Abstract 5090: TU2218, a dual inhibitor against ALK5/VEGFR2, increases anti-CTLA4 antitumor efficacy in syngeneic tumor models

Field: Pharmacology, Toxicology and Pharmaceutics (Life Sciences)

Abstract The combination of pembrolizumab with low-dose ipilimumab shows substantial antitumor activity and manageable profile of toxicity in anti-PD-(L)1 antibody failure-setting (NCT02743819). This suggests a breakthrough for the absence of treatment option after relapsed/refractory anti-PD-(L)1 therapy. Accordingly, the anti-CTLA4 drug-based combination can be considered as a promising strategy for beneficial outcomes against resistance acquired from immunotherapy. Herein, we demonstrate that TU2218, a first-in-class, orally available inhibitor against ALK5 and VEGFR2, showed synergistic antitumor efficacy when combined with an anti-CTLA4 antibody in preclinical tumor models which is being accompanied by increasing ratio of CD8 T cell to regulatory T cell and enhanced immunological memory. In this work, antitumor efficacy of TU2218 combination with an anti-CTLA4 antibody was assessed with CT26-, 4T1-, B16F10- and WEHI-164-bearing mice. In the CT26 model, the combination of TU2218 with an anti-CTLA4 antibody significantly inhibited tumor growth up to 92% compared to vehicle, thus being superior to single treatments (e.g., tumor growth inhibition (TGI) 46% for TU2218, TGI 74% for anti-CTLA4). In this combination group, the complete regression (CR) rate was 75 % (i.e., six cases among eight mice), while single treatments showed lower CR rates (e.g., CR 10% (1/10) for TU2218, CR 30% (3/10) for anti-CTLA4). Meanwhile, the role of CD8+ T cell in antitumor activity was elucidated by in vivo depleting CD8+ T cell in mice treated with combination therapy. The depletion of CD8+ T cells reduced the antitumor response, which suggests the indispensable role of CD8+ T cells in the antitumor efficacy of TU2218 and anti-CTLA-4 antibody combination. In addition, the long-term immune-memory was evaluated by re-implanting tumor cells into both mice cured by combination therapy and age-matched tumor-naïve mice. In this case, 6 mice cured of original implantation with CT26 tumors showed complete resistance to the re-implantation of CT26 cells during an untreated period for 21 days, whereas all age-matched tumor-naïve mice have developed tumors after 10 days from cell-transplants. Importantly, we could confirm the positive correlation between the immunological memory-response of combination therapy and the increasing rate of effector memory CD4+ and CD8+ T cells in spleens compared to those of age-matched group. In 4T1-, B16F10- and WEHI-164-bearing mice, combination of TU2218 with an anti-CTLA4 antibody led to higher CR rate as well as enhanced inhibition of tumor growth. Overall, our findings showed that TU2218 plays multifaceted roles in inducing immune activation under combination with an anti-CTLA4 antibody, which may be attributed to the increased ratio of cytotoxic CD8 T cell to regulatory T cell and improvement of adaptive immunity with long-term immunological memory. Citation Format: Nam-Hoon Kim, Jihyun Lee, Hun-Taek Kim. TU2218, a dual inhibitor against ALK5/VEGFR2, increases anti-CTLA4 antitumor efficacy in syngeneic tumor models. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5090.