Abecma (idecabtagene vicleucel)

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.

P1/2, N=21, Terminated, Celgene | Completed --> Terminated; Business objectives have changed

Our results present important clinical evidence that cilta-cel can serve as an effective salvage treatment following ide-cel failure. By providing a direct patient-matched comparison between two CAR therapies, our study uncovers important insights into both CAR T-cell intrinsic properties and immune environmental factors that contribute to effective BCMA CAR T-cell treatment.

Duration of response was associated with tumour genomic features and quality of engraftment indicated by more robust CD4+ CAR T-cell expansion, higher levels of persistent ide-cel and sustained suppression of BCMA-expressing cells. A working model is proposed whereby patient and microenvironment features that may modulate ide-cel activation and expansion influence the probability of response initiation, and that tumour-intrinsic resistance features and sustained engraftment of ide-cel influence the durability of responses.

In 2021, idecabtagene vicleucel, a BCMA-targeting agent, became the first CAR-T therapy approved for relapsed/refractory MM, marking a significant milestone in MM treatment. Subsequently, ciltacabtagene autoleucel has also been approved...To address these challenges, strategies such as BCMA non-targeted or dual-targeted CAR-T, memory T cells, humanized CAR-T, and rapidly manufactured PHE885 cells have been developed...In conclusion, studies are exploring the use of CAR-T at an earlier stage, including at diagnosis, with an aim to replace ASCT. CAR-T has introduced a new dimension to MM treatment; however, limited efficacy in high-risk MM and the emergence of resistance to CAR-T remain key challenges to be addressed.

This in-depth biomonitoring report following real-world cilta-cel or ide-cel highlights intrinsic biological differences between BCMA-targeting CAR T products, potentially explaining differences in clinical activity and toxicity. Our findings may guide optimization of cellular immunotherapy strategies in MM.

To identify risk factors for CAR-T manufacturing failure in patients with myeloma, a nationwide cohort study was performed, analyzing patients who underwent apheresis for idecabtagene vicleucel in Japan...Manufacturing failure remains an obstacle to CAR-T therapy for patients with myeloma. Avoiding risk factors, such as alkylating agents, and adopting risk-adapted strategies may optimize CAR-T therapy for patients with myeloma.

P2, N=40, Completed, Marcelo Pasquini, MD | Active, not recruiting --> Completed | Trial primary completion date: Jan 2025 --> Aug 2024

P2, N=264, Active, not recruiting, Celgene | Trial completion date: Dec 2030 --> Oct 2025

P2, N=32, Recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: May 2025 --> May 2026 | Trial primary completion date: May 2025 --> May 2026

P1/2, N=21, Completed, Celgene | Active, not recruiting --> Completed | N=312 --> 21

Patients who received idecabtagene vicleucel, a BCMA-targeted CAR-T cell therapy, were divided into two groups according to a cut-off value of 180 days for the progression-free survival (PFS) event...When these two T cell subsets were combined into CCR7-positive CD8 T cells, the patients with high levels of CCR7-positive CD8 T cells showed significantly better PFS. In the future, our results will help us to select specific patients that are likely to have a more favorable outcome and should contribute to establishing an optimal application strategy for CAR-T cell therapies in RRMM.