Abstract 5936: A novel class of orally bioavailable small molecules induces potent and sustained tumor growth inhibition and T cell infiltration in various solid tumor mouse models

Abstract The introduction of targeted immunomodulating agents has transformed cancer treatment over the last decade by demonstrating unprecedented efficacy in patients who respond. However, limited clinical response rates as well as adverse events underline the need to identify additional novel modalities in cancer immunotherapy. Here we report on the discovery of a novel class of low molecular weight compounds for oral application that selectively enhance tumor-reactive T cell cytotoxicity. Hit-to-lead development of compound hit series A was performed based on medicinal chemistry to investigate structure-activity-relations. A-306, a representative of the A compound class, induced increased T cell proliferation, elevated levels of the activation markers CD25 and CD69 as well as enhanced secretion of IFN-γ, IL-2 and TNF-α upon anti-CD3/CD28 stimulation. A-306 treatment without T cell receptor ligation had no effect on T cell activation, suggesting selective activation potential only in the context of antigen encounter. Furthermore, A-306 strengthened T-cell mediated killing of M21 melanoma cells and enhanced T cell function in response to viral antigens by showing a Th1 signature. Medicinal chemistry efforts resulted in front runner compounds A-481 and A-687 that show a similar profile and potencies down to nanomolar level. In a murine B16-SIY melanoma and EO771 breast cancer model oral single-agent administration with front runner compounds was well tolerated, showed good bioavailability in lymphoid organs and plasma and resulted in significant tumor growth inhibition beyond the end of treatment (D21). T cells from tumor draining lymph nodes of long-term surviving mice in both cancer models showed a distinct activation pattern indicative of anti-tumor immunity. Furthermore, oral application of A-481 in combination with intra peritoneal administration of anti-PD1 antibodies eradicated B16-SIY melanoma cells in a synergistic manner. Taken together, we report on the identification of a novel class of small molecules possessing high potential for selective anti-tumor activation of the immune system upon oral administration. Front runner compounds A-481 and A-687, which significantly inhibit tumor growth in a B16-SIY melanoma and EO771 breast cancer mouse model, lead to prolonged survival beyond the end of treatment and display a good safety profile. The final candidate compound will undergo testing in toxicity studies and enter a first-in-human trial in selected solid tumors in 2025. Citation Format: Bianca Gapp, Gunther Zischinsky, Maria Urban, Nora Birnbacher, Alice Schwarzböck, Sabine Grünaug, Tommaso Gastaldi, Anton Stütz, Peter Nussbaumer, Stefan Stranner, Julia Buchberger, Andreas Birbach, Daniela Schögl, Mario Kuttke, Alexander Dohnal, Romana Gugenberger. A novel class of orally bioavailable small molecules induces potent and sustained tumor growth inhibition and T cell infiltration in various solid tumor mouse models 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 (6Suppl): Abstract nr 5936.