biostudies-literatureFang CShenzhen Medical Research FundShenzhen Natural Science FundChinese National Major Project for New Drug InnovationShenzhen Science and Technology FoundationNational Natural Science Foundation of ChinaShenzhen Clinical Research Center for hematologic diseaseSanming Project of Medicine in ShenzhenShenzhen Key LaboratoryHaiYa Young Scientist Foundation of Shenzhen University General HospitalNatural Science Foundation of Shenzhen University General Hospital1251https://www.ebi.ac.uk/biostudies/studies/S-EPMC12604393biostudies-literatureUnknown23(1)<h4>Background</h4>Despite therapeutic advances, multiple myeloma (MM) remains incurable, especially in relapsed/refractory (R/R) disease. B-cell maturation antigen (BCMA)-targeted CAR-T therapy, exemplified by FDA-approved agents like ide-cel and cilta-cel, offers promise, yet accessibility barriers necessitate local production.<h4>Methods</h4>This single-arm trial evaluated safety/efficacy of autologous BCMA CAR-T cells in six R/R MM patients.<h4>Results</h4>Cytokine release syndrome (CRS) occurred in 83% (grade 1), managed with tocilizumab without neurotoxicity. Toxicities were transient and resolved. Serum cytokine (IFN-γ, IL-6/8/10) peaked during CRS. Responses included 83% overall response (67% stringent complete response), unaffected by extramedullary disease or high-risk cytogenetics. Median PFS/OS were unreached, with an estimated 12-month OS rate of 83.33% and PFS rate of 66.67%. CAR-T cell persistence, with a median Cmax at 20.5 days, remained detectable in 83% at 1 month and 67% at 6 months. Single-cell RNA sequencing (scRNA-seq) and T-cell receptor sequencing (TCR-seq) demonstrated complementary roles of functionally specialized CD8⁺ Te subsets. Clonal evolution in the sustained responder (patient 2) revealed a shift from a polyclonal infusion product (IP) to oligoclonal dominance, with shared clones exhibiting enhanced cytotoxic and NK-like activity. Transcriptional adaptation of persistent clones over time indicated distinct phases of proliferation, stress response, and long-term persistence, with a concomitant shift in cellular phenotype from IP-derived Tem/circling T cells to a mixed Tem/Te_1/Te_2 population. Comparative analysis of two patients with divergent clinical outcomes (sustained remission vs. transient remission) revealed that early CAR-T exhaustion and increased regulatory T cells (Tregs) were associated with relapse.<h4>Conclusions</h4>Locally produced BCMA CAR-T is safe and effective in heavily pretreated R/R MM, inducing deep responses. scRNA-seq/TCR-seq findings highlight interplay of CAR-T heterogeneity, clonal adaptability, and immune regulation. CD8⁺ subset specialization and clonal persistence matter for durable responses; exhaustion and immunosuppression may cause relapse.Journal of translational medicineIntegrated clinical and single-cell profiling of BCMA CAR-T therapy in relapsed/refractory multiple myeloma.PMC1260439382030076, 82070161, 81970151, 81670162 and 81870134ZDSYS20200811143757022JCYJ20190808163601776, JCYJ20200109113810154SZSM202111004C23010032019ZX09201002003SUGH2019QD012LCYSSQ2022082309140100220200830182623001HY002Tan KYu LGuo XZhao WFang CWang HMeng XWang LLi YChen ZHe ZYu CHuang WWang SMei JWang YQiao JXu YfalseIntegrated clinical and single-cell profiling of BCMA CAR-T therapy in relapsed/refractory multiple myeloma.<h4>Background</h4>Despite therapeutic advances, multiple myeloma (MM) remains incurable, especially in relapsed/refractory (R/R) disease. B-cell maturation antigen (BCMA)-targeted CAR-T therapy, exemplified by FDA-approved agents like ide-cel and cilta-cel, offers promise, yet accessibility barriers necessitate local production.<h4>Methods</h4>This single-arm trial evaluated safety/efficacy of autologous BCMA CAR-T cells in six R/R MM patients.<h4>Results</h4>Cytokine release syndrome (CRS) occurred in 83% (grade 1), managed with tocilizumab without neurotoxicity. Toxicities were transient and resolved. Serum cytokine (IFN-γ, IL-6/8/10) peaked during CRS. Responses included 83% overall response (67% stringent complete response), unaffected by extramedullary disease or high-risk cytogenetics. Median PFS/OS were unreached, with an estimated 12-month OS rate of 83.33% and PFS rate of 66.67%. CAR-T cell persistence, with a median Cmax at 20.5 days, remained detectable in 83% at 1 month and 67% at 6 months. Single-cell RNA sequencing (scRNA-seq) and T-cell receptor sequencing (TCR-seq) demonstrated complementary roles of functionally specialized CD8⁺ Te subsets. Clonal evolution in the sustained responder (patient 2) revealed a shift from a polyclonal infusion product (IP) to oligoclonal dominance, with shared clones exhibiting enhanced cytotoxic and NK-like activity. Transcriptional adaptation of persistent clones over time indicated distinct phases of proliferation, stress response, and long-term persistence, with a concomitant shift in cellular phenotype from IP-derived Tem/circling T cells to a mixed Tem/Te_1/Te_2 population. Comparative analysis of two patients with divergent clinical outcomes (sustained remission vs. transient remission) revealed that early CAR-T exhaustion and increased regulatory T cells (Tregs) were associated with relapse.<h4>Conclusions</h4>Locally produced BCMA CAR-T is safe and effective in heavily pretreated R/R MM, inducing deep responses. scRNA-seq/TCR-seq findings highlight interplay of CAR-T heterogeneity, clonal adaptability, and immune regulation. CD8⁺ subset specialization and clonal persistence matter for durable responses; exhaustion and immunosuppression may cause relapse.2025-01-01T00:00:00Z2025 Nov2026-06-05T15:06:39.043Z2026-05-18T03:12:56.872ZS-EPMC126043934121467910.1186/s12967-025-07106-w