Abstract 4438: Time restricted eating improves antitumor immune responses via modulation of insulin-like growth factor 1 in patients with head and neck cancer

Abstract Background- Treatment of metastatic head and neck cancer remains an area of unmet need with median survival less than a year. We tested the efficacy of a novel circadian aligned fasting intervention called “time restricted eating” (TRE), to improve ICB response in tumor bearing head and neck syngeneic mice models (MOC1), and showed significant reduction in tumor growth, which we then recapitulated in a pilot, open labeled, interventional clinical trial in 30 metastatic head and neck cancer patients. We noted significant improvement in median progression free survival (5 months vs not reached (NR), HR-0.2, p-0.0008) and overall survival (8 months vs NR, HR-0.00000045) in patients observing TRE vs those who did not. The favorable effect of TRE was mediated via modulation of gut microbiome, microbial tryptophan metabolome, and insulin signalling, specifically reduction in circulating insulin-like growth factor 1 (IGF1). We hypothesized that IGF1 mediates ICB resistance via protecting tumor cells from cytotoxic T cell activity. Methods- We performed in vitro luciferase cytotoxicity assays using HLA-A2+NY-ESO+ squamous cell cancer 4 (SCC-4) human cancer cells as targets, and HLA-A2-restricted NY-ESO-1-specific T cell receptor (TCR) -transduced T cells. We co-cultured the tumor cells and the T cells for 24 hours under different conditions of IGF-1 concentration (100 ng, 50 ng, and 10 ng) and T cell-to-tumor cell ratio (1:5, 1:10, and 1:20). We also treated the tumor cells with IGF-1 alone to assess its direct cytotoxic effect. Results We observed that IGF-1 impaired the ability of the T cells to kill the tumor cells in a dose-dependent manner, while IGF-1 had no cytotoxic effect on the tumor cells in the absence of T cells. Conclusion- While the role of IGF1 in treatment resistance has been described, its role and mechanism in antitumor immune response is largely unknown. We, for the first time demonstrate the role of IGF1 in impairing T cell mediated antitumor activity in a dose dependent fashion, thus contributing to ICB resistance. Further work will help us develop alternative strategies to modulate IGF1 and improve ICB resistance, in patients who are unable to tolerate TRE. Citation Format: Mostafa Eysha, Carmen A. Galindo, Jameel Muzaffar, Jessica Mine, Ricardo Chauriogonzalez, Mariam Baig, Luis Lopez-bailon, Muhammad Alhomsi, Mahmoud Hathout, Jiangbo Wang, Wanyu Zhang, Daliya Rizvi, Angie Huang, Kate Lee, Daniel Kye, Amit Sen, Jose Conejo-Garcia, Shahla Bari. Time restricted eating improves antitumor immune responses via modulation of insulin-like growth factor 1 in patients with head and neck cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4438.