Hutchings Martin, Korfi Koorosh, Montesinos Pau, Santoro Armando, Hou Hsin-An, Martinez-Sanchez Pilar, Vives Susana, Galimberti Sara, Chen Tsai-Yun, Frigeni Marco, Garciaz Sylvain, Salamero Garcia Olga, Yeh Su-Peng, Yee Karen, Esteve Jordi, Bajel Ashish, Fleming Shaun, Bretz Anne Catherine, Attig Jan, Sun Min, Nassiri Sina, Rutishauser Tobias, Klein Christian, Ma Y May, Schnetzler Gabriel, Vauleon Stephanie, Yu Huixin, Barata Teresa, Richard Muriel, Simon Silke, Hinton Heather, Keshelava Nino, Subklewe Marion
Department of Hematology and Phase 1 Unit, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
Blood Neoplasia. 2025 May 11;2(3):100110. doi: 10.1016/j.bneo.2025.100110. eCollection 2025 Aug.
A novel T-cell bispecific antibody (TCB), RO7283420, engaging CD3 and the HLA-A2-Wilms tumor protein 1 complex, was evaluated in this phase 1 study to characterize safety and tolerability, determine the maximum tolerated dose (MTD), and recommend a phase 2 dose for patients with relapsed/refractory acute myeloid leukemia in 2 groups: hematologic (group I, n = 57) and molecular (group 2, n = 5) relapse. In group I, 51 received RO7283420 intravenously (IV) and 6 subcutaneously. The IV doses ranged from 0.15-4 mg (flat; n = 13), 3-18 mg (step-up; n = 34) every 3 weeks, or 9 mg weekly (step-up; n = 4). The MTD was 1/3/12 mg every 3 weeks. The most frequent adverse event in the overall population was cytokine release syndrome (61.3%) with grade ≥3 recorded in 9.7% of patients. Twelve dose-limiting toxicities were reported in 11 patients and 12 (19.4%) grade 5 adverse events, including 1 hemophagocytic lymphohistiocytosis case related to RO7283420. Among the 42 efficacy-evaluable IV patients in group I, 4.8% achieved complete remission (CR), and 2.4% achieved CR with incomplete hematologic recovery. RO7283420 induced pharmacodynamic changes in peripheral blood (PB) at doses ≥1 mg, including significant T-cell activation and expansion in the PB and bone marrow (BM). Significant associations were found between blast reduction and baseline immunophenotype, including lower regulatory T cells and higher non-exhausted CD8 T cells in BM. Although dose escalation was discontinued because of limited efficacy and lack of an exposure-BM response relationship, the observed pharmacodynamics underscore the promising potential of this class of TCBs targeting intracellular antigens. This trial was registered at www.clinicaltrials.gov as #NCT04580121.
在这项1期研究中，对一种新型T细胞双特异性抗体（TCB）RO7283420进行了评估，该抗体可结合CD3和HLA - A2 - 威尔姆斯肿瘤蛋白1复合物，以确定其安全性和耐受性，确定最大耐受剂量（MTD），并为复发/难治性急性髓系白血病患者推荐2期剂量，分为两组：血液学复发组（I组，n = 57）和分子复发组（2组，n = 5）。在I组中，51例接受静脉注射（IV）RO7283420，6例接受皮下注射。静脉注射剂量范围为每3周0.15 - 4 mg（固定剂量；n = 13）、3 - 18 mg（剂量递增；n = 34）或每周9 mg（剂量递增；n = 4）。MTD为每3周1/3/12 mg。总体人群中最常见的不良事件是细胞因子释放综合征（61.3%），9.7%的患者记录为≥3级。11例患者报告了12例剂量限制性毒性，12例（19.4%）5级不良事件，包括1例与RO7283420相关的噬血细胞性淋巴组织细胞增生症病例。在I组42例可评估疗效的静脉注射患者中，4.8%达到完全缓解（CR），2.4%达到伴有血液学不完全恢复的CR。RO7283420在剂量≥1 mg时可诱导外周血（PB）中的药效学变化，包括PB和骨髓（BM）中显著的T细胞活化和扩增。在原始细胞减少与基线免疫表型之间发现了显著关联，包括BM中较低的调节性T细胞和较高的未耗竭CD8 T细胞。尽管由于疗效有限和缺乏暴露 - BM反应关系而停止了剂量递增，但观察到的药效学强调了这类靶向细胞内抗原的TCB的潜在前景。该试验已在www.clinicaltrials.gov上注册，编号为#NCT04580121。
