Home Journals Articles Updates About
CN
image
收藏切换
Phase I clinical study of humanized BCMA-single-domain antibodies targeting CAR-T in patients with relapsed or refractory multiple myeloma
收藏切换
PDF
Gaofeng Zheng1, *, Ruyi Xu1, *, Heng Mei2, Xiaoyan Han1, Donghua He1, Yanling Weng1, Cheng Wen3, Zhuoxiao Cao3, Zhen Cai1
Cancer Biology & Medicine | 2025, 22(11) : 1377 - 1380
Less
收藏切换
Cancer Biology & Medicine | 2025, 22(11): 1377-1380
• LETTER •
Phase I clinical study of humanized BCMA-single-domain antibodies targeting CAR-T in patients with relapsed or refractory multiple myeloma
Full
Gaofeng Zheng1, *, Ruyi Xu1, *, Heng Mei2, Xiaoyan Han1, Donghua He1, Yanling Weng1, Cheng Wen3, Zhuoxiao Cao3, Zhen Cai1
Affiliations
  • 1Multiple Myeloma Treatment Center and Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China
  • 2Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
  • 3Shanghai Simnova Biotechnology Co., Ltd, Shanghai 200120, China
Published: 2025-11-15 doi: 10.20892/j.issn.2095-3941.2024.0581
Outline
收藏切换
Gaofeng Zheng, Ruyi Xu, Heng Mei, Xiaoyan Han, Donghua He, Yanling Weng, Cheng Wen, Zhuoxiao Cao, Zhen Cai. Phase I clinical study of humanized BCMA-single-domain antibodies targeting CAR-T in patients with relapsed or refractory multiple myeloma[J]. Cancer Biology & Medicine, 2025 , 22 (11) : 1377 -1380 . DOI: 10.20892/j.issn.2095-3941.2024.0581
Full Text
Less
Multiple myeloma (MM), one of the most common hematological neoplasms worldwide, originates from malignant plasma cells in the bone marrow. MM remains an incurable disease, although continued treatment advancements have markedly increased overall survival. Many patients with MM eventually experience relapse or become treatment-refractory1. Patients with relapsed or refractory multiple myeloma (RRMM) become progressively more challenging to manage and have poor prognosis2.
Novel therapeutic strategies, such as chimeric antigen receptor T (CAR-T) cell therapy, are being explored to treat RRMM3. B cell maturation antigen (BCMA) is expressed only on normal and malignant plasma cells and some terminally differentiated B cells, and is considered an ideal CAR target in RRMM4,5. BCMA-directed CAR-T has been reported to achieve remission in patients with RRMM by leveraging their immune cells to specifically recognize and destroy MM cells5,6. However, the remission is often temporary. Additional clinical trials are ongoing to increase the persistence and efficacy of BCMA CAR-T products.
The CAR structure of BCMA CAR-T is composed of a single-domain antibody targeting BCMA, CD8 hinge region, transmembrane region, 4-1BB co-stimulatory domain, and CD3-ζT cell activation domain7,8. CAR-T cells, expressing single-domain anti-BCMA antibodies, can target BCMA-expressing MM tumor cells. Preclinically, BCMA CAR-T has been found to exhibit potent in vitro cytotoxicity against BCMA-high expressing MM cell lines and to effectively eliminate tumor cells in cell line-derived xenograft models7. In a phase I clinical study (NCT05346198) conducted in China, the safety and efficacy of BCMA CAR-T were initially evaluated through a dose escalation and dose expansion design, and the recommended dose for follow-up studies was determined. The detailed methods used in this study are listed in the Supplementary material, and the method for preparing the BCMA single-domain antibody was as described previously7.
Clinical characteristics and disposition
Less
As of May 13, 2024, 15 patients with RRMM received BCMA CAR-T cell infusion therapy at 2.5 × 106 (n = 3), 5.0 × 106 (n = 11), or 7.5 × 106 CAR-positive T cells/kg (n = 1) (Figure S1), according to the dose at enrollment. The median age was 63.0 years (range, 36.0–73.0; Table S1). Overall, 73.3% of the participants (n = 11) had previously received ≥4 lines of MM therapy, and the median was 5.0 lines (range, 3.0–9.0). After CAR-T therapy, no patients in this study received subsequent maintenance therapy or transplantation.
Safety
Less
All 15 patients experienced grade 3–4 treatment-emergent adverse events (AEs) during the study period. The most common grade ≥3 AEs were hematological toxicity, including neutropenia (n = 14, 93.3%), leukopenia (n = 12, 80.0%), lymphopenia (n = 11, 73.3%), anemia (n = 9, 60.0%), and thrombocytopenia (n = 4, 26.7%). One patient in the 7.5 ×106 CAR-positive T cells/kg dose group had a dose-limiting toxicity (DLT) event of grade 4 thrombocytopenia. The most common non-hematologic grade ≥3 AEs were infections (n = 3, 20.0%), but no infectious events occurred in the 0.25 × 106 CAR-positive T cells/kg dose group. Renal calculus was the second most common non-hematologic grade ≥3 AE (n = 1, 6.7%; Table 1).
All 15 patients (100.0%) developed grade 1–2 cytokine release syndrome (CRS), whereas no grade ≥ 3 CRS occurred (Table S2). The median time to CRS was 2.0 days (range, 1.0–13.0 days), and the median duration was 6.0 days (range, 2.0–17.0 days). All CRS recovered without sequelae after supportive treatment (tocilizumab, n = 6; glucocorticoids, n = 4). No immune effector cell-associated neurotoxicity (ICANS) or death was observed.
Efficacy
Less
At the data cut-off, the median follow-up time for all patients was 22.5 months. The median time to first response was 1.0 month (range, 0.9–2.2 months). The overall remission rate (ORR) was 100.0% (95% confidence interval, 78.2%–100.0%; Figure S2); 10 (66.7%) patients achieved strict complete remission (sCR), 3 (20.0%) patients achieved very good partial response (VGPR), and 2 (13.3%) patients achieved PR as the best response. All patients with sCR achieved minimal residual disease negativity. The ORR of 6 patients with extramedullary plasmacytoma was 100.0%: 2 patients achieved sCR, and 4 achieved VGPR. Notably, a gradual deepening of remission was observed in 11 patients (73.3%) during 60–90 days after infusion, and 7 patients (46.7%) achieved sCR at day 360. One year after CAR-T cell infusion, 7 patients achieved sCR, and 4 patients maintained sCR after 2 years.
CAR-T cell pharmacokinetic characteristics
Less
As of May 7, 2024, the CAR transgene in peripheral blood increased rapidly post-infusion and peaked at a median of 14.0 days (range, 8.0–28.0 days). The median persistence of the CAR transgene was 65.0 days (range, 15.0–457.0 days), and BCMA CAR-T was detectable in 26.7% (4/15) of patients at 6 months after infusion (Figure S3).
Preliminary exploratory case observation
Less
A 64-year-old female patient with RRMM received BCMA CAR-T cell infusion therapy with 7.5 × 106 CAR-positive T cells/kg. At baseline, her ECOG performance status was 1. She experienced a DLT event of grade 4 thrombocytopenia after BCMA CAR-T cell infusion therapy. Other grade ≥3 AEs included leukopenia, neutropenia, lymphopenia, anemia, and infection. She developed grade 1–2 CRS, including fever, anoxia, and hypotension. A PR was observed on day 28 post-infusion, and she achieved a VGPR by day 90. One year after infusion, she had reached a sCR, which was sustained for at least 1 year.
BCMA-targeted CAR-T cells have the potential to induce durable and deep remission in patients with RRMM. Currently, 4 BCMA-targeted CAR-T therapies have been approved: Carvykti, Abecma, Equecabtagene Autoleucel, and Zevalocel9,10. The therapeutic effects of BCMA-targeted CAR-T therapy are encouraging. In a clinical trial by Carvykti, the response rate was 97%, and 67% of patients achieved a complete response5. All these BCMA-targeted CAR-T therapies showed similar results in clinical trials, and Zevalocel achieved an ORR of 100.0%. In our study, we achieved an ORR of 100.0%, among which the best response in 10 patients (66.7%) was sCR, and all patients achieving sCR showed minimal residual disease negativity. Moreover, we observed that patients with extramedullary plasmacytoma also achieved an ORR of 100%. We therefore applied BCMA-targeted CAR-T cells to patients with heavy tumor burden. However, further trials are required to investigate the efficacy of this treatment in this population.
All patients in our study experienced grade 1–2 CRS, whereas no grade ≥3 CRS occurred. No significant differences were observed among dose groups. In agreement with previous reports, CRS was among the most reported AEs in BCMA-targeted CAR-T therapies5,6. The time to onset of CRS post CAR-T infusion varies across studies and is influenced by multiple factors, such as the design of the CAR construct, the CAR-T cell dose, the cellular composition of the CAR-T cell product, the manufacturing process used to generate the CAR-T cells, and host characteristics (e.g., tumor burden and patient age)11. The onset of CRS toxicity usually occurs within the first week after CAR-T cell therapy1. In our study, the median time to onset of CRS was 2.0 days, in agreement with this expected pattern and the reported range for other anti-BCMA CAR-T therapies in RRMM (2.0–9.0 days)5,6,12. No neurotoxicity was observed, and common grade ≥3 AEs were hematological toxicities. One patient in the 7.5 × 106 CAR-positive T cells/kg dose group had a DLT event of grade 4 platelet count decrease, whereas no DLT events occurred in the other low-dose groups. Additional studies are required to explore the relationship between hematologic toxicity and CAR-T therapies. The most common non-hematologic grade ≥3 AEs were infections (20.0%), and all patients recovered. Overall, the BCMA CAR-T cells showed a manageable safety profile.
The CAR structure in this study, used by BCMA CAR-T, is composed of a single-domain antibody targeting BCMA, a CD8 hinge region, transmembrane region, 4-1BB co-stimulatory domain, and CD3-ζT cell activation domain. Heavy-chain antibodies consist of only 2 heavy chains without light chains but retain the function of conventional antibodies, thereby forming a small, stable, single-domain structure with high affinity and specificity, which is easily humanized for therapeutic purposes. In this study, we observed no ICANS in response to BCMA CAR-T cell administration. BCMA CAR-T cells are safe and effective for treating patients with MM and induce sustained remission.
Ill-defined generalizability
Less
This study has several limitations. First, the relatively small sample size limits the generalizability of the findings, and the primary objective was to evaluate the initial safety profile of BCMA CAR-T cells. Efficacy outcomes should therefore be interpreted with caution, and further studies are needed to confirm our findings in patients with RRMM. Second, given the exploratory nature of this study and the limited follow-up duration, survival data are currently immature and therefore are not reported herein. Moreover, the Kaplan-Meier method, although widely used, might overestimate survival probabilities in small cohorts, and the generated curves should therefore be interpreted in light of this limitation. Third, although ORR estimates were accompanied by 95% confidence intervals calculated with the Clopper-Pearson method, these intervals were wide, thereby reflecting the limited sample size, and consequently do not necessarily imply statistical precision. Collectively, these statistical and methodological limitations highlight the need for further investigation in larger clinical studies with longer follow-up.
In conclusion, BCMA CAR-T is well tolerated and highly efficacious in patients with RRMM. Patients with extramedullary plasmacytoma showed comparable responses to those without extramedullary disease.
References
Less
1.
Malard F, Neri P, Bahlis NJ, Terpos E, Moukalled N, Hungria VTM, et al.Multiple myeloma.Nat Rev Dis Primers. 2024; 10: 45.
2.
Minakata D, Fujiwara SI, Yokoyama D, Noguchi A, Aoe S, Oyama T, et al.Relapsed and refractory multiple myeloma: a systematic review and network meta-analysis of the efficacy of novel therapies. Br J Haematol. 2023; 200: 694–703.
3.
Parikh RH, Lonial S.Chimeric antigen receptor T-cell therapy in multiple myeloma: a comprehensive review of current data and implications for clinical practice.CA Cancer J Clin. 2023; 73: 275–85.
4.
Novak AJ, Darce JR, Arendt BK, Harder B, Henderson K, Kindsvogel W, et al.Expression of BCMA, TACI, and BAFF-R in multiple myeloma: a mechanism for growth and survival.Blood. 2004; 103: 689–94.
5.
Berdeja JG, Madduri D, Usmani SZ, Jakubowiak A, Agha M, Cohen AD, et al.Ciltacabtagene autoleucel, a B-cell maturation antigen-directed chimeric antigen receptor T-cell therapy in patients with relapsed or refractory multiple myeloma (CARTITUDE-1): a phase 1b/2 open-label study.Lancet. 2021; 398: 314–24.
6.
Zhao WH, Liu J, Wang BY, Chen YX, Cao XM, Yang Y, et al.A phase 1, open-label study of LCAR-B38M, a chimeric antigen receptor T cell therapy directed against B cell maturation antigen, in patients with relapsed or refractory multiple myeloma.J Hematol Oncol. 2018; 11: 141.
7.
Han L, Zhang JS, Zhou J, Zhou KS, Xu BL, Li LL, et al.Single VHH-directed BCMA CAR-T cells cause remission of relapsed/refractory multiple myeloma.Leukemia. 2021; 35: 3002–6.
8.
Bao C, Gao Q, Li LL, Han L, Zhang B, Ding Y, et al.The application of nanobody in CAR-T therapy.Biomolecules. 2021; 11: 238.
9.
Watanabe N, Mo F, McKenna MK.Impact of manufacturing procedures on CAR T cell functionality.Front Immunol. 2022; 13: 876339.
10.
Khan AN, Chowdhury A, Karulkar A, Jaiswal AK, Banik A, Asija S, et al.Immunogenicity of CAR-T cell therapeutics: evidence, mechanism and mitigation.Front Immunol. 2022; 13: 886546.
11.
Neelapu SS, Tummala S, Kebriaei P, Wierda W, Gutierrez C, Locke FL, et al.Chimeric antigen receptor T-cell therapy – assessment and management of toxicities.Nat Rev Clin Oncol. 2018; 15: 47–62.
12.
Raje N, Berdeja J, Lin Y, Siegel D, Jagannath S, Madduri D, et al.Anti-BCMA CAR T-cell therapy bb2121 in relapsed or refractory multiple myeloma.N Engl J Med. 2019; 380: 1726–37.
Appendix
Less
Year 2025 volume 22 Issue 11
PDF
32
18
Cite this Article
BibTeX
Article Info
doi: 10.20892/j.issn.2095-3941.2024.0581
  • Receive Date：2025-06-09
  • Online Date：2026-04-03
  • Published：2025-11-15
Article Data
Affiliations
History
  • Received：2025-06-09
  • Accepted：2025-08-18
Affiliations
    1Multiple Myeloma Treatment Center and Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China
    2Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
    3Shanghai Simnova Biotechnology Co., Ltd, Shanghai 200120, China

Corresponding:

Correspondence to: Zhen Cai, E-mail:
References
Share
https://castjournals.cast.org.cn/joweb/cbm/EN/10.20892/j.issn.2095-3941.2024.0581
Share to
QR

Scan QR to access full text

Cite this article
BibTeX
Citations
表12种不同金属材料的力学参数
科
Family		 属数
Number of
genus		 种数
Number of
species		 占总种数比例
Percentage of
total species (%)		 属
Genus		 种数
Number of
species		 占总种数比例
Percentage of total
species (%)
鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
关闭全屏
  • BibTeX
  • EndNote
  • RefWorks
  • TxT
Links
Articles
Latest Articles
Most Read
Collections
Updates
Events
News
Multimedia
About
About Us
Contact
No. 86 Xueyuan South Road, Haidian District, Beijing
100081
010-62199257
qkjq@cast.org.cn

Copyright © 2025 China Association for Science and Technology. All rights reserved. For all open access content, the relevant licensing terms apply.
Sponsored by the Office of the Leading Group for Cybersecurity and Informatization of CAST, and supported by Science and Technology Review Publishing House