Zhang Xian G, Wang Lin, Yang Junfang, Hu Xiaona N, Wang Hui, Zhang Lina N, Zhou Xiaoge, Liu Ying, Wang Qinglong, Lu Peihua H
Department of Hematology, Hebei Yanda Lu Daopei Hospital, Langfang, China.
Lu Daopei Institute of Hematology, Beijing, China.
Blood Adv. 2025 Sep 23;9(18):4543-4552. doi: 10.1182/bloodadvances.2025016322.
B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T-cell therapy has demonstrated promising therapeutic efficacy in relapsed or refractory (R/R) multiple myeloma. However, distinct CAR T-cell constructs exhibit varying therapeutic outcomes. As the antigen-recognition domain, nanobodies offer a small, stable, single-domain structure with enhanced affinity and specificity compared with conventional single-chain variable fragments. We explored the use of nanobody-based BCMA(S103) CAR T-cell therapy for R/R plasma cell myeloma. The CAR construct incorporates dual-nanobody variable domain of the heavy chain of heavy chain antibody (VHHs) targeting BCMA. A cohort of 27 patients was treated with S103 CAR T-cell therapy, which included 4 patients of plasma cell leukemia, and 1 patient of anaplastic plasma cell myeloma. Eleven patients had multiple extramedullary lesions, and 11 patients exhibited high-risk genetic abnormalities, including 4 with TP53 mutations. One month after CAR T-cell infusion, the overall response rate (ORR) was 96.3% (26/27), with a complete response (CR) + very good partial response (VGPR) rate of 59.2% (16/27). At the 3-month follow-up, the ORR increased to 100% (27/27), with a CR + VGPR rate of 81.5% (22/27). The median duration of remission was 11 months (range, 2-36 months). The 1-year overall survival rate was 61.1%, and progression-free survival was 57.2%. In conclusion, BCMA CAR T-cell therapy, utilizing dual-nanobody VHHs targeting BCMA, demonstrates a high ORR and manageable safety profile in treating patients with R/R plasmacytic myeloma, including those with high-risk features such as extramedullary lesions, high-risk cytogenetic abnormalities, plasma cell leukemia, or anaplastic plasmacytoma. This trial was registered at www.ClinicalTrials.gov as #NCT04447573.
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（R/R）多发性骨髓瘤中已显示出有前景的治疗效果。然而，不同的CAR T细胞构建体表现出不同的治疗结果。作为抗原识别结构域，纳米抗体提供了一种小的、稳定的单结构域结构，与传统的单链可变片段相比，具有更高的亲和力和特异性。我们探索了基于纳米抗体的BCMA(S103) CAR T细胞疗法用于R/R浆细胞骨髓瘤的治疗。该CAR构建体包含靶向BCMA的重链抗体（VHHs）重链的双纳米抗体可变结构域。一组27例患者接受了S103 CAR T细胞疗法治疗，其中包括4例浆细胞白血病患者和1例间变性浆细胞骨髓瘤患者。11例患者有多处髓外病变，11例患者表现出高危基因异常，包括4例TP53突变患者。CAR T细胞输注后1个月，总缓解率（ORR）为96.3%（26/27），完全缓解（CR）+非常好的部分缓解（VGPR）率为59.2%（16/27）。在3个月随访时，ORR增至100%（27/27），CR+VGPR率为81.5%（22/27）。缓解持续时间中位数为11个月（范围2 - 36个月）。1年总生存率为61.1%，无进展生存率为57.2%。总之，利用靶向BCMA的双纳米抗体VHHs的BCMA CAR T细胞疗法在治疗R/R浆细胞骨髓瘤患者（包括那些具有髓外病变、高危细胞遗传学异常、浆细胞白血病或间变性浆细胞瘤等高风险特征的患者）中显示出高ORR和可控的安全性。该试验已在www.ClinicalTrials.gov注册，编号为#NCT04447573。
