06:39:50Z
• Authors: Bruna C. Bertol; Elise S. Bales; Jacob D. Calhoun; Alanna Mayberry; Melissa L. Ledezma; Sharon B. Sams; David J. Orlicky; Eduardo A. Donadi; Bryan R. Haugen; Jena D. French
• Keywords: Lenvatinib; Acquired resistance

Background: Combination therapy with lenvatinib plus programmed death-1 (PD-1) immune checkpoint blockades (ICBs) is under investigation in many solid tumors, including thyroid cancer. Lenvatinib known to reduce angiogenesis and may overturn the immunosuppressive effects of vascular endothelial growth factor tumor microenvironment. Previous studies investigating VEGF receptor inhibition on response were performed rapidly growing models where equilibrium not established before treatment. We hypothesize that physiologically relevant preclinical are necessary define mechanisms resistance immune-targeted combination therapies. Methods: utilized TPO-CreER/BrafV600E/wt/Trp53Δex2–10/Δex2–10 inducible transgenic model advanced cancer investigate treatment context an anti-PD-1 ICB. Following establishment, 3.5 months postinduction, mice treated high- (10 mg/kg) or low-dose (2 lenvatinib, anti-PD-1, anti-PD-1. Tumor volume lung metastases assessed each group. Immune infiltrate was characterized by flow cytometry immunohistochemistry, TCRß sequencing further T cell response. Results: Both low- high-dose reduced volume, while had no effect, alone combination. Although both density, superior controlling size. Lung survival improved despite primary Low-dose led a subtle reduction dominant Ly6G+CD11b+ myeloid population associated increased CD4+ enrichment 4–1BB+ granzyme B+ cells FoxP3+ regulatory cells. Polyclonal expansion evident majority mice, suggesting tumor-specific generated. Conclusions: The most pronounced dose should be considered clinical application. While immune-modulating potential encouraging, alterations milieu activation status insufficient sustain durable regression, even added Additional develop more effective approaches low-mutation burden such as