Abstract 5595: Statin drugs have anti-tumor activity and enhance responses to anti-PD-1 therapy in preclinical models of head and neck cancer
Authors: Burnham Andre J. , Kansal Vikash , Kinney Brendan L. , Paulos Chrystal M. , Lesinski Gregory B. , Saba Nabil F. , Schmitt Nicole C. 
Published: June 2022

Abstract
Background/Rationale: Head and neck squamous cell carcinoma (HNSCC) is a common malignancy with significant morbidity and mortality. Approximately half of patients with HNSCC develop recurrent or metastatic disease. Recently, anti-PD-1 immune checkpoint blockade was FDA-approved for first-line treatment of recurrent or metastatic disease, and although relatively well tolerated, only a minority of patients respond. There is an unmet clinical need for agents that enhance responses to anti-PD-1 therapy without excessive toxicity. HMG-CoA reductase inhibitors, also known as statin drugs, are in wide clinical use for hyperlipidemia and are inexpensive and well tolerated. Statin drugs are associated with superior survival outcomes in retrospective population studies of several cancers, including HNSCC. Moreover, statins may reduce multiple treatment-related toxicities, such as radiation-induced skin fibrosis and cisplatin chemotherapy-induced hearing loss. Emerging data suggest that statins may also enhance some aspects of anti-tumor immunity, but this has not been studied in HNSCC. Further, the pleiotropic effects of different statin drugs are highly variable. We hypothesized that a subset of statin drugs would enhance anti-tumor immunity and delay tumor growth in preclinical models of HNSCC.
Methods: Two immunocompetent, syngeneic murine models of oral cancer (MOC1 and MOC22) were used. To identify which of the seven FDA-approved statin drugs are capable of antitumor activity and enhancing T-cell induced killing, we used a high-throughput ex vivo co-culture assay of murine oral cancer cells and tumor infiltrating CD8+ T lymphocytes. Tumor-bearing mice were then treated with anti-PD-1 antibody (twice weekly IP) and/or statin drug (daily by oral gavage) for up to three weeks, and tumor kinetics and survival were tracked.
Results: When added at or near physiologic drug concentrations, all 7 statins strongly inhibited proliferation of MOC1 and MOC22 cell lines. Moreover, the combination of CD8+ T cells and a subset of statins mediated nearly two-fold tumor cell killing effect versus either treatment used alone. In mice, tumor growth delay did not reach statistical significance with statins or anti-PD-1 alone. However, combination therapy induced a significant tumor growth delay versus control mice (p&lt;0.05).
Conclusions: Our results have significant implications for both biologic mechanisms and therapeutic applications of statin drugs in HNSCC. Additional experiments to investigate the mechanisms by which statins inhibit tumor cell proliferation and enhance anti-tumor immunity are currently underway.
Funding: supported by Winship Cancer Institute and the Morningside Center for Innovative and Affordable Medicine.
Citation Format: Andre J. Burnham, Vikash Kansal, Brendan L. Kinney, Chrystal M. Paulos, Gregory B. Lesinski, Nabil F. Saba, Nicole C. Schmitt. Statin drugs have anti-tumor activity and enhance responses to anti-PD-1 therapy in preclinical models of head and neck cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5595.