Abstract 4038: TU2218 (TGFβRI/VEGFR2 dual inhibitor) maximizes the benefit of cancer immunotherapies

Abstract

Abstract Approved anti-PD-1 antibodies play a pivotal role in driving innovative clinical outcomes through combination with cytotoxic agents, targeted therapies, or other immune checkpoint inhibitors in various cancers. Anti-PD-1 antibody-based combination therapies have led to a paradigm shift in cancer treatment from cytotoxic agents or targeted therapy to immunotherapy. Considering this change in the regimen, the clinical development of TU2218 aims to accelerate approval and clinical application by improving the efficacy and safety of clinically proven combination therapies. TU2218 is characterized by the following four mechanisms of action: 1) improvement of T lymphocyte activity, 2) suppression of Treg, 3) improvement of costimulatory signal defects, and 4) overcoming endothelial cell anergy. Based on the mechanisms of action, TU2218 is expected to show significant clinical effects when combined with immune checkpoint inhibitors by lowering the intensity of immune evasion and changing more favorably to immune checkpoint inhibitors. To test the feasibility of various combination options based on TU2218, in vivo efficacy studies were conducted in 4T1, MC38, and CT26 syngeneic tumor models. In the 4T1 of TNBC type, a level of tumor reduction was significant to p<0.001 on TU2218 and anti-PD-1 antibody combination group compared to vehicle, whereas anti-PD-1 antibody alone or anti-PD-1 antibody and paclitaxel combination group was not significant. Combination therapy with anti-CTLA4 antibody and anti-PD-1 antibody has been approved for some cancers but has therapeutic limitations due to safety issues such as immune-related toxicity and needs improvement. In the MC38, the effectiveness of a dose-sparing strategy of anti-CTLA4 antibody was evaluated by adding TU2218 to the anti-CTLA4 antibody and anti-PD-1 antibody combination regimen to improve safety concerns. In the anti-CTLA4 antibody sparing group, co-administration of TU2218 maintained the anti-tumor activity despite reducing 90% or 60% of the original anti-CTLA4 antibody dose. In effect, the difference in anti-tumor activity between the group with a reduced dose of anti-CTLA4 antibody and the group without was not statistically significant. In CT26, the efficacy of Lenvatinib and anti-PD-1 antibody combination therapy was compared with the combination of Lenvatinib, anti-PD-1 antibody, and TU2218. The efficacy of the Lenvatinib anti-PD-1 antibody, and TU2218 combination group was superior to that of TGI 99% and CR 67% than the Lenvatinib and anti-PD-1 antibody combination group of TGI 76% and CR 17%. Moreover, a statistical difference in anti-tumor activity between the two groups was significant at p<0.001. Collectively, the combination therapies using TU2218 not only improved efficacy but also showed high safety profiles without weight loss or any toxicity signs, supporting the feasibility of the combination strategy of TU2218. Citation Format: Jihyun Lee, Nam-Hoon Kim, Jeong Su Park, Jihyun Noh, Sowon Bae, Hun-Taek Kim. TU2218 (TGFβRI/VEGFR2 dual inhibitor) maximizes the benefit of cancer immunotherapies [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 4038.