功能性阻断转化生长因子-β (TGFβ) 信号通路可提高细胞毒性和免疫疗法的疗效。在此，我们进行了一项 1b 期研究（ClinicalTrials.gov.，NCT03143985），以确定口服 TGFβ I 型受体激酶抑制剂 vactosertib 联合用药的安全性、耐受性和最大耐受剂量（200mg，每日两次）的主要终点泊马度胺治疗已接受≥2 种化学免疫疗法的复发性和/或难治性多发性骨髓瘤 (RRMM) 患者。次要终点显示出持续的临床反应、良好的药代动力学参数和 82% 的 6 个月无进展生存率。 Vactosertib 联合泊马度胺在所有剂量水平下均具有良好的耐受性，并且不良事件情况可控。探索性分析表明，vactosertib 与泊马度胺联合治疗还降低了患者骨髓中的 TGFβ 水平以及表达免疫抑制标记物 PD-1 的 CD8 T 细胞的水平。体外实验表明，vactosertib pomalidomide 联合治疗降低了 MM 细胞系和患者肿瘤细胞的活力，并增加了 CD8 T 细胞的细胞毒活性。 Vactosertib 是一种安全的治疗药物，具有肿瘤内在活性，可以克服肿瘤微环境中的免疫抑制挑战，从而重振 T 细胞健康。 Vactosertib 有望改善对传统药物耐药的、经过大量治疗的 MM 患者的免疫治疗反应。© 2024。作者。

Functional blockade of the transforming growth factor-beta (TGFβ) signalling pathway improves the efficacy of cytotoxic and immunotherapies. Here, we conducted a phase 1b study (ClinicalTrials.gov., NCT03143985) to determine the primary endpoints of safety, tolerability, and maximal tolerated dose (200 mg twice daily) for the orally-available TGFβ type I receptor kinase inhibitor vactosertib in combination with pomalidomide in relapsed and/or refractory multiple myeloma (RRMM) patients who had received ≥2 lines of chemoimmunotherapy. Secondary endpoints demonstrated sustained clinical responses, favorable pharmacokinetic parameters and a 6-month progression-free survival of 82%. Vactosertib combined with pomalidomide was well-tolerated at all dose levels and displayed a manageable adverse event profile. Exploratory analysis indicated that vactosertib co-treatment with pomalidomide also reduced TGFβ levels in patient bone marrow as well as the level of CD8+ T-cells that expressed the immunoinhibitory marker PD-1. In vitro experiments indicated that vactosertib+pomalidomide co-treatment decreased the viability of MM cell lines and patient tumor cells, and increased CD8+ T-cell cytotoxic activity. Vactosertib is a safe therapeutic that demonstrates tumor-intrinsic activity and can overcome immunosuppressive challenges within the tumor microenvironment to reinvigorate T-cell fitness. Vactosertib offers promise to improve immunotherapeutic responses in heavily-pretreated MM patients refractory to conventional agents.© 2024. The Author(s).