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
{"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. We developed anti-BCMA/GPRC5D bispecific CARs to mitigate the limitations and potentiate the functions of CAR T cells.</p><p><strong>Methods: </strong>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 × 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patients were excluded after apheresis (two patients discontinued due to rapid disease progression and one patient was withdrawn because of failed manufacture of CAR T cells), so 21 patients were infused with anti-BCMA/GPRC5D bispecific CAR T cells.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":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Lancet Haematology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/S2352-3026(24)00176-5","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/7/23 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"HEMATOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
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.