肿瘤细胞治疗研究
英文原题：Anti-GPRC5D CAR T-cell therapy as a salvage treatment in patients with progressive multiple myeloma after anti-BCMA CAR T-cell therapy: a single-centre, single-arm, phase 2 trial.
抗 GPRC5D CAR-T 细胞挽救治疗可诱导高缓解率，对于抗 BCMA CAR-T 细胞治疗后进展的复发或难治性多发性骨髓瘤患者，可能是一种潜在的治疗选择。
背景：抗BCMA嵌合抗原受体（CAR）T细胞治疗后多发性骨髓瘤进展患者的最佳挽救治疗策略尚不明确。靶向GPRC5D的CAR-T细胞可能是一种选择。本试验旨在研究抗GPRC5D CAR-T细胞治疗抗BCMA CAR-T治疗后疾病进展患者的活性和安全性。方法：这项在中国徐州医科大学附属医院开展的开放标签、单臂2期试验，纳入18–70岁、接受抗BCMA CAR-T后疾病进展、预期寿命超过12周且无活动性感染及严重肝脏、心脏或其他疾病的复发/难治性多发性骨髓瘤患者。患者单次静脉输注每千克2×10^6个抗GPRC5D CAR-T细胞。主要终点为总缓解率，按国际骨髓瘤工作组标准缓解评估标准计算，包括严格完全缓解、完全缓解、非常好的部分缓解和部分缓解。按方案规定，对接受抗GPRC5D CAR-T细胞输注的患者进行疗效和安全性分析。试验在中国临床试验注册中心注册，编号ChiCTR2100048888，目前仍在进行。结果：2021年12月1日至2024年5月1日筛查42例，37例入组并接受抗GPRC5D CAR-T治疗。中位年龄59岁（四分位距51–65岁），男性17例（46%），女性20例（54%），均为亚洲人。中位随访12.6个月（四分位距8.2–20.8个月）时，总缓解率为84%（95% CI 68%–94%；31/37），其中13例（35%）达到完全缓解或更佳。最常见的3–4级不良事件为血液学毒性：37例中白细胞减少34例（92%）、淋巴细胞减少36例（97%）、中性粒细胞减少29例（78%）、贫血23例（62%）、血小板减少23例（62%）。37例中26例（70%）发生细胞因子释放综合征，其中2例（5%）为3级。观察到1例1级免疫效应细胞相关神经毒性综合征。试验中未发生治疗相关死亡。解读：抗GPRC5D CAR-T挽救治疗诱导了较高缓解率，可作为抗BCMA CAR-T治疗后进展的复发/难治性多发性骨髓瘤患者的潜在治疗选择。仍需进一步研究以确定该疗法的长期疗效和安全性。资金支持：中国国家自然科学基金及江苏省卫生健康委员会一般项目。
BACKGROUND: For patients with multiple myeloma progression after anti-BCMA chimeric antigen receptor (CAR) T-cell therapy, the optimal salvage treatment strategies remain unclear. GPRC5D-directed CAR T cell might be a potential option. The aim of this trial was to investigate the activity and safety of anti-GPRC5D CAR T cells in patients with progressive multiple myeloma after anti-BCMA CAR T-cell therapy. METHODS: In this phase 2, open-label, single-arm, phase 2 trial, at the Affiliated Hospital of Xuzhou Medical University in China, we enrolled patients (aged 18-70 years old) with relapsed or refractory multiple myeloma who had progressed disease after anti-BCMA CAR T-cell therapy and a life expectancy of more than 12 weeks without active infections, serious liver, heart, or other diseases. Patients were assigned to receive a single dose of intravenous anti-GPRC5D CAR T cell at 2 10 6 cells per kg. The primary endpoint was the overall response rate, including stringent complete response, complete response, very good partial response, and partial response, according to the standard International Myeloma Working Group response assessment criteria. Activity and safety analyses were done in the patients who received a dose of anti-GPRC5D CAR T cell as defined in the protocol. This trial is registered with the Chinese Clinical Trial Registration Center, ChiCTR2100048888, and is ongoing. FINDINGS: Between Dec 1, 2021, and May 1, 2024, 42 patients were screened, 37 were enrolled and received anti-GPRC5D CAR T-cell therapy. Median age was 59 years (IQR 51-65), 17 (46%) of 37 patients were male and 20 (54%) female. All patients were Asian. At a median follow-up of 12 6 months (IQR 8 2-20 8), the overall response rate was 84% (95% CI 68-94, 31 of 37 patients), including 13 (35%) complete responses or better. The most common grade 3-4 adverse events were haematological toxicities, including leukopenia (34 [92%] of 37 patients), lymphopenia (36 [97%]), neutropenia (29 [78%]), anaemia (23 [62%]), and thrombocytopenia (23 [62%]). 26 (70%) of 37 patients had cytokine release syndrome, which was of grade 3 in two (5%) patients. One case of grade 1 immune effector cell-associated neurotoxicity syndrome was observed. There were no treatment-related deaths in the trial. INTERPRETATION: Anti-GPRC5D CAR T-cell salvage therapy induced a high response rate, and could be a potential treatment option in relapsed or refractory multiple myeloma patients who have progressed after anti-BCMA CAR T-cell treatment. Further investigations are warranted to establish the long-term efficacy and safety of this therapeutic approach. FUNDING: National Natural Science Foundation of China and the General Project of Jiangsu Commission of Health.
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