Abstract C065: Dietary deprivation of non-essential amino acids improves anti-PD-1 immunotherapy in murine colon cancer

Cancer cells require outside supply of some non-essential amino acids (NEAAs) to survive, which is probably due to their rewired metabolism. Dietary deprivation of some NEAAs can slow down the growth of multiple solid tumors in mice, creating a new non-drug strategy in cancer treatment where immunotherapy represents one of the most promising technologies. However, it is not clear whether dietary NEAAs deprivation could be combined with immunotherapy for better safety-efficacy profiles. Deprivation of NEAAs could negatively impact the immune activation, an essential process for immunotherapy, because fast cell proliferation poses a higher demand for building blocks such as NEAAs. In this study, we tested the effects of NEAA-deprived diets and checkpoint inhibitor anti-PD-1 in colon cancer using syngeneic mouse model (BALB/c) bearing tumors of mouse colorectal cancer cell line CT-26. Three diets were tested, including a natural rodent diet Teklad ENVIGO Global 16% Protein Rodent Diet (control 1), a formulated NEAA-complete diet COMPLETE (control 2, using amino acid mix in place of protein), and a formulated NEAA-deprived diet FTN203 (treatment, using amino acid mix in place of protein). Both COMPLETE and FTN203 have the same nutritional structures, contain 17% w/w protein equivalent, and are isocaloric. After tumor size-based randomization, these diets were provided to mice ad libitum throughout the whole test. Each of these diets was used alone or combined with anti-PD-1 antibody (i.p., twice per week for 2 weeks) on mice. We found 1) On day 24 post tumor implantation, NEAAs-deprived diet FTN203 significantly reduced tumor growth when used alone, compared to the group fed with Teklad ENVIGO (by 49%, P=0.0054, unpaired t-test after Welch correction) and COMPLETE (by 50%, P=0.013), respectively; 2) The efficacy of FTN203 is comparable with that of anti-PD-1 in tumor growth and median survival; 3) FTN203 did not negate the efficacy of anti-PD-1 immunotherapy antibody when combined; 4) FTN203 significantly improved the efficacy of anti-PD-1 by further reducing the tumor growth (by 19% on day 26, P=0.046) and increasing the median survival (by 5 days or 14%, Log-rank test P= 0.031), against the combo of COMPLETE and anti-PD-1; 5) None of the mono or combo treatments caused body weight loss or altered tumor-infiltrating lymphocytes. Our data supports the use of dietary NEAAs deprivation to improve the efficacy of anti-PD-1 immunotherapy for colorectal cancer without noticeable side effects. With further development, dietary NEAA deprivation may become the promising foundation for a broad spectrum of cancer therapies. Citation Format: Zehui Li, Grace Yang, Shuang Zhou, Xin Wang, Xiyan Li. Dietary deprivation of non-essential amino acids improves anti-PD-1 immunotherapy in murine colon cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C065. doi:10.1158/1535-7163.TARG-19-C065