Abstract 3971: MEK inhibitors limit inflammatory cytokine production and modulate the immune response in the setting of Cholangiocarcinoma
| Autor: | Lauren Dennison, Matthew R. Farren, Gregory B. Lesinski, Amanda Ruggieri, Bassel El-Reyes, Mark Yarchoan, Nilofer S. Azad |
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| Rok vydání: | 2019 |
| Předmět: | |
| Zdroj: | Cancer Research. 79:3971-3971 |
| ISSN: | 1538-7445 0008-5472 |
| Popis: | Cholangiocarcinoma (CC) is a rare but aggressive cancer of the bile ducts with a five-year survival rate of only 2% in patients with metastatic disease. MAP kinase signaling is important in the pathogenesis of CC and serves as a key regulator of cell proliferation and survival. Our data indicate this pathway is constitutively active in several CC cell lines and accompanied by production of immunomodulatory cytokines including IL-6, MCP-1 and GM-CSF. Cobimetinib is a potent and selective inhibitor of MEK that has been utilized clinically in patients with advanced CC. Although MEK inhibitors (MEKi) have been studied in a variety of solid tumors, the mechanisms by which they act upon CC cells are not completely defined. These agents have modest single agent activity in CC, and their impact in combination with immunotherapy is under active investigation. We hypothesized that MEKi can modulate cytokine and chemokine expression from CC tumors, thereby complementing immunotherapy in this aggressive disease. Using a novel panel of human CC cell lines, we demonstrated a variable impact of cobimetinib on in vitro cell proliferation, with a reduction in viability no greater than 35%. However, MEKi reproducibly limited cytokine (GM-CSF and IL-1β) and chemokine (MIP-1α) production from human CC cell lines in vitro. The ability of cobimetinib to limit MAPK signal transduction in these cells was confirmed via immunoblot. These data complement prior published observations by Ebert et al.in 2016 indicating that single agent MEKi is sufficient to elicit T cell infiltration into tumors. We have completed enrollment of a Phase II clinical trial (NCT03201458) evaluating the efficacy of cobimetinib in combination with the PD-L1 inhibitor, atezolizumab. An extensive series of correlative studies are underway in peripheral blood and tumor biopsies to examine the impact of cobimetinib on modulating cytokine and chemokine signatures in the context of PD-L1 targeted therapy. These data will provide new insight into the impact of MEK inhibitors as a complement to immunotherapy in a disease that is refractory to most conventional therapies. Citation Format: Amanda N. Ruggieri, Matthew R. Farren, Mark Yarchoan, Nilofer S. Azad, Lauren Dennison, Bassel El-Reyes, Gregory B. Lesinski. MEK inhibitors limit inflammatory cytokine production and modulate the immune response in the setting of Cholangiocarcinoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3971. |
| Databáze: | OpenAIRE |
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