Dian Zhou, Qian Sun, Jieyun Xia, Weiying Gu, Jun Qian, Wanchuan Zhuang, Zhiling Yan, Hai Cheng, Wei Chen, Feng Zhu, Kunming Qi, Depeng Li, Wei Sang, Lili Zhu, Sha Ma, Hujun Li, Huanxin Zhang, Tingting Qiu, Dongmei Yan, Yanlei Zhang, Shuixiu Peng, Alex H Chang, Kailin Xu, Zhenyu Li
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The trial enrolled patients aged 18-75 years with relapsed or refractory multiple myeloma and an Eastern Cooperative Oncology Group performance status of 0-3. Anti-BCMA/GPRC5D bispecific CAR T cells were administered at 0·5 × 10<sup>6</sup>, 1·0 × 10<sup>6</sup>, 2·0 × 10<sup>6</sup>, and 4·0 × 10<sup>6</sup> CAR T cells per kg in the dose-escalation phase, with additional patients included at the dose selected for the dose-expansion phase. The primary endpoint was safety, which included dose-limiting toxicity and maximum tolerated dose. Activity was also evaluated as a secondary endpoint. The maximum tolerated dose was chosen for the dose-expansion phase. Safety and activity analyses were done in all patients who received anti-BCMA/GPRC5D bispecific CAR T cells as defined in the protocol. This trial is registered with ClinicalTrials.gov (NCT05509530) and is complete.</p><p><strong>Findings: </strong>Between Sept 1, 2022, and Nov 3, 2023, 24 patients were enrolled and underwent apheresis. Three patients were excluded after apheresis (two patients discontinued due to rapid disease progression and one patient was withdrawn because of failed manufacture of CAR T cells), so 21 patients were infused with anti-BCMA/GPRC5D bispecific CAR T cells. Median follow-up was 5·8 months (IQR 5·2-6·7). Median age was 62 years (IQR 56-67). Eight (38%) patients were male, and 13 (62%) female. All patients were Chinese. At the 4·0 × 10<sup>6</sup> CAR T cells per kg dose, two patients had dose-limiting toxicities, of whom one died of subarachnoid haemorrhage (which was not considered to be related to the study treatment). The maximum tolerated dose was identified as 2·0 × 10<sup>6</sup> CAR T cells per kg. The most common grade 3 or worse adverse events were haematological toxicities in 19 (90%) patients (except lymphopenia). 15 (71%) patients had cytokine release syndrome, of which all cases were grade 1 or 2. One case of grade 1 immune effector cell-associated neurotoxicity syndrome (ICANS) was observed in a patient who received 4·0 × 10<sup>6</sup> CAR T cells per kg. No ICANS or grade 3 or worse organ toxicities were observed in patients who received 0·5-2·0 × 10<sup>6</sup> CAR T cells per kg. The overall response rate was 86% (18 of 21 patients), with 13 (62%) patients having a complete response or better, and 17 (81%) patients having measurable residual disease negativity. Of the 12 patients who received 2·0 × 10<sup>6</sup> CAR T cells per kg (three in the dose-escalation phase and an addition nine in the dose-expansion phase), the overall response rate was 92% (11 of 12 patients) with nine (75%) patients having a complete response or better.</p><p><strong>Interpretation: </strong>Anti-BCMA/GPRC5D bispecific CAR T cells show a good safety profile and encouraging activity in patients with relapsed or refractory multiple myeloma.</p><p><strong>Funding: </strong>National Natural Science Foundation of China.</p><p><strong>Translation: </strong>For the Chinese translation of the abstract see Supplementary Materials section.</p>","PeriodicalId":48726,"journal":{"name":"Lancet Haematology","volume":null,"pages":null},"PeriodicalIF":15.4000,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Anti-BCMA/GPRC5D bispecific CAR T cells in patients with relapsed or refractory multiple myeloma: a single-arm, single-centre, phase 1 trial.\",\"authors\":\"Dian Zhou, Qian Sun, Jieyun Xia, Weiying Gu, Jun Qian, Wanchuan Zhuang, Zhiling Yan, Hai Cheng, Wei Chen, Feng Zhu, Kunming Qi, Depeng Li, Wei Sang, Lili Zhu, Sha Ma, Hujun Li, Huanxin Zhang, Tingting Qiu, Dongmei Yan, Yanlei Zhang, Shuixiu Peng, Alex H Chang, Kailin Xu, Zhenyu Li\",\"doi\":\"10.1016/S2352-3026(24)00176-5\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Some challenges still exist with single-target B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T-cell therapies due to variable or negative BCMA expression, although they have yielded remarkable efficacy in relapsed or refractory multiple myeloma. 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引用次数: 0
摘要
背景：尽管单靶点B细胞成熟抗原（BCMA）嵌合抗原受体（CAR）T细胞疗法在复发或难治性多发性骨髓瘤中取得了显著疗效，但由于BCMA表达可变或阴性，该疗法仍面临一些挑战。我们开发了抗BCMA/GPRC5D双特异性CAR，以缓解CAR T细胞的局限性并增强其功能：这项单臂一期试验在徐州医科大学附属医院（中国徐州）进行。该试验招募了年龄在18-75岁之间、患有复发性或难治性多发性骨髓瘤且东部合作肿瘤学组表现状态为0-3的患者。在剂量递增阶段，抗BCMA/GPRC5D双特异性CAR T细胞的给药剂量分别为每千克0-5×106、1-0×106、2-0×106和4-0×106个CAR T细胞，并在剂量扩展阶段按选定的剂量纳入更多患者。主要终点是安全性，包括剂量限制毒性和最大耐受剂量。活性也作为次要终点进行评估。剂量扩展阶段选择的是最大耐受剂量。所有接受抗BCMA/GPRC5D双特异性CAR T细胞治疗的患者都按照方案规定进行了安全性和活性分析。该试验已在ClinicalTrials.gov（NCT05509530）上注册，并已完成：2022年9月1日至2023年11月3日期间，24名患者入组并接受了血液净化。3名患者在血液净化后被排除（2名患者因疾病快速进展而中止治疗，1名患者因CAR T细胞制造失败而退出治疗），因此21名患者输注了抗BCMA/GPRC5D双特异性CAR T细胞。中位随访时间为 5-8 个月（IQR 5-2-6-7）。中位年龄为 62 岁（IQR 56-67）。8例（38%）患者为男性，13例（62%）患者为女性。所有患者均为中国人。在每公斤4-0×106个CAR T细胞的剂量下，两名患者出现了剂量限制性毒性反应，其中一人死于蛛网膜下腔出血（认为与研究治疗无关）。最大耐受剂量被确定为每公斤 2-0 × 106 个 CAR T 细胞。最常见的3级或更严重不良事件是19名（90%）患者出现血液学毒性反应（淋巴细胞减少除外）。15例（71%）患者出现细胞因子释放综合征，其中所有病例均为1级或2级。在一名接受每公斤 4-0 × 106 个 CAR T 细胞治疗的患者身上观察到了 1 级免疫效应细胞相关神经毒性综合征（ICANS）。每公斤接受0-5-2-0×106个CAR T细胞治疗的患者未观察到ICANS或3级或更严重的器官毒性。总体反应率为86%（21例患者中有18例），其中13例（62%）患者获得完全反应或更好的反应，17例（81%）患者的可测量残留疾病呈阴性。12名患者接受了每公斤2-0 × 106个CAR T细胞治疗（3名患者在剂量递增阶段，另外9名患者在剂量扩大阶段），总反应率为92%（12名患者中的11名），其中9名患者（75%）获得了完全反应或更好的反应：抗BCMA/GPRC5D双特异性CAR T细胞在复发或难治性多发性骨髓瘤患者中显示出良好的安全性和令人鼓舞的活性：国家自然科学基金：摘要中文译文见补充材料部分。
Anti-BCMA/GPRC5D bispecific CAR T cells in patients with relapsed or refractory multiple myeloma: a single-arm, single-centre, phase 1 trial.
Background: Some challenges still exist with single-target B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T-cell therapies due to variable or negative BCMA expression, although they have yielded remarkable efficacy in relapsed or refractory multiple myeloma. We developed anti-BCMA/GPRC5D bispecific CARs to mitigate the limitations and potentiate the functions of CAR T cells.
Methods: This single-arm, phase 1 trial was conducted at the Affiliated Hospital of Xuzhou Medical University (Xuzhou, China). The trial enrolled patients aged 18-75 years with relapsed or refractory multiple myeloma and an Eastern Cooperative Oncology Group performance status of 0-3. Anti-BCMA/GPRC5D bispecific CAR T cells were administered at 0·5 × 106, 1·0 × 106, 2·0 × 106, and 4·0 × 106 CAR T cells per kg in the dose-escalation phase, with additional patients included at the dose selected for the dose-expansion phase. The primary endpoint was safety, which included dose-limiting toxicity and maximum tolerated dose. Activity was also evaluated as a secondary endpoint. The maximum tolerated dose was chosen for the dose-expansion phase. Safety and activity analyses were done in all patients who received anti-BCMA/GPRC5D bispecific CAR T cells as defined in the protocol. This trial is registered with ClinicalTrials.gov (NCT05509530) and is complete.
Findings: Between Sept 1, 2022, and Nov 3, 2023, 24 patients were enrolled and underwent apheresis. Three patients were excluded after apheresis (two patients discontinued due to rapid disease progression and one patient was withdrawn because of failed manufacture of CAR T cells), so 21 patients were infused with anti-BCMA/GPRC5D bispecific CAR T cells. Median follow-up was 5·8 months (IQR 5·2-6·7). Median age was 62 years (IQR 56-67). Eight (38%) patients were male, and 13 (62%) female. All patients were Chinese. At the 4·0 × 106 CAR T cells per kg dose, two patients had dose-limiting toxicities, of whom one died of subarachnoid haemorrhage (which was not considered to be related to the study treatment). The maximum tolerated dose was identified as 2·0 × 106 CAR T cells per kg. The most common grade 3 or worse adverse events were haematological toxicities in 19 (90%) patients (except lymphopenia). 15 (71%) patients had cytokine release syndrome, of which all cases were grade 1 or 2. One case of grade 1 immune effector cell-associated neurotoxicity syndrome (ICANS) was observed in a patient who received 4·0 × 106 CAR T cells per kg. No ICANS or grade 3 or worse organ toxicities were observed in patients who received 0·5-2·0 × 106 CAR T cells per kg. The overall response rate was 86% (18 of 21 patients), with 13 (62%) patients having a complete response or better, and 17 (81%) patients having measurable residual disease negativity. Of the 12 patients who received 2·0 × 106 CAR T cells per kg (three in the dose-escalation phase and an addition nine in the dose-expansion phase), the overall response rate was 92% (11 of 12 patients) with nine (75%) patients having a complete response or better.
Interpretation: Anti-BCMA/GPRC5D bispecific CAR T cells show a good safety profile and encouraging activity in patients with relapsed or refractory multiple myeloma.
Funding: National Natural Science Foundation of China.
Translation: For the Chinese translation of the abstract see Supplementary Materials section.
期刊介绍：
Launched in autumn 2014, The Lancet Haematology is part of the Lancet specialty journals, exclusively available online. This monthly journal is committed to publishing original research that not only sheds light on haematological clinical practice but also advocates for change within the field. Aligned with the Lancet journals' tradition of high-impact research, The Lancet Haematology aspires to achieve a similar standing and reputation within its discipline. It upholds the rigorous reporting standards characteristic of all Lancet titles, ensuring a consistent commitment to quality in its contributions to the field of haematology.
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