A Phase 1b/2a Study to Assess the Safety, Pharmacokinetics, and Preliminary Efficacy of TU2218, an Oral TGFβR Serine/Threonine Kinase Inhibitor, Administered in Combination With Pembrolizumab in Patients With Advanced Solid Tumors

This study consists of phase 1b and 2a to evaluate safety, Pharmacokinetics, and efficacy of TU2218 in combination with Pembrolizumab in patients with advanced solid tumors. The main purpose of phase 1b is to determine the RP2DC of TU2218 and Pembrolizumab while the main purpose of phase 2a is to evaluate the antitumor efficacy of TU2218 in combination with Pembrolizumab in 3 different selected tumor type cohorts.

开始日期2023-03-10

申办/合作机构

TiumBio Co., Ltd.

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100 项与 TU-2218 相关的临床结果

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100 项与 TU-2218 相关的转化医学

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100 项与 TU-2218 相关的专利（医药）

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项与 TU-2218 相关的文献（医药）

Cancer Immunology, Immunotherapy

ALK5/VEGFR2 dual inhibitor TU2218 alone or in combination with immune checkpoint inhibitors enhances immune-mediated antitumor effects

Article

作者: Bae, Sowon ; Kim, Hun-Taek ; Lee, Jihyun ; Kim, Nam-Hoon ; Yu, Chan-Hee ; Kang, Seong-Ho ; Kim, Seung-Hyun ; Seo, Jeongmin

AbstractTransforming growth factor β (TGFβ) is present in blood of patients who do not respond to anti-programmed cell death (ligand) 1 [PD-(L)1] treatment, and through synergy with vascular endothelial growth factor (VEGF), it helps to create an environment that promotes tumor immune evasion and immune tolerance. Therefore, simultaneous inhibition of TGFβ/VEGF is more effective than targeting TGFβ alone. In this study, the dual inhibitory mechanism of TU2218 was identified through in vitro analysis mimicking the tumor microenvironment, and its antitumor effects were analyzed using mouse syngeneic tumor models. TU2218 directly restored the activity of damaged cytotoxic T lymphocytes (CTLs) and natural killer cells inhibited by TGFβ and suppressed the activity and viability of regulatory T cells. The inactivation of endothelial cells induced by VEGF stimulation was completely ameliorated by TU2218, an effect not observed with vactosertib, which inhibits only TGFβ signaling. The combination of TU2218 and anti-PD1 therapy had a significantly greater antitumor effect than either drug alone in the poorly immunogenic B16F10 syngeneic tumor model. The mechanism of tumor reduction was confirmed by flow cytometry, which showed upregulated VCAM-1 expression in vascular cells and increased influx of CD8 + CTLs into the tumor. As another strategy, combination of anti-CTLA4 therapy and TU2218 resulted in high complete regression (CR) rates in CT26 and WEHI-164 tumor models. In particular, immunological memory generated by the combination of anti-CTLA4 and TU2218 in the CT26 model prevented the development of tumors after additional tumor cell transplantation, suggesting that the TU2218-based combination has therapeutic potential in immunotherapy.

100 项与 TU-2218 相关的药物交易

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研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
胆道癌	临床2期	韩国	TiumBio Co., Ltd.	2024-10-04
结直肠癌	临床2期	韩国	TiumBio Co., Ltd.	2024-10-04
头颈部鳞状细胞癌	临床2期	韩国	TiumBio Co., Ltd.	2024-10-04
晚期恶性实体瘤	临床2期	美国	TiumBio Co., Ltd.	2023-03-10