Department of Hematology, Amsterdam UMC, Vrije Universiteit, Amsterdam, The Netherlands.
Cancer Biology and Immunology, Cancer Center, Amsterdam, The Netherlands.
J Immunother Cancer. 2024 Jul 25;12(7):e008769. doi: 10.1136/jitc-2023-008769.
Autologous BCMA-specific CAR T-cell therapies have substantial activity in multiple myeloma (MM). However, due to logistical limitations and BCMA 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.
自体 BCMA 特异性 CAR T 细胞疗法在多发性骨髓瘤（MM）中具有显著的疗效。然而，由于物流限制和 BCMA 复发，需要寻找替代方法。UCARTCS1 细胞是一种“现成的”异体 CAR T 细胞，来源于针对 SLAMF7（CS1）的健康供体，该靶点在 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。
用 UCARTCS1 细胞或对照（未转导、SLAMF7/TCRαβ 双敲除）T 细胞以不同的效应物与靶细胞比值孵育转 Luciferase 的 MM 细胞系 24 小时。通过生物发光法评估 MM 细胞裂解。在 24 小时流式细胞术细胞毒性测定中，还评估了 UCARTCS1 在 29 例新诊断患者（n=10）、达雷妥尤单抗初治复发/难治患者（n=10）和达雷妥尤单抗难治患者（n=9）的 BM 样本中的抗 MM 活性。最后，评估了 UCARTCS1 在小鼠异种移植模型中的活性。
UCARTCS1 细胞诱导了强烈的 CAR 介导的、剂量依赖性的 MM 细胞系和原代 MM 细胞裂解。在预处理程度较重的患者和新诊断患者之间，UCARTCS1 的体外活性没有差异。此外，UCARTCS1 的疗效不受 MM 细胞上 SLAMF7 表达水平、肿瘤细胞比例或 BM 样本中调节性 T 细胞频率的影响。UCARTCS1 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，正常细胞的裂解程度较轻。此外，在 MM 异种移植模型中观察到 UCARTCS1 具有持久的抗 MM 反应。
这些结果表明，UCARTCS1 对 MM 细胞系和原代 MM 细胞具有强大的抗 MM 活性，并且在 MM 异种移植模型中也具有活性，支持在晚期 MM 患者中评估 UCARTCS1。
