自体 BCMA 特异性 CAR T 细胞疗法在多发性骨髓瘤 (MM) 中具有显着的活性。然而，由于后勤限制和 BCMA 低复发，需要替代方案。 UCARTCS1 细胞是“现成的”同种异体 CAR T 细胞，源自健康供体，靶向 SLAMF7 (CS1)，该细胞在 MM 细胞中高度表达。在这项研究中，我们评估了 UCARTCS1 在 MM 细胞系、MM 患者骨髓 (BM) 样本和 MM 小鼠模型中的临床前活性。荧光素酶转导的 MM 细胞系与 UCARTCS1 细胞或对照细胞（非转导的 SLAMF7/TCRαβ 双敲除）T 细胞以不同的效应子与靶标比率持续 24 小时。通过生物发光评估MM细胞裂解。还在 24 小时内从新诊断患者 (n = 10)、未接受过 daratumumab 治疗的复发/难治性患者 (n = 10) 和 daratumumab 难治性患者 (n = 9) 获得的 29 个 BM 样本中评估了 UCARTCS1 的抗 MM 活性基于流式细胞术的细胞毒性测定。最后，在小鼠异种移植模型中评估了 UCARTCS1 活性。UCARTCS1 细胞诱导 MM 细胞系和原代 MM 细胞的有效 CAR 介导且剂量依赖性裂解。接受过大量治疗的患者和新诊断的患者之间 UCARTCS1 的离体活性没有差异。此外，UCARTCS1的功效不受MM细胞上SLAMF7表达水平、肿瘤细胞比例或从MM患者获得的BM样本中调节性T细胞频率的影响。 UCARTCS1治疗以剂量依赖性方式消除SLAMF7非恶性免疫细胞，但与MM细胞相比，正常细胞的裂解不太明显。此外，在 MM 异种移植模型中观察到 UCARTCS1 持久的抗 MM 反应。这些结果表明，UCARTCS1 对 MM 细胞系和原代 MM 细胞以及 MM 异种移植模型中具有有效的抗 MM 活性，并支持对 MM 异种移植模型的评估。 UCARTCS1 用于晚期 MM 患者。© 作者（或其雇主）2024。根据 CC BY-NC 允许重复使用。禁止商业再利用。请参阅权利和权限。英国医学杂志出版。

Autologous BCMA-specific CAR T-cell therapies have substantial activity in multiple myeloma (MM). However, due to logistical limitations and BCMAlow relapses, there is a need for alternatives. UCARTCS1 cells are 'off-the-shelf' allogeneic CAR T-cells derived from healthy donors targeting SLAMF7 (CS1), which is highly expressed in MM cells. In this study, we evaluated the preclinical activity of UCARTCS1 in MM cell lines, in bone marrow (BM) samples obtained from MM patients and in an MM mouse model.Luciferase-transduced MM cell lines were incubated with UCARTCS1 cells or control (non-transduced, SLAMF7/TCRαβ double knock-out) T-cells at different effector to target ratios for 24 hours. MM cell lysis was assessed by bioluminescence. Anti-MM activity of UCARTCS1 was also evaluated in 29 BM samples obtained from newly diagnosed patients (n=10), daratumumab-naïve relapsed/refractory patients (n=10) and daratumumab-refractory patients (n=9) in 24-hour flow cytometry-based cytotoxicity assays. Finally, UCARTCS1 activity was assessed in mouse xenograft models.UCARTCS1 cells induced potent CAR-mediated, and dose-dependent lysis of both MM cell lines and primary MM cells. There was no difference in ex vivo activity of UCARTCS1 between heavily pretreated and newly diagnosed patients. In addition, efficacy of UCARTCS1 was not affected by SLAMF7 expression level on MM cells, proportion of tumor cells, or frequency of regulatory T-cells in BM samples obtained from MM patients. UCARTCS1 treatment eliminated SLAMF7+ non-malignant immune cells in a dose-dependent manner, however lysis of normal cells was less pronounced compared to that of MM cells. Additionally, durable anti-MM responses were observed with UCARTCS1 in an MM xenograft model.These results demonstrate that UCARTCS1 has potent anti-MM activity against MM cell lines and primary MM cells, as well as in an MM xenograft model and support the evaluation of UCARTCS1 in patients with advanced MM.© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.