Curated Papers > Recent high-impact research on CAR-T therapy (IF ≥ 30, last 5 years)

Anti-BCMA CAR-T therapy in patients with progressive multiple sclerosis.

Literature Information

DOI	10.1016/j.cell.2025.09.020
PMID	41101309
Journal	Cell
Impact Factor	42.5
JCR Quartile	Q1
Publication Year	2025
Times Cited	0
Keywords	B cell maturation antigen, CAR, chimeric antigen receptor T cell, progressive multiple sclerosis, single-cell RNA sequencing
Literature Type	Journal Article, Clinical Trial, Phase I
ISSN	0092-8674
Pages	6414-6423.e11
Issue	188(23)
Authors	Chuan Qin, Ming-Hao Dong, Luo-Qi Zhou, Yun-Hui Chu, Xiao-Wei Pang, Jia-Yi He, Ke Shang, Jun Xiao, Li Zhu, Huan Ye, Song-Bai Cai, Di Wang, Bi-Tao Bu, Gerd Meyer Zu Hörste, Chun-Rui Li, Dai-Shi Tian, Wei Wang

TL;DR

This study investigates the efficacy of anti-B cell maturation antigen (BCMA) chimeric antigen receptor T (CAR-T) cell therapy in five patients with progressive multiple sclerosis (PMS), showing promising results such as plasma cell depletion in the central nervous system and minimal adverse effects. These findings suggest that anti-BCMA CAR-T therapy could potentially enhance clinical management of PMS by effectively targeting CNS inflammation.

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B cell maturation antigen · CAR · chimeric antigen receptor T cell · progressive multiple sclerosis · single-cell RNA sequencing

Abstract

Progressive multiple sclerosis (PMS), which is characterized by relentless disease progression, lacks effective treatment. While recent studies have highlighted the importance of B cells in driving compartmentalized central nervous system (CNS) inflammation in PMS pathogenesis, current B cell depletion therapies, such as CD20 monoclonal antibodies, face challenges in targeting plasma cells within the CNS. Here, we treated five patients with PMS (one primary PMS and four secondary PMS) with anti-B cell maturation antigen (BCMA) chimeric antigen receptor T (CAR-T) cell therapy in an ongoing phase 1 clinical trial (ClinicalTrials.gov: NCT04561557). Only grade 1 cytokine release syndrome was observed, and all grade ≥3 cytopenias occurred within 40 days post-infusion in all five patients. Meanwhile, we detected plasma cell depletion in CNS compartments, prolonged expansion and relieved exhaustion of CAR-T cells in the cerebrospinal fluid, and attenuation of microglial activation. These findings provided insights into the potential application of anti-BCMA CAR-T therapy for advancing clinical management of PMS.

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Primary Questions Addressed

1. What are the long-term effects of anti-BCMA CAR-T therapy on the progression of multiple sclerosis?
2. How does the mechanism of action of anti-BCMA CAR-T therapy differ from traditional B cell depletion therapies?
3. What are the potential biomarkers that could predict the response to anti-BCMA CAR-T therapy in patients with PMS?
4. In what ways could anti-BCMA CAR-T therapy be combined with other treatments to enhance efficacy in PMS?
5. What are the implications of plasma cell depletion in the CNS for the overall immune response in progressive multiple sclerosis?

Key Findings

Research Background and Purpose

Progressive multiple sclerosis (PMS) is a debilitating condition characterized by relentless disease progression and currently lacks effective treatments. Recent studies have indicated the significant role of B cells in the inflammation associated with PMS. Traditional B cell depletion therapies, particularly CD20 monoclonal antibodies, struggle to effectively target plasma cells in the central nervous system (CNS). This study aims to evaluate the safety and efficacy of anti-B cell maturation antigen (BCMA) chimeric antigen receptor T (CAR-T) cell therapy in patients with PMS.

Main Methods/Materials/Experimental Design

The study was conducted as a phase 1 clinical trial (ClinicalTrials.gov: NCT04561557) involving five patients diagnosed with PMS, including one with primary PMS and four with secondary PMS. The treatment involved administering anti-BCMA CAR-T cells, and the following methodologies were employed to assess the outcomes:

• Patient Selection: Five patients with confirmed PMS.
• Treatment Administration: Infusion of anti-BCMA CAR-T cells.
• Monitoring and Assessment:
  • Observation of cytokine release syndrome (CRS) and cytopenias post-infusion.
  • Evaluation of plasma cell levels in CNS compartments.
  • Analysis of CAR-T cell dynamics in cerebrospinal fluid (CSF).
  • Assessment of microglial activation levels.

Key Results and Findings

• Safety Profile: Only grade 1 cytokine release syndrome was observed, with all patients experiencing grade ≥3 cytopenias within 40 days post-infusion.
• Efficacy Indicators:
  • Significant depletion of plasma cells was noted in CNS compartments.
  • CAR-T cells exhibited prolonged expansion and reduced exhaustion in the cerebrospinal fluid.
  • A decrease in microglial activation was observed, indicating a potential reduction in CNS inflammation.

Main Conclusions/Significance/Innovation

The findings suggest that anti-BCMA CAR-T cell therapy is a promising approach for treating PMS, demonstrating a favorable safety profile and the ability to target plasma cells effectively in the CNS. This innovative therapy may advance the clinical management of PMS by addressing the limitations of existing B cell depletion therapies.

Research Limitations and Future Directions

• Limitations:

  • Small sample size (only five patients) limits the generalizability of the results.
  • Short follow-up period may not fully capture long-term effects and potential adverse events.

• Future Directions:

  • Larger-scale studies are needed to confirm these findings and evaluate the long-term safety and efficacy of anti-BCMA CAR-T therapy in PMS.
  • Further research should explore the mechanisms behind the observed effects on microglial activation and the overall immune response in the CNS.

Aspect	Findings
Safety Profile	Grade 1 CRS, grade ≥3 cytopenias within 40 days
Plasma Cell Depletion	Significant depletion in CNS compartments
CAR-T Cell Dynamics	Prolonged expansion, reduced exhaustion in CSF
Microglial Activation	Attenuation observed

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