Banner MD Anderson Cancer Center, Gilbert, Arizona.
Sarah Cannon Research Institute, Nashville, Tennessee.
Transplant Cell Ther. 2024 Feb;30(2):241.e1-241.e8. doi: 10.1016/j.jtct.2023.10.014. Epub 2023 Oct 26.
The antibody-coupled T cell receptor (ACTR) platform is an autologous engineered T cell therapy combining the cell-killing ability of T cells and the tumor-targeting ability of coadministered antibodies. Activation of the T cell product ACTR707 is dependent on the engagement of antibody bound to target cells via the CD16 domain of the chimeric receptor (CD16V-CD28-CD3ζ). ACTR707 in combination with the anti-CD20 monoclonal antibody rituximab was evaluated in the ATTCK-20-03 study, a multisite, single-arm, open-label phase I trial in B cell non-Hodgkin lymphoma (NHL). The primary objectives of this study were to evaluate the safety of the combination of ACTR707 and rituximab and to determine a recommended phase 2 dose (RP2D). Secondary objectives included evaluation of antitumor activity and ACTR T cell persistence. The study design included an ACTR707 cell dose escalation phase and an expansion phase at the RP2D. Escalating dose levels of ACTR707 in combination with rituximab were explored in 5 dose cohorts, with 25 subjects receiving study treatment. Subjects received lymphodepleting chemotherapy (cyclophosphamide 400 mg/m/day and fludarabine 30 mg/m/day) for 3 days, followed by rituximab 375 mg/m and, 24 to 48 hours later, a single dose of ACTR707. Additional doses of rituximab were administered every 3 weeks until disease progression, unacceptable toxicity, or investigator decision. Blood samples were collected at various time points to assess levels of rituximab, cytokines, inflammatory markers, and ACTR707 T cells. The overall response rate of ACTR707 plus rituximab was 56% (14 of 25) across all dose levels. Ten subjects (40.0%) achieved a complete response, with the longest duration of 586 days (range, 85 to 586 days), and 4 subjects (16.0%) experienced a partial response, with the longest duration of 130 days (range, 44 to 130 days). Only 1 case of cytokine release syndrome (grade 2) and no events of neurotoxicity were reported. There were no dose-limiting toxicities or events leading to death. ACTR707 plus rituximab resulted in only 1 adverse event (neutropenia), leading to study discontinuation of rituximab. The ATTCK-20-03 trial serves as proof of principle regarding the ACTR approach that potentially could be used with other antibodies targeting other markers in other malignancies. Although the ACTR707 program has been discontinued, these results may support other programs in the use of similar novel approaches of antibody-coupled T cell activation.
抗体偶联的 T 细胞受体（ACTR）平台是一种自体工程化的 T 细胞疗法，结合了 T 细胞的细胞杀伤能力和联合使用的抗体的肿瘤靶向能力。ACTR707 的激活依赖于通过嵌合受体（CD16V-CD28-CD3ζ）的 CD16 结构域与靶细胞结合的抗体的结合。在 ATTCK-20-03 研究中评估了 ACTR707 与抗 CD20 单克隆抗体利妥昔单抗的联合应用，这是一项在 B 细胞非霍奇金淋巴瘤（NHL）中的多中心、单臂、开放标签 I 期试验。这项研究的主要目的是评估 ACTR707 和利妥昔单抗联合应用的安全性，并确定推荐的 2 期剂量（RP2D）。次要目标包括评估抗肿瘤活性和 ACTR T 细胞的持久性。研究设计包括 ACTR707 细胞剂量递增阶段和 RP2D 扩展阶段。在 5 个剂量组中探索了与利妥昔单抗联合使用的递增剂量的 ACTR707，每组有 25 名受试者接受治疗。受试者接受为期 3 天的淋巴细胞耗竭化疗（环磷酰胺 400mg/m/天和氟达拉滨 30mg/m/天），然后给予利妥昔单抗 375mg/m，并在 24 至 48 小时后给予单次剂量的 ACTR707。每 3 周给予额外剂量的利妥昔单抗，直到疾病进展、不可接受的毒性或研究者决定为止。采集各种时间点的血液样本，以评估利妥昔单抗、细胞因子、炎症标志物和 ACTR707 T 细胞的水平。在所有剂量水平下，ACTR707 加利妥昔单抗的总体反应率为 56%（25 名受试者中的 14 名）。10 名受试者（40.0%）达到完全缓解，最长缓解时间为 586 天（范围为 85 至 586 天），4 名受试者（16.0%）出现部分缓解，最长缓解时间为 130 天（范围为 44 至 130 天）。仅报告了 1 例细胞因子释放综合征（2 级）和无神经毒性事件。没有剂量限制性毒性或导致死亡的事件。ACTR707 加利妥昔单抗仅导致 1 例不良事件（中性粒细胞减少症），导致利妥昔单抗研究终止。ATTCK-20-03 试验证明了 ACTR 方法的原理，该方法可能与其他针对其他恶性肿瘤中其他标志物的抗体一起使用。尽管 ACTR707 项目已被终止，但这些结果可能支持其他项目使用类似的新型抗体偶联 T 细胞激活方法。
