Blood Advances | Dual Nanobody-Based BCMA-Targeted CAR-T Cell Therapy Demonstrates Outstanding Efficacy in Relapsed/Refractory Plasma Cell Myeloma

This study evaluates the efficacy and safety of a dual nanobody-based BCMA CAR-T cell therapy in patients with relapsed/refractory (R/R) plasma cell myeloma, showing an overall response rate (ORR) of 96.3% at 1 month and 100% at 3 months. Additionally, the therapy demonstrates significant efficacy in high-risk subgroups including cytogenetic abnormalities, extramedullary disease, plasmacytic leukemia, and undifferentiated plasmacytoma, with favorable safety profiles, providing new clinical prospects for BCMA-targeted cellular therapies.

 

Literature Overview
This article, 'Efficacy and safety of BCMA nanobody CAR T-cell therapy in relapsed or refractory plasma cell myeloma' published in Blood Advances, reviews the application of nanobody-based chimeric antigen receptor (CAR) T cell therapy targeting B-cell maturation antigen (BCMA) in 27 patients with relapsed/refractory multiple myeloma (R/R MM). The study shows an ORR of 96.3% at 1 month, with complete response (CR) + very good partial response (VGPR) at 59.2%. By 3 months, ORR increases to 100%, with CR + VGPR rising to 81.5%. Median duration of response is 11 months, with 1-year overall survival (OS) at 61.1% and progression-free survival (PFS) at 57.2%. Subgroup analyses of high-risk patients, including those with extramedullary disease, high-risk cytogenetic abnormalities, plasmacytic leukemia, and undifferentiated plasmacytoma, show robust responses. This study provides strong evidence supporting BCMA-targeted CAR-T therapy in high-risk R/R MM populations.

Background Knowledge
Multiple myeloma (MM) is a plasma cell malignancy where BCMA serves as a critical therapeutic target due to its specific expression on plasma cell surfaces. CAR-T cell therapy, which genetically engineers patients' T cells to target BCMA, has been extensively studied. However, conventional single-chain variable fragments (scFv) face limitations including high immunogenicity and poor stability. Nanobodies (VHHs), with their low molecular weight, high stability, and reduced immunogenicity, represent superior antigen-recognition domains. This study employs a tandem dual-nanobody configuration targeting distinct BCMA epitopes to enhance binding affinity and minimize off-target effects. Preclinical data from animal models and in vitro cytotoxicity assays demonstrate effective BCMA+ tumor cell clearance at low doses. Clinical trials further confirm sustained remissions in high-risk subgroups (e.g., TP53 mutations, extramedullary disease), expanding the potential of CAR-T therapy in high-risk R/R MM and informing future clinical and personalized treatment strategies.

 

 

Research Methods and Experiments
This study constructs S103 CAR-T cells using tandem-duplicated nanobodies (VHH) as antigen-recognition domains, linked to CD8α hinge and transmembrane domains, 4-1BB co-stimulatory domain, and CD3ζ signaling domain to create a second-generation lentiviral vector. CAR-T cell manufacturing involved isolating peripheral blood mononuclear cells from R/R MM patients, followed by CD3+ T cell isolation, activation, lentiviral transduction, and 12-14 days of culture before cell harvest. Flow cytometry assessed transduction efficiency using BCMA-His protein and anti-His secondary antibodies. In vitro cytotoxicity assays utilized NCI-H929-Luc cell lines at effector-to-target ratios of 1:1, 3:1, and 10:1 to measure CAR-T cell lytic activity. In vivo antitumor activity was evaluated in NPG mice engrafted with MM.1S-Luc tumor cells. Clinical trials administered CAR-T cell infusions at doses of 0.3×10^6 to 2×10^6/kg following lymphodepleting chemotherapy (Flu/Cy), with efficacy/safety assessments incorporating multiparameter flow cytometry for minimal residual disease (MRD) and BCMA expression, alongside bone marrow aspiration, PET-CT imaging, and serum/urine light chain analysis.

Key Conclusions and Perspectives

• Overall response rate (ORR) reached 96.3% at 1 month, with 59.2% achieving complete response (CR) or very good partial response (VGPR).
• ORR improved to 100% at 3 months, with CR + VGPR increasing to 81.5%.
• Median duration of response was 11 months, with 1-year OS at 61.1% and PFS at 57.2%.
• High-risk subgroups (extramedullary disease, TP53 mutations, plasmacytic leukemia) showed robust clinical responses.
• The therapy induced durable remissions even in BCMA-low-expressing patients, suggesting BCMA expression levels may not limit CAR-T efficacy.
• Overall safety was favorable, with few patients experiencing grade 2-3 cytokine release syndrome (CRS) or neurotoxicity, though infection-related adverse events were observed, including four deaths from infection-related complications.
• Preclinical models confirmed high specificity and dose-dependent cytotoxicity of S103 CAR-T cells.

Research Significance and Prospects
This study establishes dual-nanobody CAR-T therapy as highly effective and safe for R/R MM, particularly demonstrating superior outcomes compared to traditional scFv-CAR-T in high-risk populations. Future research should expand patient cohorts and extend follow-up to validate long-term efficacy and recurrence mechanisms. Combining this therapy with CAR-T cells targeting alternative antigens may overcome antigen escape. These findings provide novel directions for personalized treatment strategies in R/R MM and highlight the unique advantages of nanobodies in CAR-T design.

 

 

Conclusion
This study represents the first systematic evaluation of dual-nanobody VHHs targeting BCMA in R/R plasma cell myeloma, demonstrating robust efficacy and safety. Preclinical and clinical data confirm high affinity and specificity of S103 CAR-T cells, with 1-month ORR at 96.3% and 3-month ORR reaching 100%. High response rates are maintained in high-risk subgroups including extramedullary disease, TP53 mutations, and plasmacytic leukemia. The therapy exhibits favorable tolerability and manageable safety profiles, with infections as the primary adverse event. Notably, immunoglobulin supplementation is emphasized to mitigate infection risks. Overall, S103 CAR-T cell therapy demonstrates durable antitumor activity in R/R MM patients, offering a novel strategy for BCMA-targeted immunotherapy and a structural-functional validation model for future CAR-T design optimization.

 

Xian G Zhang, Lin Wang, Junfang Yang, Qinglong Wang, and Peihua H Lu. Efficacy and safety of BCMA nanobody CAR T-cell therapy in relapsed or refractory plasma cell myeloma. Blood Advances.