肿瘤细胞治疗研究
英文原题：GPRC5D-targeted CAR T-cell therapy (CT071) in patients with relapsed or refractory multiple myeloma: a first-in-human, single-centre, single-arm, phase 1 trial.
CT071 在复发/难治性多发性骨髓瘤患者中显示出令人鼓舞的安全性特征和引人注目的活性。
背景：复发或难治性多发性骨髓瘤仍无法治愈。CT071是一种全人源、自体、靶向G蛋白偶联受体C类第5组成员D（GPRC5D）的嵌合抗原受体（CAR）T细胞疗法，具有快速制造特点。本试验旨在评估CT071治疗复发或难治性多发性骨髓瘤的初步活性、安全性及细胞动力学。方法：这项首次人体、单中心、单臂I期研究在中国上海长征医院开展。符合条件者年龄≥18岁，患复发或难治性多发性骨髓瘤，既往接受≥3线治疗（包括蛋白酶体抑制剂和免疫调节剂），或对两类药物均难治，并且末线治疗期间疾病进展；ECOG体能状态须为0–2。患者接受每公斤0.1×10^6或0.3×10^6个CAR-T细胞。主要终点为安全性，包括剂量限制性毒性、不良事件及剂量确定；活性为次要终点。所有接受CT071的患者均纳入安全性和疗效分析。本试验在ClinicalTrials.gov注册（NCT05838131），目前已完成入组。结果：2023年4月28日至2024年6月21日，共入组并接受单采的23例患者中，3例在单采后被排除（1例因疾病快速进展停止，1例因活动性感染，1例因CAR-T制造失败退出），最终20例接受输注。中位年龄63.0岁（IQR 53.0–65.5）；12例（60%）为男性，8例（40%）为女性，所有患者均为中国人。中位随访10.71个月（IQR 6.13–12.02）。未观察到剂量限制性毒性，推荐II期剂量确定为每公斤0.1×10^6个CAR-T细胞。最常见的≥3级治疗相关不良事件为血液学毒性，所有患者均发生。20例中12例（60%）发生CRS，均为1–2级；1例（5%）发生3级ICANS。7例（35%）发生严重治疗相关不良事件，未发生治疗相关死亡。皮肤不良事件包括4例（20%）甲分离和1例（5%）皮疹，均为1级。客观缓解率为100%（95% CI 83.2–100），完全缓解或更好比例为50%（20例中10例）。解读：CT071在复发或难治性多发性骨髓瘤患者中显示出令人鼓舞的安全性及显著活性。经费：国家自然科学基金和上海市医院发展中心临床研究计划。
BACKGROUND: Relapsed or refractory multiple myeloma remains incurable. CT071 is a fully human, autologous, chimeric antigen receptor (CAR) T-cell therapy directed against G protein-coupled receptor class C group 5 member D (GPRC5D), with expedited manufacturing. This trial aimed to assess the preliminary activity, safety, and cellular kinetics of CT071 in relapsed or refractory multiple myeloma. METHODS: This first-in-human, single-centre, single-arm, phase 1 study was conducted in China at Shanghai Changzheng Hospital. Eligible patients were aged 18 years or older with relapsed or refractory multiple myeloma who had received three or more previous lines of therapy including a proteasome inhibitor and an immunomodulatory agent, or had double-class refractory therapy, and had progressive disease on the last line of therapy. Eastern Cooperative Oncology Group performance status 0-2 was required. Patients received CT071 at 0 1 10 6 CAR T cells per kg or 0 3 10 6 CAR T cells per kg. The primary endpoint was safety, which included dose-limiting toxicities, adverse events, and dose determination. Activity was also evaluated as a secondary endpoint. All patients receiving CT071 were included in the safety and activity analyses. This trial is registered with ClinicalTrials.gov (NCT05838131) and enrolment is complete. FINDINGS: Between April 28, 2023, and June 21, 2024, 23 patients were enrolled and underwent apheresis. Three patients were excluded after apheresis (one discontinued due to rapid disease progression, one due to active infection, and one was withdrawn because of failed manufacture of CAR T cells), thus 20 patients were infused. Median age was 63 0 years (IQR 53 0-65 5). 12 (60%) of 20 patients were male and eight (40%) were female; all patients were Chinese. Median follow-up was 10 71 months (IQR 6 13-12 02). No dose-limiting toxicities were observed, and the recommended phase 2 dose was determined at 0 1 10 6 CAR T cells per kg. Haematological toxicities were the most common grade 3 or worse treatment-related adverse events, occurring in all patients. Cytokine release syndrome occurred in 12 (60%) of 20 patients, all of which were grade 1-2. One (5%) patient had grade 3 immune effector cell-associated neurotoxicity syndrome. Serious treatment-related adverse events were reported in seven (35%) patients; no treatment-related deaths occurred. Skin-related events included onychomadesis reported in four (20%) patients and rash in one (5%) patient, all of which were grade 1. The objective response rate was 100% (95% CI 83 2-100), with a complete response or better rate of 50% (ten of 20 patients). INTERPRETATION: CT071 demonstrated an encouraging safety profile with compelling activity in patients with relapsed or refractory multiple myeloma. FUNDING: National Natural Science Foundation of China and Clinical Research Plan of Shanghai Hospital Development Center.
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